The serotonergic system in ageing and Alzheimer's disease

Progress in Neurobiology 99 (2012) 15–41

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Progress in Neurobiology journal homepage: www.elsevier.com/locate/pneurobio

The serotonergic system in ageing and Alzheimer’s disease Jose´ Julio Rodrı´guez a,b,c,d,*, Harun N. Noristani e, Alexei Verkhratsky a,b,c,e,** a

IKERBASQUE, Basque Foundation for Science, 48011, Bilbao, Spain Instituto de Investigacio´n Sanitaria Biodonostia, Hospital Donostia, 20014, San Sebastia´n, Spain c Instituto de Investigacio´n Sanitaria Biodonostia, Hospital Donostia and Centro de Investigaciones Biome´dicas en Red Enfermedades Neurodegenerativas (CIBERNED), 20014 San Sebastia´n, Spain d Institute of Experimental Medicine, ASCR, Videnska 1083, 142 20, Prague, Czech Republic e Faculty of Life Sciences, The University of Manchester, Manchester, United Kingdom b

A R T I C L E I N F O

A B S T R A C T

Article history: Received 1 May 2011 Received in revised form 24 May 2012 Accepted 22 June 2012 Available online 2 July 2012

Alzheimer’s disease (AD) is one of the major neurodegenerative diseases that deteriorates cognitive functions and primarily affects associated brain regions involved in learning and memory, such as the neocortex and the hippocampus. Following the discovery and establishment of its role as a neurotransmitter, serotonin (5-HT), was found to be involved in a multitude of neurophysiological processes including mnesic function, through its dedicated pathways and interaction with cholinergic, glutamatergic, GABAergic and dopaminergic transmission systems. Abnormal 5-HT neurotransmission contributes to the deterioration of cognitive processes in ageing, AD and other neuropathologies, including schizophrenia, stress, mood disorders and depression. Numerous studies have confirmed the pathophysiological role of the 5-HT system in AD and that several drugs enhancing 5-HT neurotransmission are effective in treating the AD-related cognitive and behavioural deficits. Here we present a comprehensive overview of the role of serotonergic neurotransmission in brain development, maturation and ageing, discuss its role in higher brain function and provide an in depth account of pathological modifications of serotonergic transmission in neurological diseases and AD. ß 2012 Elsevier Ltd. All rights reserved.

Keywords: Alzheimer’s disease Dementia Serotonin Serotonin transporter Serotonin receptors Hippocampus Raphe nucleus Plasticity

Abbreviations: [11C]-WAY100635, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridyl)cyclohexanecarboxamide; 3xTg-AD, triple transgenic mouse model of AD; 5,7-DHT, 5,7-dihydroxytryptamine; 5-HIAA, 5-hydroxyindoleacetic acid; 5-HT, 5-hydroxytrptamine (serotonin); 5HTR, 5-hydroxytrptamine receptor (serotonin receptor); 8-OH-DPAT, 8-hydroxy-2-(di-n-propylamino)-tertralin; ACh, acetylcholine; AChEIs, acetylcholinesterase inhibitors; AD, Alzheimer’s disease; ALS, amyotrophic lateral sclerosis; AMPA, a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; APP, amyloid precursor protein; APP-23, transgenic mouse expressing APP swedish mutation; APPS, non-amyloidogenic processing of APP metabolite; AS 19, selective 5-HT7 receptor agonist, (2S)-N,N-dimethyl-5-(1,3,5-trimethylpyrazol-4-yl)-1,2,3,4-tetrahydronaphthalen-2-amine; Ab, amyloid beta; Ab1–42, Fibrillogenic amyloid beta; AbPPswe/PS1DE9, Transgenic mouse expressing APP swedish and PS1DE9 mutations; BDNF, brain derived neurotrophic factor; BF, beaded fibres; Bmax, receptor density; BP, binding potencial; CA1, cornu amonis 1; CA3, cornu amonis 3; CA4, cornu amonis 4; CaMKII, Ca2+/calmodulin-dependent protein kinase II; cAMP, cyclic adenosine monophosphate; cLH, congenital learned helplessness rat; CNS, central nervous system; CSF, cerebrospinal fluid; D, dopaminergic; DEXNOR, dexnorfenfluramine; DOI, 1-[2,5-dimethoxy-4-iodophenyl]-2-aminopropane; DR, dorsal raphe nucleus; E, embryonic day; FAD, familial Alzheimer’s disease; FF, fine fibres; GABA, g-aminobutyric acid; Gi/Go protein, Guanine nucleotide-binding proteins; Gs protein, Stimulatory guanine nucleotidebinding proteins; HPLC, high-pressure liquid chromatography; KD, receptor affinity; kDa, Kilo Dalton; ltd, Laterodorsal tegmental; LTP, long-term potentiation; MAOIs, Monoamine oxidase inhibitors; MDMA, (3,4-methylenedioxymethamphetamine; MMSE, Mini-Mental State Examination; MRI, magnetic resonance imaging; mRNA, messenger ribonucleic acid; MS, medial septum; NBM, nucleus basalis magnocellularis; NBQX, AMPA receptor blocker; NCB-20, mouse neuroblastoma-Chinese hamster brain hybrid cell line; NFT, neurofibrillary tangles; OBX, olfactory bulbectomized rat; P, postnatal day; PCPA, p-chlorophenylalanine; PET, positron emission tomography; PKA, protein kinase A; ppt, pedunculopontine tegmental; PS-1, presenilin-1; PS-2, presenilin-2; RT-PCR, reverse transcriptase polymerase chain reaction; S-100b, astroglialderived Ca2+-binding protein; SA, stem axons; SAD, Sporadic Alzheimer’s disease; SERT, serotonin transporter; SPECT, single positron emission computed tomography; SSRI, selective serotonin reuptake inhibitor; TPH, tryptophan hydroxylase; VaD, vascular dementia; vDBB, ventricular limb of the diagonal band of Broca; WAY100635, 5-HT1A receptor antagonista N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridyl)cyclohexanecarboxamide. * Corresponding author at: University of the Basque Country UPV/EHU Zamudio, Functional Neuroanatomy, IKERBASQUE, Basque Foundation for Science Department of Neuroscience Faculty of Medicine and Odontology, Technological Park Laida Bidea, Bldg. 205, Floor –1, 48170 Zamudio Bizkaia, Spain. Tel.: +34 946018305; fax: +34 946018289. ** Corresponding author at: Faculty of Life Sciences, The University of Manchester, Manchester, United Kingdom. E-mail addresses: [email protected] (J.J. Rodrı´guez), [email protected] (A. Verkhratsky). 0301-0082/$ – see front matter ß 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.pneurobio.2012.06.010

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J.J. Rodrı´guez et al. / Progress in Neurobiology 99 (2012) 15–41

Contents 1. 2.

3.

4.

5. 6. 7.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Serotonergic neurotransmission . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Serotonin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Serotonergic neurones in the brain . . . . . . . . . . . . . . . . . . . . . . . . 2.2. 2.3. Serotonergic projections in the brain. . . . . . . . . . . . . . . . . . . . . . . Serotonin receptors in the brain . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Serotonergic transmission in short-term and long-term memory 2.5. 5-HT receptors in learning and memory . . . . . . . . . . . . . . . . . . . . 2.6. 5-HT1A receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6.1. 5-HT2A receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6.2. Other 5-HT receptors. . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6.3. The serotonergic system in ageing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Serotonergic neurotransmission in ageing. . . . . . . . . . . . . . . . . . . 3.1. Serotonin receptors in ageing. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. 5-HT1A receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.1. 5-HT2A receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.2. Other 5-HT receptors in ageing. . . . . . . . . . . . . . . . . . . . 3.2.3. Serotonin in Alzheimer’s disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Serotonergic neurones in AD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Serotonergic neurotransmission in AD. . . . . . . . . . . . . . . . . . . . . . 4.2. 4.2.1. Serotonergic projections in AD . . . . . . . . . . . . . . . . . . . . 5-HT receptors in AD. . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.2. Serotonin transporter in AD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Serotonergic neurotransmission in non-AD dementia . . . . . . . . . . . . . . . The serotonergic system as a potential therapeutic target in AD . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction An increase in life expectancy coincides with an increased risk of dementia at an advanced age. Over 35 million people worldwide are affected by dementia (Cumming and Brodtmann, 2010), with Alzheimer’s disease (AD) being one of the most common causes in the elderly population (Qiu et al., 2009). Initially described by Alois Alzheimer (Alzheimer, 1907) as dementia praecox (and named Alzheimer’s disease after him by his colleague and friend Emil Kraepelin several years later (Kraepelin, 1910)). AD is a severe neurodegenerative pathology associated with specific histopathological markers: (i) focal extracellular deposits of fibrillar bamyloid (also called neuritic or senile plaques) in the parenchyma of the brain and the walls of blood vessels, and (ii) intraneuronal accumulation of neurofibrillary tangles composed of abnormal hyperphosphorylated tau filaments (Braak and Braak, 1991; for review see Duyckaerts et al., 2009). AD affects specific brain regions associated with learning and memory, notably the basal forebrain, the hippocampus and the neocortex (Takeda et al., 2006; Truchot et al., 2007). Clinical symptoms of AD are manifested by a progressive impairment of cognitive functions including short- and long-term memory (Mohs, 2005). At advanced stages of the disease, AD patients also exhibit behavioural disturbances including agitation, irritability, anxiety, delusions and depression (Lyketsos and Olin, 2002). Epidemiologically, AD is classified into early-onset familial Alzheimer’s disease (FAD) and late-onset sporadic AD, or SAD (Blennow et al., 2006). Late-onset SAD accounts for the majority (95%) of AD cases in people above 65 years of age (Kern and Behl, 2009; Shastry and Giblin, 1999). FAD is associated with mutations in three genes coding for amyloid precursor protein (APP), presenilin-1 (PS-1) and presenilin-2 (PS-2), which are inherited in an autosomal dominant mode (Shastry and Giblin, 1999). FAD most commonly occurs in patients between 40 and 65 years of age

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and is characterised by a rapid progression (Shastry and Giblin, 1999). The AD-related lesions begin with degeneration of acetylcholine (ACh)-ergic neurones in the nucleus basalis of Meynert and septum followed by accumulation of intraneuronal b amyloid (Ab), subsequent formation of extracellular neuritic plaques and intracellular neurofibrillary tangles (NFTs), synaptic loss and neuronal death (Mesulam et al., 2004). Synaptic malfunction and synaptic loss occur prior to the development of Ab-plaques and NFTs; these synaptic alterations are directly associated with deteriorated synaptic strength and synaptic plasticity, including long-term potentiation (LTP) (Scheff et al., 2006; Selkoe, 2002). The neurodegenerative process also involves impaired neurogenesis (Rodrı´guez and Verkhratsky, 2011a) and multiple reactions of neuroglia from astroglial atrophy and reactive astrogliosis to activation of microglia (Heneka et al., 2010; Rodrı´guez et al., 2009b; Rodrı´guez and Verkhratsky, 2011b; Verkhratsky et al., 2010). AD-related neurodegeneration severely affects neurochemistry of the brain. Traditionally, the primary role in AD pathology was assigned to degeneration and demise of ACh neurones and an overall decrease in the activity of choline acetyltransferase (the enzyme responsible for ACh synthesis) (Birks and Melzer, 2000; Bowen et al., 1976; Fibiger, 1991). Other neurotransmitter systems, however, are also involved in cognitive processes and can undergo pathological remodelling in AD; including noradrenalin, dopamine and serotonin, which is the focus of the present review (Dringenberg, 2000; Garcia-Alloza et al., 2005; Grudzien et al., 2007; Lai et al., 2002; Nazarali and Reynolds, 1992). Furthermore, drugs that enhance cholinergic function have only modest success in treating cognitive deficits associated with AD, further alluding to the involvement of other neurotransmitter systems (Birks and Melzer, 2000; Takeda et al., 2006). Serotonin (5-hydroxytriptamine, 5-HT) plays an acknowledged role in cognition including short- and long-term memory. The

J.J. Rodrı´guez et al. / Progress in Neurobiology 99 (2012) 15–41

raphe nuclei, which contain the majority of 5-HT neurones, give rise to serotonergic projections that are widely distributed throughout the brain notably in areas critical for cognitive functions such as septum, frontal cortex, temporal cortex and the hippocampal formation (Vertes, 1991; Vertes et al., 1999). The effects of 5-HT occur both directly and indirectly through activation of 5-HT-specific receptors and the modulation of other neurotransmission system including cholinergic, glutamatergic, dopaminergic and GABAergic (for review see Buhot, 1997; Buhot et al., 2000; Jeltsch-David et al., 2008; Olvera-Cortes et al., 2008). Patients with AD-type pathology show decreases in central and peripheral 5-HT neurotransmissions, as revealed by reduced concentrations of 5-HT in the cerebrospinal fluid (Tohgi et al., 1992, 1995) and platelets (Mimica et al., 2008; Muck-Seler et al., 2009). Positron emission tomography (PET) and magnetic resonance imaging (MRI) studies have further corroborated an ADrelated decrease of 5-HT receptors in the CNS (Kepe et al., 2006; Meltzer et al., 1998a, 1999). Post-mortem examination of AD brains revealed decreases in extracellular levels of 5-HT and its metabolite (5-hydroxyindoleacetic acid, 5-HIAA) as well as decreases in expression of 5-HT receptors in various brain regions including the neocortex and the hippocampus (Chen et al., 1996; Garcia-Alloza et al., 2005; Lai et al., 2002; Lorke et al., 2006; Nazarali and Reynolds, 1992; Palmer et al., 1987; Truchot et al., 2008). The impairment of 5-HT neurotransmission in AD is consistent with a loss of 5-HT neurones in the raphe nuclei and associated loss of cortical 5-HT projections (Chen et al., 2000; Yamamoto and Hirano, 1985). AD-related deficits in 5-HT neurotransmission are associated with accelerated cognitive decline as determined by the MiniMental State Examination (MMSE) score (Lai et al., 2002) and with behavioural symptoms including psychosis (Garcia-Alloza et al., 2005) as well as with the severity of dementia. It may therefore, be responsible for the cognitive and non-cognitive abnormalities associated with AD. Treatments with selective serotonin reuptake inhibitors (SSRIs) increase the CSF concentration of 5-HT and improve cognitive function and memory in patients with dementia of AD type (Marksteiner et al., 2003; Mossello et al., 2008; Mowla et al., 2007; Tohgi et al., 1995). Drugs acting at specific 5-HT receptors have also been suggested as therapeutic agents to enhance cognitive function in AD (Terry et al., 2008). In this paper we provide a comprehensive overview of the 5-HT neurotransmission pathology in ageing and neurodegeneration with specific emphasis on AD. 2. Serotonergic neurotransmission 2.1. Serotonin Serotonin was discovered as an enterochromaffin substance, which was originally named ‘‘enteramine’’ (Vialli and Erspamer, 1937, 1942). Subsequent studies identified 5-HT as a ‘‘serum vasoconstrictor’’ and coined the name serotonin because of its original purification from serum (sero-) and its effect on vessel tone (-tonin) (Rapport, 1949; Rapport et al., 1948a,b). Some years later, the enteramine-serotonin identity was confirmed, 5-HT was found in the brain and its role as a neurotransmitter was suggested (Erspamer and Asero, 1952; Bogdanski et al., 1956; Harper, 1964). 2.2. Serotonergic neurones in the brain The first anatomical description of the raphe nuclei was made in the early 1900, by Santiago Ramo´n y Cajal, describing it as an ‘‘intermediate or unpaired nucleus’’ of the ‘‘median subaqueductal nucleus of the raphe’’ (Fig. 1, Ramo´n y Cajal, 1904), see also

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Fig. 1. Santiago Ramo´n y Cajal´s drawing showing a section through the superior colliculus in a few-days-old kitten. One can see the cells of the ‘‘subaqueductal nucleus of the raphe’’ most likely resemble dorsal raphe nucleus neurones (E). Others include: the cells of the trochlear nerve nucleus and their collaterals (A–B), the medial longitudinal fasciculus (C), the fibres of the superior cerebellar peduncles (D), the ventral cells of the raphe (F) and the radicular fibres of the trochlear nerve (G). From the annotated and edited translation of Cajal’s (1904) ‘‘Texture of the Nervous System of Man and the Vertebrates’’ by Pasik and Pasik (2000).

(Michelsen et al., 2007). Sixty years later Dahlstro¨m and Fuxe using fluorescent histochemistry (Dahlstro¨m and Fuxe, 1964) described the anatomical distribution of 5-HT neurones in the central nervous system (CNS). In this study, nine clusters of 5-HTcontaining neurones were identified and classified as B1–B9 neurones (Dahlstro¨m and Fuxe, 1964). These cell groups are located within the midline raphe nuclei of the brain stem (Steinbusch, 1981; Jacobs and Azmitia, 1992). The serotonergic system is arguably the most abundant monoaminergic system in the brain, with the highest neuronal population compared to other monoamines including the noradrenergic and dopaminergic systems (Sirvio et al., 1994). Afferent inputs into the raphe nuclei include projections from the brain stem (cholinergic, noradrenergic and dopaminergic), the hypothalamus (peptidegic or histaminergic) and glutamatergic from the limbic system (Sirvio et al., 1994; Steckler and Sahgal, 1995). Although some of the raphe neurones express other neurotransmitters (e.g. dopamine, glutamate and GABA) 5-HT neurones represent the main neuronal population (Michelsen et al., 2007). Nine serotonergic cell groups (B1–B9) are generally divided into inferior and superior groups depending on their anatomical localisation (Jacobs and Azmitia, 1992; Sirvio et al., 1994). The inferior group includes 5-HT neurones in nucleus raphe pallidus (B1), raphe obscurus (B2), nucleus raphe magnus (B3), the area postrema and lateral medulla, which all send descending projections to the cerebellum and the spinal cord (Jacobs and Azmitia, 1992; Sirvio et al., 1994). The superior group includes neurones in nucleus ponti central oralis (B4), median raphe nucleus (B5), dorsal raphe nucleus (B6–B7) and caudal linear nucleus (B8), which all project to the forebrain and the brain stem (Jacobs and Azmitia, 1992). The B9 group in medial lemniscus was, for a while, viewed as a minor serotonergic nucleus of the superior group; later studies however demonstrated that it contains a large number of 5-HT neurones (Vertes and Crane, 1997) that heavily project to the thalamus (Rodrı´guez et al., 2011). The groups B6 and B7 in the dorsal raphe nucleus (DR) represent the largest 5-HT neuronal population in the brain (Steckler and Sahgal, 1995). Cajal’s description of the neuronal morphology within what was to be later called the raphe nuclei is still fully applicable (Ramo´n y Cajal, 1904; Michelsen et al., 2007). Cajal identified four types of neurones, which he called ‘‘voluminous, fusiform,

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18

triangular and stellate’’ (Ramo´n y Cajal, 1904). Subsequent immunohistochemical studies described raphe neurones as circular, ovoid, triangular and fusiform (Baker et al., 1990; Michelsen et al., 2007, 2008; Steinbusch et al., 1981). A main feature of 5-HTimmunoreactive (5-HTIR) neurones compared to other neuronal types in the raphe nuclei is their larger cell bodies. For example, 5HT-immunoreactive neurones from the dorsal raphe nucleus exhibit relatively large, rounded or ovoid cell bodies with sparse dendritic arborisations. The median raphe nucleus contains clusters of small to medium-sized 5-HT neurones, which constitute only a small fraction of the neuronal population within this nucleus. 2.3. Serotonergic projections in the brain The projections from 5-HT neurones are widely distributed throughout the CNS and innervate thalamus, hypothalamus, septum, caudate–putamen, all cortical areas and the hippocampal formation as well as the cerebellum and the spinal cord (Azmitia and Segal, 1978; Vertes, 1991; Vertes et al., 1999). The 5-HT innervation of the hippocampus originating from the midbrain raphe nuclei is relatively dense. Serotonergic neurones from the dorsal and median raphe nuclei project to multiple areas of the forebrain in a non-overlapping manner (Vertes, 1991; Vertes et al., 1999) but rarely innervate separate parts of the same brain structure, except for the septum, where 5-HT projections from the dorsal raphe nucleus innervate the lateral part, whereas 5-HT projections from the median raphe nucleus innervate the medial part (Vertes, 1991; Vertes et al., 1999). Serotonergic projections from the dorsal raphe nucleus innervate many forebrain regions including frontal cortex, amygdala, lateral septum, striatum and ventral hippocampus (Vertes, 1991). Median raphe projections mostly innervate structures located close to midline forebrain regions such as dorsal diagonal band of Broca nuclei, medial septum and dorsal hippocampus (Vertes et al., 1999). It has been claimed that 5-HT axons have a distinct morphology depending on their nuclei of origin and projection sites (Bjarkam et al., 2005; Hensler, 2006; Kosofsky and Molliver, 1987; Molliver, 1987; Noristani et al., 2010). Median raphe neurones project straight, non-varicose axons (stem axons, SA), as well as thick fibres with large and spherical varicosities that are irregularly spaced (also known as beaded fibres (BF)) (Bjarkam et al., 2005; Hensler, 2006; Kosofsky and Molliver, 1987; Molliver, 1987; Noristani et al., 2010). Serotonergic axons arising from the dorsal raphe neurones mostly correspond to fine fibres (FF) with small fusiform or granular varicosities that are regularly spaced (Kosofsky and Molliver, 1987; Hensler, 2006; Noristani et al., 2010). Through these multiple projections, 5-HT neurotransmission is involved in a great variety of physiological processes. 5-HT input to the hypothalamus and limbic regions regulates body temperature, food intake and the sleep–wakefulness cycle (Dryden et al., 1996; Imeri et al., 1994; Weber and Angell, 1967; Yasumatsu et al., 1998); projections to the spinal cord are involved in pain perception (Dogrul et al., 2009; Millan, 2002; Zhuo and Gebhart, 1991). Cortical 5-HT

projections play an important role in motor functions and in shaping emotions (Cools et al., 2008; Jacobs and Fornal, 1997; Loubinoux et al., 2002). 5-HT input to the hippocampus is essential for adult neurogenesis (Brezun and Daszuta, 1999, 2000a); and together with its septum and cortical innervation plays a direct and fundamental role in cognition via modulation of memory acquisition, consolidation and storage (Buhot et al., 2000; Schmitt et al., 2000). This remarkable physiological versatility of 5-HT transmission is mediated through an extended family of specific receptors. 2.4. Serotonin receptors in the brain The presence of 5-HT in the brain was identified in 1954 (Amin et al., 1954). Subsequent studies of Gaddum and colleagues (Gaddum and Hameed, 1954; Gaddum and Picarelli, 1957) identified two types of 5-HT receptors designated as M and D receptors (due to their blockage by morphine and a-adrenergic blocker dibenzyline (see Green, 2006 for historic account)). Further investigations led to the identification of 5-HT1, 5-HT2 and 5-HT3 receptors (Bradley et al., 1986; Peroutka et al., 1981). Molecular cloning identified seven classes of 5-HT receptors represented by G-protein coupled receptors (5HTR1,2,4–7) and by ligand gated cation channels (5-HTR3). Molecular structure, physiology and molecular pharmacology of 5-HT receptors have been extensively covered in many excellent reviews (Barnes and Sharp, 1999; Hoyer et al., 2002; Descarries et al., 2006; Niesler et al., 2008; Feuerstein, 2008; Pucadyil et al., 2005; Muller and Jacobs, 2009; Bjork et al., 2010), which can provide the reader with necessary details and references. 2.5. Serotonergic transmission in short-term and long-term memory 5-HT plays a critical role in cognitive function including learning, short-term and long-term memory as well as cognitive flexibility (Evers et al., 2007; Meneses, 1999; Meneses and PerezGarcia, 2007; Schmitt et al., 2000); affecting memory directly and indirectly via cholinergic, glutamatergic, GABAergic and dopaminergic neurotransmission modulation (Table 1, Buhot et al., 2000; Garcia-Alloza et al., 2006; Meneses, 1999; Merens et al., 2008; Olvera-Cortes et al., 2008). Anatomically, the 5-HT/ACh interactions occur at (i) nuclei of origin and (ii) common target structures where 5-HT and ACh projections converge (Cassel and Jeltsch, 1995; Jeltsch-David et al., 2008; Steckler and Sahgal, 1995). 5-HT projections from the raphe nuclei terminate in forebrain, which has a high density of ACh neurones such as in medial septum (MS), in the ventricular limb of the diagonal band of Broca (vDBB), in nucleus basalis magnocellularis (NBM), in pedunculopontine tegmental (PPT) nucleus and in laterodorsal tegmental (LTD) nucleus (Jones and Cuello, 1989; Kohler et al., 1982; Milner and Veznedaroglu, 1993; Semba et al., 1988; Steckler and Sahgal, 1995; Vertes, 1988, 1991; Vertes et al., 1999). These forebrain structures, in turn, send ACh projections to the hippocampus, cerebral cortex, amygdala, thalamus and prefrontal cortex (Amaral and Kurz, 1985; Cassel and Jeltsch,

Table 1 Mechanisms of cognitive-enhancing effects of different 5-HT receptors. 5-HT receptor

Agonis/Antagonist

Mechanism

5-HT1A 5-HT2A 5-HT3 5-HT4 5-HT5 5-HT6 5-HT7

Antagonist Agonist Antagonist Agonist/Partial agonist nr Antagonist Agonist

Increase Increase Increase Increase nr Increase nr

Key: nr: not reported.

in in in in

Reference ACh and glutamate release ACh and glutamate release ACh release and suppression of GABA ACh

in ACh and glutamate release

Borg (2008), Koenig et al. (2008) Harvey (2003), Hirano et al. (1995), Meneses (2002) Arnsten et al. (1997), Puig et al. (2004), Staubli and Xu (1995) Mohler et al. (2007), Orsetti et al. (2003) nr Dawson et al. (2001), West et al. (2009) Martin-Cora and Pazos (2004), Ballaz et al. (2007)

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1995; Mesulam et al., 1983; Senut et al., 1989). The raphe nuclei receive ACh projections from PPT and LTD nuclei (Jones, 1990; Steckler and Sahgal, 1995; Woolf and Butcher, 1989). The 5-HT/ ACh interactions also occur at target structures (i.e. neocortex and the hippocampus, intimately involved in learning and memory), which receive converging 5-HT and ACh projections from the raphe nuclei and the forebrain nuclei, respectively (Cassel and Jeltsch, 1995; Jeltsch-David et al., 2008; Steckler and Sahgal, 1995). Lesion studies indicated the importance of 5-HT/ACh interactions in mnesic processes (Lehmann et al., 2002; Richter-Levin et al., 1993; Richter-Levin and Segal, 1991b, 1992). Although the selective lesion of either 5-HT neurones (via intracerebroventricular injection of the neurotoxic agent 5,7-dihydroxytryptamine) or ACh neurones (via intracerebroventricular injection of immunotoxin 192 IgG-saporin), causes minor behavioural alterations, concomitant lesion of both systems induces severe deficit in learning (Lehmann et al., 2002; Richter-Levin et al., 1993; RichterLevin and Segal, 1991a,b) and spatial memory (Jeltsch-David et al., 2008; Lehmann et al., 2000; Nilsson et al., 1988); which can be rescued by hippocampal (i) embryonic raphe grafts (rich in 5-HT neurones) (Richter-Levin et al., 1994, 1993) and (ii) simultaneous transplantation of septal grafts (rich in ACh neurones) and raphe grafts (Nilsson et al., 1990). Electrophysiological studies demonstrated that the activation of 5-HT projections has an inhibitory effect on ACh release in the forebrain (Steckler and Sahgal, 1995) and in the septum, which is mediated by 5-HT1A receptors (Bertrand et al., 2000; Jeltsch et al., 2004; Koenig et al., 2008). Increased 5-HT input inhibits ACh release in the forebrain, thus compromising memory acquisition and consolidation (Jeltsch-David et al., 2008). Combined pharmacological blockade of 5-HT synthesis (by intraperitoneal injection of pchlorophenylalanine, which selectively and irreversibly inhibits tryptophan hydroxylase) and ACh neurotransmission (by the anticholinergic alkaloid scopolamine, or the muscarinic M2 antagonist atropine) induces a severe deficit in spatial and working memory (Richter-Levin and Segal, 1989, 1991a,b; Riekkinen et al., 1991). Selective lesioning of the midbrain 5-HT neurones is also associated with reduced adult neurogenesis in the subgranular layer of the dentate gyrus and the subventricular zone (Brezun and Daszuta, 1999, 2000a,b), therefore directly affecting learning and memory. Depressed neurogenesis can be reversed by the transplantation of foetal raphe grafts in the hippocampus and graft-derived serotonergic re-innervation of the hippocampus (Brezun and Daszuta, 2000b). The intracisternal administration of 5,7-dihydroxytryptamine (5,7-DHT) also prevents environmental enrichment-induced neurogenesis in the adult rat hippocampus (Ueda et al., 2005). The inhibition of 5-HT synthesis by administration of PCPA hampers proliferation and survival of adult stem cells in vitro (Benninghoff et al., 2010). Incidentally, selective memory impairment associated with the recreational use of 3,4-methylenedioxymethamphetamine, MDMA (commonly known as ‘‘extasy’’) may be due to its the specific neurotoxic effects on 5-HT projections (de Sola Llopis et al., 2008; Morgan, 1999; O’Hearn et al., 1988; Wilson et al., 1989). Decreased 5-HT neurotransmission following reduced dietary intake of the 5-HT precursor, L-tryptophan also results in altered object memory in rodents (Lieben et al., 2004; Nomura, 1992). Chronic deprivation of L-tryptophan decreases proliferation rate, dendrite arborisation and dendritic spine density in the subgranular zone of dentate gyrus (Zhang et al., 2006), which may contribute to the impairment of hippocampal contextual fear memory formation (Uchida et al., 2007). Similarly, the inhibition of 5-HT synthesis (by subcutaneous administration of the tryptophan hydroxylase inhibitor, parachlorophenylalanine) significantly reduces the density of synapses and spines in the hippocampus (Alves et al., 2002; Brezun and Daszuta, 2000a; Mazer et al., 1997).

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In contrast, daily injections and oral administration of Ltryptophan improve spatial memory in aged rats (Levkovitz et al., 1994; Richter-Levin and Segal, 1996) as well as memory acquisition, consolidation and storage in normal rodents (Haider et al., 2006, 2007; Khaliq et al., 2006). In humans, healthy volunteers as well as AD patients, Ltryptophan-deficient diet also affects short- and long-term memory by altering memory encoding, consolidation and storage (Merens et al., 2008; Newhouse et al., 2002; Porter et al., 2003, 2000; Riedel et al., 1999; Rubinsztein et al., 2001; Sambeth et al., 2007, 2009; Schmitt et al., 2000; Scholtissen et al., 2006). Furthermore, acute administration of the SSRI (citalopram) increases memory consolidation and long-term memory in healthy volunteers (Harmer et al., 2002). Chronic treatment with other SSRIs including fluoxetine also improves memory function in AD patients (Mossello et al., 2008; Mowla et al., 2007). Interestingly, increased 5-HT transmission (following chronic treatment with SSRI, fluoxetine) also promotes adult neurogenesis and synaptogenesis in the hippocampus, which may contribute to the memory improvement (Hajszan et al., 2005; Malberg et al., 2000; Marcussen et al., 2008), see also (Aboukhatwa et al., 2010). In summary, reduced 5-HT neurotransmission impairs learning and memory function, whereas increased 5-HT neurotransmission is associated with improved memory and cognitive performance, not only in rodents, but also in humans. 2.6. 5-HT receptors in learning and memory 2.6.1. 5-HT1A receptors In general, the activation of 5-HT1A receptors affects cognitive function by interfering with memory acquisition and consolidation, whilst the blockade of 5-HT1A receptors improves cognition by increasing ACh and glutamate neurotransmitter release (Harder et al., 1996; Harder and Ridley, 2000; Koenig et al., 2008; Luttgen et al., 2005a; Misane and Ogren, 2003) (Table 1). However, in young adult (3 months) but not aged (22 months) mice, genetic deletion of 5-HT1A receptors reduces hippocampus-dependent spatial memory and working memory impairment (assessed by Morris water maze, Y maze and the spontaneous-alteration tasks) (Sarnyai et al., 2000; Wolff et al., 2004). This discrepancy may be due to combined lack of 5-HT1A heteroreceptors in the hippocampus and 5-HT1A autoreceptors in the raphe nuclei (Sarnyai et al., 2000). In fact, the stimulation of 5-HT1A autoreceptors in the dorsal raphe nucleus reverses memory impairment induced by intrahippocampal injection of the cholinergic muscarinic antagonist scopolamine, suggesting a region-specific role of these 5-HT1A receptors (Carli et al., 1998). The introduction of the selective 5-HT1A/7 receptor agonist 8hydroxy-2-(di-n-propylamino)-tertralin (8-OH-DPAT) has been of major importance in addressing the role of 5-HT1A receptors in cognitive function (Arvidsson et al., 1981; Meneses and PerezGarcia, 2007). Systemic treatment with 8-OH-DPAT reduces LTP (Edagawa et al., 1998) and also affects water maze performance (Carli et al., 1992a; Carli and Samanin, 1992; Meneses, 1999), object recognition (Pitsikas et al., 2005) and passive avoidance (Carli et al., 1992b; Elvander-Tottie et al., 2009) in rodents. The detrimental effect of 8-OH-DAPT on memory function appears to be mediated by activation of 5-HT1A heteroreceptors in the septum and the hippocampus (Egashira et al., 2006; ElvanderTottie et al., 2009). In particular, (i) local injection of 8-OH-DPAT into the dorsal hippocampus impairs memory function in a dosedependent manner (Egashira et al., 2006) and (ii) 8-OH-DPATinduced memory impairment is not affected by 5-HT depletion with 5,7-DHT suggesting that the absence of 5-HT1A autoreceptors is not required for this effect (Carli and Samanin, 1992). In contrast, 5,7-DHT-induced serotonin depletion alters 5-HT turnover, which

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is regulated by activation of 5-HT1A autoreceptors (Carli and Samanin, 1992). Immunohistochemical studies have demonstrated 5-HT1A receptor co-localisation on GABAergic and ACh neurones in the septum and the diagonal band of Broca (Kia et al., 1996a; Luttgen et al., 2005b). 5-HT1A receptors antagonists and partial agonists enhance ACh release in the cerebral cortex and hippocampus, which is associated with improved memory performance (Hirst et al., 2008; Kehr et al., 2010; Millan et al., 2004; Schechter et al., 2005). In addition, 5-HT1A receptor antagonists reverse the memory impairments resulting from cholinergic and glutamatergic deficits (following intrahippocampal injection of the cholinergic muscarinic antagonist scopolamine and the NMDA receptor complex antagonist 7-chloro-kynurenic acid) (Carli et al., 1997). The 5-HT1A receptor antagonist WAY100635 prevents the learning deficits induced by intraperitoneal injection of AMPA receptor blocker NBQX (Schiapparelli et al., 2006). It was also suggested that the blockade of hippocampal 5-HT1A receptors by WAY100635 promotes molecular cascades implicated in memory formation, including (i) phosphorylated Ca2+/calmodulin-dependent protein kinase II (CaMKII), (ii) Ca2+-independent CaMKII and protein kinase A (PKA) enzyme activity and (iii) GluR1 AMPA receptor subunit in the hippocampus (Schiapparelli et al., 2005). 2.6.2. 5-HT2A receptors Conceptually, the activation of 5-HT2A receptor enhances learning and memory consolidation, whereas antagonists of the receptor have a negative effect on learning (Harvey, 1996, 2003; Meneses and Hong, 1997b). At the behavioural level, 5-HT2A receptor activation improves working memory (as indicated by delayed-response task in monkeys), an effect that is reversed by selective blockade of the receptors (Williams et al., 2002). Such cognitive-stimulating effect of 5-HT2A receptor activation is associated with enhanced release of other neurotransmitters including ACh and glutamate (Hirano et al., 1995; Meneses, 2002) (Table 1). Concordant data from in situ hybridisation, immunohistochemical and ultrastructural studies indicate that 5-HT2A receptors co-localise with NMDA and (to a smaller extend) with g-aminobutyric acid (GABA) receptors in the hippocampus and cerebral cortex, further supporting a modulatory role of 5HT2A receptors in glutamatergic and GABAergic neurotransmissions (de Almeida and Mengod, 2007; Jakab and Goldman-Rakic, 1998; Peddie et al., 2008b; Santana et al., 2004; Willins et al., 1997). Activation of cortical 5-HT2A receptors enhances glutamate and GABA release from presynaptic terminals (Abi-Saab et al., 1999; Aghajanian and Marek, 1999; Marek and Aghajanian, 1999; Scruggs et al., 2003). This effect results from 5-HT2Ainduced inhibition of voltage-gated K+ channels, which in turn increases neuronal firing (Lambe and Aghajanian, 2001). On the contrary, another study reported a 5-HT2A receptor-mediated depression of glutamate release (Wang et al., 2006). This latter study used a preparation of isolated nerve terminals (synaptosomes) rich in presynaptic receptors, whereas the majority of cortical and hippocampal 5-HT2A receptors are postsynaptic (Cornea-Hebert et al., 1999; Peddie et al., 2008a). This may explain the apparent discrepancy in 5-HT2A receptor-mediated release of glutamate in isolated presynaptic nerve terminals (Wang et al., 2006) as opposed to the previous studies performed on in vitro slice preparation (Aghajanian and Marek, 1999) or employing in vivo microdialysis (Scruggs et al., 2003). The 5-HT2A receptors also exhibit affinity for hallucinogenic and antipsychotic drugs (Scruggs et al., 2003; Wang et al., 2006). The cognitive-enhancing effect of atypical antipsychotic is attributed at least in part to their effect on 5-HT2A receptors (Harvey, 2003).

2.6.3. Other 5-HT receptors 5-HT3 receptors inhibition is associated with the enhancement of LTP induction, memory retention and spatial memory in rats (Staubli and Xu, 1995) as well as age-related deficits in memory function (Pitsikas and Borsini, 1996) after intraperitoneal administration of the selective 5-HT3 receptor antagonists itasetron and ondansetron. In addition, subcutaneous administration of ondansetron reverses the cognitive deficits associated with muscarinic receptor inhibition in rats (Carli et al., 1997; Pitsikas and Borsini, 1997) and marmosets (Carey et al., 1992). Furthermore, acute oral administration of ondansetron and SEC-579 enhances memory acquisition in aged rhesus monkeys (Arnsten et al., 1997). The majority of 5-HT3immunoreactive neurones are GABA positive, indicating a clear interaction between both systems (Morales et al., 1996; Morales and Bloom, 1997; Puig et al., 2004). The cognitive-enhancing effects of 5HT3 receptor antagonists are probably mediated indirectly via suppression of GABA transmission and a concomitant increase in the firing rate of the pyramidal neurones in the hippocampus (Choi et al., 2007; Reznic and Staubli, 1997). The inhibition of 5-HT3 receptors also enhances ACh release, which may explain its pro-cognitive effects (Ramirez et al., 1996) (Table 1). Clinically, 5-HT3 receptor antagonists are well tolerated and do not exert the cardio respiratory, extra pyramidal, genitourinary, musculoskeletal symptoms and sleep disturbances associated with cholinesterase inhibitors (Haus et al., 2004; Thompson et al., 2004). Stimulation of 5-HT4 receptors improves attention, learning, memory and LTP in rodents (Hille et al., 2008; Marchetti et al., 2004; Mohler et al., 2007; Moser et al., 2002). 5-HT4 receptor agonists and partial agonists are effective in reversing the cognitive and memory impairments associated with muscarinic receptor blockade (Galeotti et al., 1998; Hille et al., 2008; Lelong et al., 2003), ageing (Moser et al., 2002) and hippocampal damages through Ab and tubulin inhibitor colchicines injection (Marchetti et al., 2008; Micale et al., 2006); as well as promote dendritic spine growth in the hippocampus (Restivo et al., 2008). In contrast, a recent study found no changes in memory performance in 5-HT4 knockout mice that might be due to compensatory increase in muscarinic receptor-mediated ACh neurotransmission (Segu et al., 2010). Although the precise mechanisms involved in cognitiveenhancing properties of 5-HT4 receptors remain unknown, it may involve a stimulation of ACh release (Consolo et al., 1994; Mohler et al., 2007) (Table 1). Activation of 5-HT4 receptors also promotes the non-amyloidogenic processing of amyloid precursor protein (APP), both in vitro (Cho and Hu, 2007; Lezoualc’h and Robert, 2003; Mohler et al., 2007; Robert et al., 2001) and in vivo (CachardChastel et al., 2007; Russo et al., 2009). Thus, manipulation of 5HT4 receptors could be useful not only for correcting cognitive deficits but also for decreasing the Ab load associated with AD (Russo et al., 2009). Activation of 5-HT6 receptors attenuates LTP (West et al., 2009) and impairs both short- and long-term memory (Meneses et al., 2008). Accordingly, inhibition of 5-HT6 receptors enhances acquisition, retention and consolidation of memory in rats and reverse age-dependent deficits in water maze spatial learning (Foley et al., 2004; Hirst et al., 2006; Marcos et al., 2008; PerezGarcia and Meneses, 2005; Rogers and Hagan, 2001; Woolley et al., 2001). This improvement in memory function is associated with a decrease in receptor expression (Meneses et al., 2007). Over-expressing 5-HT6 receptors in the rat striatum causes amnesia in procedural memory, an effect that is reversed by administration of the selective 5-HT6 receptor antagonist, SB258585 (Mitchell et al., 2007). Although the underlying mechanisms are not clear, a stimulation of ACh and glutamate release could be involved (Dawson et al., 2001; Hirst et al., 2006) (Table 1). Recently, several 5-HT6 receptor antagonists have advanced into clinical trials for the treatment of cognitive deficits associated

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with neurodegenerative diseases (Geldenhuys and Van der Schyf, 2008; Kwon et al., 2004; Upton et al., 2008). Pharmacological stimulation of 5-HT7 receptors (using a selective agonist, AS 19) enhances memory consolidation, reverses scopolamine-induced amnesia in rats (Perez-Garcia et al., 2006) and improves long-term memory (Meneses et al., 2008). However, it impairs short-term memory, which may be due to differences in (i) molecular mechanism between short- and long-term memory and (ii) drug timing and pharmacological mechanisms mediating the memory task (Meneses et al., 2008). Conversely, pharmacological inhibition of 5-HT7 receptors reliably reduces objectrecognition memory and spatial memory in mice (Ballaz et al., 2007; Sarkisyan and Hedlund, 2009). 5-HT7 receptor knockout mice also demonstrate decreased hippocampal LTP, impaired contextual learning and spatial memory (Roberts et al., 2004; Sarkisyan and Hedlund, 2009). In addition, stimulation of 5-HT7 receptors counteracts memory impairment induced by activation of 5-HT1A receptors (Eriksson et al., 2008). It has however been reported by Gasbarri et al. (2008) that the 5-HT7 receptor antagonist SB-269970 improves reference memory in the radial arm maze, suggesting that further studies will be needed to decipher the precise role of 5-HT7 receptors in learning and memory. Thus, 5-HT mediated improvement in cognitive function is mediated by promoting ACh and glutamate release by either inhibition of postsynaptic 5-HT1A, 5-HT3 and 5-HT6 receptors or activation of 5-HT2A and 5-HT4 receptors (Table 1). 3. The serotonergic system in ageing Age-related alterations of the 5-HT system occur at multiple levels including changes in (i) density of 5-HT-positive neurones in the raphe nuclei, (ii) 5-HT metabolism and hence 5-HT levels in the

21

CNS, (iii) density of 5-HT projections throughout the brain and the spinal cord (iv) expression of 5-HT uptake transporter and (v) expression of 5-HT receptors (see for review Meltzer et al., 1998a; Palmer and DeKosky, 1993). 3.1. Serotonergic neurotransmission in ageing Most commonly, rats at different ages have been used to study age-associated changes in 5-HT system (Table 2). The density of 5HT neurones in the raphe nuclei does not change in aged rats (up to 19–24 months) (van Luijtelaar et al., 1992). Similarly 5-HT neurones remain stable in aged humans (62–84 years) (Kloppel et al., 2001). The rate of 5-HT synthesis (measured by accumulation of 5-hydroxytryptophan after decarboxylase blockade) is unchanged in aged rats up to 24 months (Herrera et al., 1991). The enzymatic activity of 5-HT neurones, as measured by monoamine oxidase pharmacodynamics, increases in aged rats that may account for age-associated increases in 5-HT in the hypothalamus of 19-month-old rats (Navarro et al., 1987), suggesting high synaptic levels. On the contrary, decreases in 5-HT release have been measured in the hippocampus and frontoparietal cortex of very old (25–27 months) rats (Birthelmer et al., 2003a,b). Contradictory results have been reported on age-related changes in 5-HT level in different regions of the brain. Stable levels of 5-HT were found in the caudate–putamen, amygdala, frontal cortex, cingulated cortex and the hippocampus of human post-mortem brains (Bucht et al., 1981; Wester et al., 1984). Similarly, the activity of monoamine oxidase A (the enzyme responsible for 5-HT metabolism) does not change with age in humans (Fowler et al., 1980). In contrast to human studies, the majority of studies in aged rats have reported reduced 5-HT neurotransmitter levels in multiple brain regions (Table 2). Specifically, decreased levels of 5-HT have been reported in frontal

Table 2 Age-associated changes in 5-HT system in rats. Age (months)

Brain region

Ageing effect

Reference

5-HT neurones 19–24

DR

No change

van Luijtelaar et al. (1992)

5-HT neurotransmission 22 24 24 24 24 24–30 25–26 26 25–26 29 19 24–35

FC, ST, Hy Me, R SuCo FC PreC ST SC OC, ST Hy, ST H, cb, ST Hy R, Hy, H

Reduced Reduced Reduced Reduced Reduced Reduced Reduced Reduced Non-change Non-change Increased Increased

Petkov et al. (1987) Bhaskaran and Radha (1983) Herrera et al. (1991) Miguez et al. (1999) Mizoguchi et al. (2010) Machado et al. (1986) Ko et al. (1997) Stemmelin et al. (2000) Simpkins (1984) Ponzio et al. (1982) Navarro et al. (1987) van Luijtelaar et al. (1992)

5-HT projections 18 28 28 28–32

Me FC, PC, ST NeoC, H, ST, NAc, T FC, PC, Pu

Reduced Reduced Reduced Reduced

5-HT transporter 24

FC

Reduced

Brunello et al. (1985)

5-HT receptors 18 18 22–24 12–24 22–24

DR, Hy SuCo, PR H H H

Reduced 5-HT1A receptors Reduced 5-HT2A receptors No changes in 5-HT2C receptor mRNA Reduced 5-HT7 receptor mRNA No changes in 5-HT7 receptor mRNA

Halpern et al. (1989) Parsons et al. (2001) Yau et al. (1999) Kohen et al. (2000) Yau et al. (1999)

5-HT 5-HT 5-HT 5-HT

fibre fibre fibre fibre

density density density density

Behan and Brownfield (1999) Steinbusch et al. (1990) Davidoff and Lolova (1991) van Luijtelaar et al. (1988)

Key: Me: medulla, R: raphe nuclei, FC: frontal cortex, Hy: hypothalamus, SC: spinal cord, OC: occipital cortex, PreC: prefrontal cortex, H: hippocampus, cb: cerebellum, NeoC: neocortex, ST: striatum, NAc: nucleus accumbens, T: thalamus, PC: parietal cortex, Pu: putamen, DR: dorsal raphe nucleus, SuCo: superior colliculus, PR: pretectum.

22

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cortex, striatum and hypothalamus of aged rats (22 months) (Petkov et al., 1987). Another study showed a generalised agedependent decrease in 5-HT levels in multiple brain regions including striatum, hippocampus, amygdala, medulla and frontal cortex through ageing; being major in striatum, cortex and amygdala in very old aged (24 months) rats that suggest an age-associated decrease in 5-HT synthesis and/or accelerated 5-HT metabolism (Miguez et al., 1999). A significant reduction in 5-HT content has also been found in the striatum of 24–30-month-old rats (Machado et al., 1986). Clinical studies have shown an agerelated decline in 5-HT concentration in human platelets (Flachaire et al., 1990). Other groups, however, reported no change or increased 5-HT levels in senescent rat brains (Rodriguez-Gomez et al., 1995; Steinbusch et al., 1990; van Luijtelaar et al., 1992; Venero et al., 1993). A general decrease in 5-HT pool (steady state level of 5-HT) has also been reported in the spinal cord and superior colliculus of aged (24 months) rats; although there is no difference in the rate of 5-HT synthesis between adult and aged (Herrera et al., 1991; Ko et al., 1997). Reduced 5-HT levels (determined by high performance liquid chromatography, HPLC and microdialysis) were detected in various brain regions including the occipital cortex, the prefrontal cortex and the spinal cord of aged rats (24–26 months), which correlated with impaired memory performance (Ko et al., 1997; Mizoguchi et al., 2010; Stemmelin et al., 2000). Other groups reported no changes in 5-HT and its metabolite (5-HIAA) concentrations (as measured using HPLC) in aged rats (25–26 months) (Ponzio et al., 1982; Simpkins, 1984). Finally, there are also reports indicating an increase in 5-HT level in mesencephalic raphe region, hypothalamus and in the hippocampus but not in the caudate–putamen complex of old rats (28 months), suggesting a regional specific alteration of 5-HT neurotransmission during ageing process (van Luijtelaar et al., 1992). Age-related changes in 5-HT neurotransmission are accompanied with morphological alterations of 5-HT projections (RodriguezGomez et al., 1995; van Luijtelaar et al., 1988). 5-HT projections show degenerative profiles in aged rats (12–32 months of age), as indicated by swollen and tortuous varicosities or abnormally thickened, ballooned or spherical axon terminals (van Luijtelaar et al., 1988, 1992; Steinbusch et al., 1990). These morphological alterations are similar to those induced by 5,7-DHT lesioning (by intracerebroventricular injection), suggesting that age-associated aberrant morphologies represent degeneration of ascending 5-HT fibres (van Luijtelaar et al., 1988, 1989, 1992). In the senescent rat brain, degenerative fibre morphology is further increased at a very advanced age (36 months) (Nishimura et al., 1998). Aged rats also exhibit a general decrease in the density of 5-HT innervation throughout the brain, including neocortex, nucleus caudate, putamen, medulla and the hippocampus (Behan and Brownfield, 1999; Davidoff and Lolova, 1991; van Luijtelaar et al., 1988) (Table 2). Reduced 5-HT fibre density was initially observed in rats at 18 months of age and progressively decreased with advanced age (Behan and Brownfield, 1999). Similar age-dependent declines in hippocampal 5-HT projections were found in Northern Tree shrew (Tupaia belangeri) (Keuker et al., 2005). There is no clear relationship, however, between the decreased density of 5-HT innervation and the presence of fibres with an aberrant morphology (van Luijtelaar et al., 1988). The precise mechanism of the age-associated decrease in 5-HT innervation is unclear, although it could be linked to the decline in brain derived neurotrophic factor (BDNF) signalling (Aznar et al., 2010; Luellen et al., 2007). Transgenic mice with reduced BDNF expression (BDNF+/) show accelerated age-associated loss of hippocampal 5HT projections, which starts around 12 months (Luellen et al., 2007). Similar accelerated age-associated decrease in the 5-HT projections have been observed and linked to the reduced BDNF

signalling in the congenital learned helplessness rat (cLH), an animal model of depression (Aznar et al., 2010). Old rats (29 months) exhibit increased 5-HT turnover (measured as 5-HIAA/5-HT ratio) in hypothalamus and median eminence (Rodriguez-Gomez et al., 1995; Stemmelin et al., 2000). Increased 5-HT turnover may reflect either a compensatory mechanism for age-associated loss of 5-HT projections (Rodriguez-Gomez et al., 1995). This increased turnover might be due to a leakage of 5-HT from degenerating fibres (Meister et al., 1995). Aged rats (24 months) also show a reduced expression of serotonin transporter (SERT, measured using [3H]-imipramine binding) when compared to young adult controls (Brunello et al., 1985) (Table 2). Binding studies using [3H]-imipramine also showed 50% age-associated reduction in SERT binding sites in the cingulate cortex of humans (Marcusson et al., 1987). However, other studies reported an age-associated increase in [3H]imipramine binding site in the human hypothalamus, parietal cortex, frontal cortex, occipital cortex and the hippocampus (Owen et al., 1986; Severson et al., 1985). Moreover, binding studies using [3H]-paroxetine reported stable density of SERT expression in aged human frontal cortex (Arranz et al., 1993). On average, there is a 10% decrease per decade in the density of SERT binding sites in human brain stem and thalamus (Yamamoto et al., 2002). Imaging studies using positron emission tomography and single positron emission computed tomography (PET and SPECT) also found age-related decline in SERT binding potential (BP) in human thalamus, midbrain, brain stem and diencephalon (Pirker et al., 2000; van Dyck et al., 2000; Yamamoto et al., 2002). However, it is important to note that binding potential represents transporter density (Bmax), affinity (KD) or a mixture of both (Meltzer et al., 1999). The reduced expression of SERT results in a decrease in 5-HT reuptake, i.e. diminished removal of the neurotransmitter from the synaptic cleft (Mathews et al., 2004). This may explain the increased levels of 5-HT in the mesencephalic raphe region and terminal regions including the hypothalamus and the hippocampus of old (at 28 months) rats (van Luijtelaar et al., 1992) together with a persistent serotonergic activity in the hypothalamus of aged (19 months) rats (Navarro et al., 1987). At the same time, immunohistochemical staining against SERT failed to find changes in the superior colliculus and pretectum of 18-month-old rats (Parsons et al., 2001). An increase in SERT mRNA was found in the raphe nuclei of aged (30 months) rats (Meister et al., 1995). Autoradiographic studies in humans also indicated age-related increase in SERT expression in human occipital cortex and in the hippocampus (Owen et al., 1986). Taken together, these data indicate that age-associated decrease in 5-HT level in the rat brain is region-specific and might be due to either reduced 5-HT release or accelerated 5-HT metabolism. Furthermore, 5-HT projections display degenerative morphology and reduced fibre density in aged brains that may be due to a decrease in neurotrophic factors such as BDNF. 3.2. Serotonin receptors in ageing 3.2.1. 5-HT1A receptors A decrease in the density of [3H]-5-HT binding sites was measured in the dorsal raphe nucleus and the hypothalamus, but not in the frontal cortex of aged rats (18 months), suggesting regionspecific alterations of 5-HT1A receptors expression (Halpern et al., 1989) (Table 2). Similarly, autoradiographic studies using [3H]-5-HT and 5-HT1A/7 receptor agonist [3H]8-OH-DPAT as radioligands demonstrated age-related decrease in 5-HT1A receptor density in human raphe nuclei, temporal cortex, frontal cortex and the hippocampus (Dillon et al., 1991; Marcusson et al., 1984a). A reduced number of 5-HT1A receptors (assessed by autoradiography

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with [3H]-5-HT) was also reported in the somatosensory cortex of aged rhesus monkey (Bigham and Lidow, 1995). In vivo PET study using the selective 5-HT1A receptor antagonist as radioligand [11C–carbonyl] WAY100635 confirmed an agerelated decline in 5-HT1A receptor binding potential in the frontal and temporal cortex of monkeys (Tsukada et al., 2001) and in the raphe nuclei, anterior cingulate, orbitofrontal, lateral, parietal and occipital cortex as well as the hippocampus of humans (Cidis Meltzer et al., 2001; Tauscher et al., 2001). In the human cortex, 10% decline in 5-HT1A receptor binding potential per 10 years has been reported (Tauscher et al., 2001). Conversely, another PET study using [3H] WAY100635 found no age-related changes in 5HT1A receptor binding potential in the human dorsal raphe nucleus, anterior cingulate cortex, amygdala, prefrontal cortex and the hippocampus (Parsey et al., 2002). 3.2.2. 5-HT2A receptors Reduced 5-HT2A receptor density has been reported in various brain regions of aged rats including the superior colliculus and the pretectum, as measured by quantitative immunohistochemistry (Parsons et al., 2001) (Table 2). Age-associated declines in 5-HT2A receptor density were also observed in the deep layer of motor cortex and the middle strata of the visual cortex in rhesus monkeys (Bigham and Lidow, 1995). Age-related decreases in the density of 5-HT2A receptor binding sites have also been measured in the frontal cortex and the hippocampus of humans (Arranz et al., 1993; Gross-Isseroff et al., 1990; Marcusson et al., 1984b). The decline in the density of 5-HT2A receptor density begins around the age of 60 years in humans and shows a negative correlation with advanced age, suggesting that comparatively greater receptor loss occurs at younger ages (Blin et al., 1993; Marcusson et al., 1984b; Rosier et al., 1996). PET studies have also found age-related losses of 5-HT2A receptors in the caudate–putamen and the cerebral cortex of humans (Blin et al., 1993; Iyo and Yamasaki, 1993; Meltzer et al., 1998b; Rosier et al., 1996; Wong et al., 1984). Immunocytochemical analysis identified age-associated decreases in 5-HT2A receptor density in the cerebella of both humans and mice (Yew et al., 2009). Furthermore, age-related declines in 5-HT2A receptor density were found in human periphery tissues and notably in human platelets (Biegon and Greuner, 1992). 3.2.3. Other 5-HT receptors in ageing The information on age-related alterations of other 5-HT receptor types is rather limited. The mRNA expression of 5-HT2C receptors was not altered in aged (22–24 months) rats, as measured by in situ hybridisation (Yau et al., 1999). An early study by Laporte et al. (1996) had similarly reported that the density of 5-HT1D and 5-HT3 receptors (determined by receptor autoradiography) was unchanged in the spinal cord of old humans (aged 81–94 years). More recently a PET study using selective 5HT4 receptor antagonist [11C]SB207145 as radioligand, has shown age-associated decreases in 5-HT4 receptor binding potentials throughout the human brains (Marner et al., 2010b). This latter study was performed on young/adult healthy volunteers (20–45 years) and demonstrated an average 7.1% decrease/decade in 5HT4 receptor binding sites (Marner et al., 2010b). To the best of our knowledge there are no reports on the effects of ageing on 5-HT5 and 5-HT6 receptors. Conflicting results have been reported on age-dependent changes in 5-HT7 receptors (Kohen et al., 2000; Yau et al., 1999). A 30% decrease in 5-HT7 receptor mRNA was demonstrated by in situ hybridisation in the ventral hippocampal CA3 subfield of rats between 3 and 12 months of age (Kohen et al., 2000). This reduced mRNA expression persisted for as long as 24 months in rats, but without further decline between 12 and 24 months of age

23

(Kohen et al., 2000). Another study using in situ hybridisation reported no age-associated changes in 5-HT7 receptor mRNA expression in hippocampal subfields including the dentate gyrus and CA1–CA4 regions in aged (24–26 months) compared to adult (8 months) rats (Yau et al., 1999). In Syrian hamsters (17–19 months) decreases in 5-HT7 receptor binding sites up to 50% have been reported by comparison to animals aged 3–4 months in the dorsal and the median raphe nuclei as well as the lateral geniculate nucleus (Duncan et al., 1999). A subsequent study, however, found no changes in 5-HT7 receptor mRNA expression in the dorsal and median raphe nuclei, amygdala, cingulate cortex and hypothalamus, suggesting that alterations in 5-HT7 mRNA transcription does not account for the age-associated decrease in 5-HT7 receptor binding sites in aged Syrian hamsters (Duncan and Franklin, 2007). In summary, the process of ageing has complex effects on 5-HT neurotransmission throughout central and peripheral system. Although there are no clear alterations in the number of 5-HT neurones, accumulated evidence suggest compromised 5-HT neurotransmission as well as altered expression of SERT and 5HT receptors in multiple brain regions. 4. Serotonin in Alzheimer’s disease 4.1. Serotonergic neurones in AD Alzheimer’s disease is associated with a decreased number of serotonergic neurones in the dorsal and the median raphe nuclei (Table 3) (Aletrino et al., 1992; Chen et al., 2000; Halliday et al., 1992; Kovacs et al., 2003; Yamamoto and Hirano, 1985). Postmortem studies on AD-affected brains consistently showed a reduced density of 5-HT neurones in the raphe nuclei (Lyness et al., 2003). Abundant Ab neuritic plaques and neurofibrillary tangles in the dorsal and median raphe nuclei of AD brains have been associated with rapid progression of clinical symptoms (Curcio and Kemper, 1984; Ebinger et al., 1987; German et al., 1987; Halliday et al., 1992). Patients with a family history of AD show increased raphe pathology associated with rapid progression of clinical symptoms (Halliday et al., 1992). AD-related demise of 5-HT neurones correlates with age and greater 5-HT neuronal loss is particularly evident at more advanced age (Hendricksen et al., 2004; Kovacs et al., 2003). Decreased density of 5-HT neurones has also been identified in a canine model of AD with Ab pathology and in the AbPPswe/PS1DE9 transgenic mice (Bernedo et al., 2009; Liu et al., 2008) but not in the triple transgenic (3xTg-AD) mouse model of AD (Noristani et al., 2010) (Table 3). Most studies of 5-HT neurones in AD brains have focused on the dorsal and the median raphe nuclei, which encompass the majority of 5-HT neurones that project to the neocortex and the hippocampus, among others (Vertes, 1991; Vertes et al., 1999). The major loss of serotonergic neurones occurs in the caudal part of the dorsal raphe nucleus (Zweig et al., 1988). These neurones provide 5-HT projections to the septum and the hippocampus, which are severely affected in AD. Earlier studies of the raphe nuclei relied upon using traditional stains, such as hematoxylin, eosin cresyl violet and Nissl staining (Aletrino et al., 1992; Burke et al., 1990; Curcio and Kemper, 1984; Halliday et al., 1992; Wilcock et al., 1988; Yamamoto and Hirano, 1985; Zweig et al., 1988). These early findings were subsequently confirmed by immunohistochemical studies using specific markers for 5-HT and notably TPH (Hendricksen et al., 2004; Kovacs et al., 2003). An early three-dimensional study of the dorsal raphe nucleus has revealed significant (40%) decrease in the number of 5-HT neurones in post-mortem AD brains (Aletrino et al., 1992). The midbrain raphe nuclei also show enhanced neurofibrillary tangle pathology, which may contribute to the death of serotonergic neurones (Chen et al., 2000; Curcio and Kemper, 1984; German

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24

Table 3 AD-associated changes in the number of serotonergic neurones: post-mortem and animal model studies. Method used

Age (AD)

N (AD)

Brain region/changes in number of neurones in serotonergic nuclei

Reference

Post-mortem studies Hematoxyline and eosin Nissl staining Cresyl violet staining

88 75 73

7 5 25

Curcio and Kemper (1984) Yamamoto and Hirano (1985) Zweig et al. (1988)

Nissl staining Hematoxyline and eosin

78 76

12 17

Nissl staining Nissl staining Immunohistochemisrty – TpH

74 75 82

8 11 12

Immunohistochemisrty – TpH

73

10

Immunohistochemisrty – TpH PET with [18F]altanserin and [(11)C]N, N-dimethyl-2-(2-amino-4-cyanopheylthio) benzylamine ([11C]DASB)

83 74

15 12

DR – no change DR – reduced to 23% of the control LC – reduction to 30%, 19% and 33% of the control for rostral, mid and caudal levels DR – reduction to 64% of the control only in caudal level CSN – no change DR – decrease in total number of neurones by 40% DR – levels of 5-HT and 5-HIAA were decreased by 41% and 50% respectively DR – overall number of neurones was reduced by 39% DR, MnR – total number of neurones reduced by 25% DR – density of neurones was reduced by 41% MnR – density of neurones was reduced by 29% MnR – significant decrease in the number of 5_HT synthesising neurones DR – 5-HT neurones density was reduced by 45% DR – in PET scanning no change in serotonin transporter binding probe was found (suggesting no change in number of 5-HT neurones/projections), however significant reduction (by 28–39%) in the binding of 5-HT2A receptor probe was observed in AD

Animal studies Immunohistochemisrty – TpH

Immunohistochemisrty – TpH

Immunohistochemisrty – 5-HT

Canine dog model of AD with Ab pathology Transgenic mouse model of AD with Ab pathology Transgenic mouse model of AD with Ab and tangle pathology

Wilcock et al. (1988) Burke et al. (1990) Aletrino et al. (1992) Halliday et al. (1992) Chen et al. (2000) Kovacs et al. (2003) Hendricksen et al. (2004) Marner et al. (2010a)

DR and MnR 33% reduction on serotonergic neurones in dogs with b-amyloid deposits

Bernedo et al. (2009)

50% loss of monoaminergic neurones in the forebrain

Liu et al. (2008)

DR and MnR – no changes

Noristani et al. (2010)

Key: Age: mean age, N: number of AD samples included in the study, H & E: hematoxyline and eosin, NS: nissl staining, CV: cresyl violet, IHC: immunohistochemisrty, TpH: tryptophan hydroxylase, LC: locus ceruleus, DR: dorsal raphe nucleus, CSN: central superior raphe nucleus, MnR: median raphe nucleus.

et al., 1987; Ishii, 1966; Kovacs et al., 2003; Yamamoto and Hirano, 1985; Zweig et al., 1988). Conceptually, the evolution of AD is divided into six stages (stage I–VI) (Braak and Braak, 1991). Cytoskeletal abnormalities such as hyperphosphorylation of tau cytoskeleton protein (measured by immunohistochemical staining against AT8) become evident early (stages I–II) in the dorsal raphe nucleus and may subsequently lead to the demise of 5-HT neurones (Hendricksen et al., 2004; Rub et al., 2000). In addition to 5-HT neuronal loss, severe shrinkage of the remaining 5-HT neurones has also been reported in AD brains (Aletrino et al., 1992). Although early studies suggested greater 5-HT neuronal loss in AD patients with concomitant depression (Halliday et al., 1992; Yamamoto and Hirano, 1985; Zweig et al., 1988), a more recent investigation has found the same degree of serotonergic neuronal death regardless of previous depression history (Hendricksen et al., 2004). This discrepancy may result from differences in methodological analysis of the raphe neurones (Kovacs et al., 2003). Indeed, whereas Zweig et al. (1988) had relied upon cresyl violet staining to quantify raphe neurones, Hendricksen et al. (2004) employed immunohistochemistry using specific antibody against TPH (see also Table 3). It is also possible that the profound neuronal losses reported by Zweig et al. (1988) reflected generalised death of nonserotonergic as well as serotonergic neurones (Michelsen et al., 2008). Stereological studies of post-mortem AD brains should be interpreted with care, as they are complicated by multiple factors including severity of dementia, volume reduction and the choice of the quantitative methods applied to study the 5-HT neuronal population. AD brains exhibit significant decreases in the grey matter volume (Dickerson et al., 2009; Thompson et al., 2001).

Therefore, it is important to include partial volume corrections as a measure of brain atrophy when quantifying neuronal density using stereology (for review see Coggeshall and Lekan, 1996). As mentioned above, quantitative immunohistochemical studies using 5-HT-specific antibodies have confirmed previous findings using traditional markers (Burke et al., 1990; Hendricksen et al., 2004). However, it is important to consider that immunohistochemical labelling also depends on the antibody penetration and tissue processing techniques (Chan et al., 1990). A PET study in AD patients at early stage of the disease has reported no overall changes in 5-HT neuronal density in midbrain raphe nuclei (Marner et al., 2010a). These findings are consistent with our data from studies in the 3xTg-AD mouse model of AD, which expresses Ab plaques and tau pathology in a spatio-temporal order resembling AD and exhibits pronounced deficits in cognitive function including learning and memory (Clinton et al., 2007; Frazer et al., 2008; Oddo et al., 2003a,b). Immunohistochemical labelling of 5-HT neurones in the dorsal and the median raphe nuclei of these mice showed no differences from age-matched controls for up to 18 months of age (Noristani et al., 2010). Conversely, in AbPPswe/PS1DE9 transgenic mice and canine model of AD with Ab pathology, a decrease in 5-HT neuronal aggregates was reported in the dorsal and median raphe nuclei (Bernedo et al., 2009; Liu et al., 2008). These discrepancies probably reflect differences in species (dog vs. mice) (Bernedo et al., 2009) and transgenic mouse lines (AbPPswe/PS1DE9 vs. 3xTg-AD) (Liu et al., 2008; Noristani et al., 2010). Early post-mortem studies have demonstrated that ADassociated degeneration of monoamine neurones is initiated at the axon terminals due to the accumulation of neurotoxins such as

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Ab at terminal sites (Marcyniuk et al., 1986; Burke et al., 1988). These neurotoxins are taken up by afferent axons and undergo retrograde transport to the neuronal cell bodies, (for review see Hardy et al., 1986). Accumulation of neurotoxins within neuronal cell bodies triggers cell detah (Hardy et al., 1986). Similarly, in the AbPPswe/PS1DE9 transgenic mouse model of AD, the deposition of Ab pathology is followed by degeneration of 5-HT axons at the projection site, which then progresses to 5-HT cell bodies in a retrograde manner (Liu et al., 2008). 4.2. Serotonergic neurotransmission in AD In AD, the decrease in the number of 5-HT neurones is accompanied with changes in 5-HT neurotransmitter levels in various regions of the brain (Table 4). Reduced levels of 5-HT and its metabolite 5-hydroxyindolacetic acid (5-HIAA) have been measured with high performance liquid chromatography (HPLC) in post-mortem AD brains (Garcia-Alloza et al., 2005; Gottfries, 1990). Levels of 5-HT were decreased in the temporal, frontal and parietal cortex as well as in the amygdala, caudate nucleus, putamen, raphe nucleus and the hippocampus (Bowen et al., 2008; Burke et al., 1990; Garcia-Alloza et al., 2005; Lai et al., 2002; Nazarali and Reynolds, 1992). Brain biopsies in AD patients also revealed significant reduction of 5-HT levels in the temporal and frontal cortex, which correlated with the progression of the disease (Table 4), see also (Bowen et al., 2008; Garcia-Alloza et al., 2005; Palmer et al., 1987), the rate of cognitive decline (measured using MMSE score) (Lai et al., 2002) as well as with behavioural symptoms including depression, aggressive behaviour and psychosis (Garcia-Alloza et al., 2005). PET studies using the selective 5HT1A antagonist radioligand [18F]MPPF revealed an increase in 5HT1A receptor binding potential in patients with mild cognitive impairment before the onset of AD symptoms, suggesting an upregulation of serotonergic metabolism (Truchot et al., 2008, 2007). A deficit in 5-HT neurotransmission seems to be somewhat specific for AD; in the frontotemporal dementia (FTD) both 5-HT levels and serotonergic projections appear to be relatively preserved despite massive loss of pyramidal neurones (Bowen et al., 2008).

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It has to be remembered, however, that post-mortem studies are prone to misinterpretation due to multiple experimental variables such as: (i) exclusive use of tissue deriving from patients at the late-stage of the disease, (ii) differences in pharmacological treatment (e.g. AChE inhibitors, antidepressants and anti-psychotics) and (iii) post-mortem delay (Chen et al., 1996; Meltzer et al., 1998a; Versijpt et al., 2003). Therefore, the use of animal models that reproduce AD pathology is of major importance for characterising specific alterations of neurotransmitter systems (including 5-HT) during the progression of the disease and the development of potential therapies (Gotz et al., 2004; Rodriguez et al., 2008, 2009a; Rodrı´guez et al., 2009b). 4.2.1. Serotonergic projections in AD Early reports suggested abnormal axonal arborisation in postmortem AD brains (Geddes et al., 1986; Masliah et al., 1991; Scheibel and Tomiyasu, 1978); however, to our knowledge, 5-HT projections have not yet been specifically examined in AD. In the AbPPswe/PS1DE9 double transgenic mice model, which develops severe amyloidosis, degeneration of serotonergic fibres was observed in the cortex, amygdala and the hippocampus between 12 and 18 months of age (Liu et al., 2008) (Table 5). However, a subsequent study in these mice revealed no alterations in SERT binding sites (measured using [3H]escitalopram radioligand) up to 11 months of age, despite Ab accumulation in the cortex and the hippocampus (Holm et al., 2010). In transgenic mice over-expressing the mutant amyloid precursor protein (APP, APP23), aberrant sprouting of non-5-HT axons was found in the hippocampus (Phinney et al., 1999). Neurotoxin lesions (achieved by injection of ibotenic acid and NMDA into the nucleus basalis magnocellular) and Ab accumulation in the striatum and in the hippocampus stimulated 5-HT fibre sprouting (Gasser and Dravid, 1987; Harkany et al., 2000, 2001; Zhou et al., 1995). An increased density of SERT-immunolabelled fibres has been also detected in hippocampus of the 3xTg-AD mouse model of AD (Noristani et al., 2010) (see also Fig. 2). Several processes may account for the stimulation of 5-HT fibre sprouting. Damage to either 5-HT or non-5-HT fibres (induced by

Table 4 AD-associated changes in the levels of 5-HT/5-HIAA: post-mortem and animal model studies. Marker/Technique

Age (years)

N (AD)

Brain region/levels of 5-HT/5-HIAA in % of the control

Reference

82 76

46 17

Palmer et al. (1987) Burke et al. (1990)

81

13

5-HT (HPLC) 5-HIAA (HPLC) 5-HT (HPLC)

81

20

82

17

5-HT (HPLC) 5-HIAA (HPLC) 5-HT (HPLC) 5-HIAA (HPLC)

81

20

74

9

FC – 65 for 5-HT, TC – 49 for 5-HT A – 59 for 5-HT, 50 for 5-HIAA DR – 215 for 5-HT, 118 for 5-HIAA TC – 37 for 5-HT, 63 for 5-HIAA CN – 45 for 5-HT, 51 for 5-HIAA A – 51 for 5-HT, 57 for 5-HIAA P – 64 for 5-HT, 81 for 5-HIAA FC – 94 for 5-HT, 144 for 5-HIAA TC – 70 for 5-HT, 117 for 5-HIAA FC – the paper indicates that the 5-HT levels were decreased but does not provide quantification FC – 45 for 5-HT, 47 for 5-HIAA TC – 48 for 5-HT, 40 for 5-HIAA FC – 75 for 5-HT, 99 for 5-HIAA TC – 118 for 5-HT, 140 for 5-HIAA PC – 55 for 5-HT, 87 for 5-HIAA

Post-mortem studies 5-HT (HPLC) 5-HT (HPLC) 5-HIAA (HPLC) 5-HT (HPLC) 5-HIAA (HPLC)

Animal studies 5-HIAA (HPLC) 5-HIAA (HPLC)

Transgenic mouse model of AD with Ab pathology Intrahippocampal injected Ab rat model

C – 74* H – 67* H – 152

Nazarali and Reynolds (1992)

Chen et al. (1996) Lai et al. (2002) Garcia-Alloza et al. (2005) Bowen et al. (2008)

Liu et al. (2008) Verdurand et al. (2011)

Key: Age: mean age, HPLC: high performance liquid chromatography, 5-HT: 5-hydroxytrptamine, 5-HIAA: 5-hydroxyindoiatic acid, N: number of AD samples included in the study, FC: frontal cortex, TC: temporal cortex, PC: parietal cortex, A: amygdala, CN: caudate nucleus, P: putamen, DR: dorsal raphe nucleus, C: cortex, H: hippocampus, nr: notreported. * Numbers were estimated from the graphs.

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Table 5 Serotonergic system in animal models of Alzheimer’s disease. AD model

Neuropathology

Brain region

5-HT alteration

Reference

APPswe/PS1DE9 APPSwe Intrahippocampal injected Ab rat model

Plaques Plaques Aggregated amyloid material

C, Am, H H H

Liu et al. (2008) Phinney et al. (1999) Verdurand et al. (2011)

Intrastriatal injected ibotenic acid rat model MBN injected NMDA rat model

Neurodegeneration

S

5-HT fibre degeneration Aberrant non-5-HT axonal sprouting Increased 5-HT activity within the vicinity of injection site Vigorous sprouting of 5-HT fibres

Increased APP expression + cholinergic lesion Cholinergic lesion Plaques Plaques and tangles

MBN

Abundant sprouting of 5-HT fibres within damaged area 5-HT fibre sprouting No change (4, 8 and 11 months) 65% increase in SERT-fibre density compare to controls (3 and 18 months)

Harkany et al. (2000)

MBN injected Ab(1–42) rat model AbetaPPswe/PS1dE9 3xTg-AD

MBN FC, PreC, H H

Zhou et al. (1995)

Harkany et al. (2001) Holm et al. (2010) Noristani et al. (2010)

From Noristani et al. (2011). Key: C: cortex, Am: amygdala, H: hippocampus, S: striatum, MBN: magnocellular nucleus basalis, NMDA: N-methyl-D-aspartate, APP: amyloid precursor protein, FC: frontal cortex, PreC: prefrontal cortex.

an injection of neurotoxins such as ibotenic acid or NMDA) can stimulate 5-HT fibre sprouting due to damage of neighbouring 5HT fibres (homotypic sprouting). 5-HT fibres also sprout in response to damage of non-5-HT fibres (heterotypic sprouting) in the forebrain, striatum and in the hippocampus (Gasser and Dravid, 1987; Harkany et al., 2000, 2001; Zhou et al., 1995). 5-HT fibre sprouting can also be triggered by an intracerebral injection of

Ab1–42 (Harkany et al., 2001). Chronic build-up of Ab plaques may likewise induce neurotoxicity resulting in neuronal damage that in turn may also stimulate sprouting of 5-HT fibres (Harkany et al., 2000, 2001). Alternatively, an increase in sprouting of serotonergic axons may be stimulated by reactive astrocytes present in the vicinity of Ab plaques (Olabarria et al., 2010; Rodrı´guez et al., 2009b; Verdurand et al., 2011). Astrocytic hypertrophy may also be

Fig. 2. Potential neuroprotective mechanism of 5-HT in Alzheimer’s disease. Increased 5-HT input at the vicinity of amyloid plaque may hyperpoarise neurones through activation of 5-HT1A/B receptors and subsequent opening of K+ channels. Hyperpolarisation in turn limits Ca2+ entry (and hence excitotoxicity) by closing voltage-gated calcium channels (VGCCs) and favouring Mg2+ block of NMDA receptors (NMDARs).

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associated with increased serotonergic fibre sprouting in the vicinity of Ab plaques (Noristani et al., 2010) (Fig. 2). Increased astroglial release of S-100b is another possible mechanism for inducing sprouting of 5-HT fibres. S-100b is a neurotrophic factor that is produced, stored and released by astrocytes and promotes the outgrowth of 5-HT fibres (Azmitia, 2001; Azmitia et al., 1990; Liu and Lauder, 1992; Whitaker-Azmitia et al., 1990). The gene for S-100b is located on chromosome 21, within the obligate region for Down’s syndrome neuropathological manifestations, many of which are similar to AD (Azmitia, 2001; Gulesserian et al., 2000). Enhanced expression of S-100b in the temporal lobe has been observed in the Down syndrome as well as in AD brains (Griffin et al., 1989). Increased expression of S-100b is most pronounced in young patients with Down’s syndrome (Griffin et al., 1989). Western blot analysis of frontal cortex also showed increased expression of SERT protein in Down’s syndrome (Gulesserian et al., 2000). A sprouting of 5-HT fibres has been observed in areas where reactive astrocytes showed increased staining for S-100b (Zhou et al., 1995). Transgenic mice with increased S-100b expression also display an increase in S-100bpositive astrocytes which is associated with increased serotonergic fibre density in the hippocampus (Shapiro et al., 2010). Furthermore, the number of S-100b-positive astrocytes correlates with the extent of 5-HT projections in the hippocampus of an aged rat (Nishimura et al., 1995). The density of 5-HT projections can also be regulated by brain derived neurotrophic factor (BDNF) and by 5HT itself (Azmitia, 2001; Mamounas et al., 2000). Ab-induced neurotoxicity involves an increased activation of the glutamatergic system with subsequent glutamate excitotoxicity (Brorson et al., 1995; Miguel-Hidalgo et al., 2002) and aberrant calcium homeostasis (Stutzmann, 2007; Supnet and Bezprozvanny, 2010). 5-HT inhibits glutamatergic neurotransmission in various regions of the brain including the hippocampus (Schmitz et al., 1998) and the spinal cord (Takahashi et al., 2001). Increased 5-HT input in AD, particularly in the vicinity of Ab plaques, might counteract NMDA-induced neurotoxicity via the inhibition of calcium currents and membrane hyperpolarisation (Fig. 2) (Harkany et al., 2000). These effects are mediated by the

27

activation of 5-HT1A and 5-HT1B receptors (Patel and Zhou, 2005; Peddie et al., 2008b). Consequently, an increased sprouting of 5HT fibres may be an intrinsic protective mechanism in response to Ab-induced excitotoxic damage in AD. 4.2.2. 5-HT receptors in AD In addition to a reduced number of 5-HT neurones and compromised 5-HT neurotransmission, there is also increasing evidence for AD-related changes in 5-HT receptors including 5HT1A, 5-HT1B, 5-HT1D, 5-HT2A and 5-HT6 receptors (Tables 6 and 7; see also Xu et al., 2012 for reviews). Different agonists and antagonists of 5-HT receptors have been proposed for treatment of cognitive impairments associated with AD (Terry et al., 2008; Upton et al., 2008). 4.2.2.1. 5-HT1A receptor. Table 6 summarises the changes in 5-HT1A receptor densities that have been related to AD. Initial studies (Bowen et al., 1983) that used [3H]-5-HT as radioligand reported reduced 5-HT1A receptor density in the frontal and temporal. Subsequent binding studies with [3H]-5-HT demonstrated 20–80% reductions in 5-HT1A receptor densities in the frontal, temporal and parietal cortex, raphe nuclei, amygdala and the hippocampus (Cross et al., 1984; Perry et al., 1984). On the contrary, other binding studies of post-mortem AD brains, using [3H]-5-HT and the 5-HT1A/7 receptor agonist [3H]8-OH-DPAT as radioligands, reported no AD-related changes in 5-HT1A binding sites in temporal cortex, neocortex and the hippocampus (Cross et al., 1986; Jansen et al., 1990; Lai et al., 2003b; Tsang et al., 2010) but an increase in the frontal cortex (Lai et al., 2002). In vivo PET studies using selective 5-HT1A antagonist radioligand [18F]MPPF are consistent with AD-related decreases in 5-HT1A receptor binding sites in raphe nuclei and the hippocampus of patients with mild AD (Kepe et al., 2006; Truchot et al., 2008). Subsequent in vitro autoradiography of AD brain specimens with [18F]MPPF confirmed earlier PET observations in the same patients, showing up to 60% decreases of 5-HT1A receptor binding sites in the hippocampus (Kepe et al., 2006). AD patients with pronounced decease in the hippocampal 5-HT1A receptor density had more severe disease

Table 6 AD-associated changes in 5-HT1A receptors: binding, PET and immunohistochemical studies. Radioligand/Marker

Age (years)

N (AD)

Brain region/5-HT1A receptor % of the control

Reference

Binding studies [3H]-5-HT [3H]-5-HT [3H]-5-HT [3H]8-OH-DPAT [3H]8-OH-DPAT [3H]-5-HT [3H]-5-HT [3H]-5-HT [3H]8-OH-DPAT [3H]8-OH-DPAT [3H]8-OH-DPAT

nr 79 79 72 82 78 72 77 81 82 82

nr nr 12 nr 24 13 5 8 33 35 17

FC – 52 PC – 74 FC – 85, TC – 53, H – 60, A – 48 FC – 53 H – 50 TC – no changes TC – no changes H – no changes FC, TC – no changes TC – no changes FC – increased density

Bowen et al. (1983) Perry et al. (1984) Cross et al. (1984) Middlemiss et al. (1986) Lai et al. (2011) Cross et al. (1986) Cross et al. (1988) Jansen et al. (1990) Lai et al. (2003a) Tsang et al. (2010) Lai et al. (2002)

Positron emission tomography studies [18F]MPPF 75 [18F]MPPF 77 18 [ F]MPPF 72 [18F]MPPF 70 [18F]MPPF 73

14 14 11 10 11 (aMCI)

H – 73, R – 59 H – 87 (aMCI) H – 65 H, InfOG – decreased binding potential H – increased binding potential

Kepe et al. (2006) Kepe et al. (2006) Truchot et al. (2007) Truchot et al. (2008) Truchot et al. (2008, 2007)

Immunohistochemical studies 5-HT1A

83

8

Yeung et al. (2010)

5-HT1A

77

11

PN – reduced density VN – reduced density R – reduced density H – reduced immunoreactivity

Mizukami et al. (2011)

Key: Age: mean age, N: number of AD samples included in the study, BS: binding studies, Au: autoradiography, PET: positron emission tomography, IHC: immunohistochemisrty, aMCI: amnesic mild cognitive impairment, FC: frontal cortex, PN: pontile nuclei, VN: vagal nucleus, TC: temporal cortex, PC: parietal cortex, A: amygdala, H: hippocampus, Neo: neocortex, R: raphe nucleus, InfOG: inferior occipital gyrus, nr: not reported.

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28

Table 7 AD-associated changes in 5-HT2A receptor: binding, imaging and immunohistochemical studies. Radioligand/Marker

Age (years)

N (AD)

Brain region/5-HT2A receptor % of the control

Reference

Binding studies [3H]-ketanserin [3H]-ketanserin [3H]-ketanserin [3H]-ketanserin [3H]-ketanserin [3H]-ketanserin [3H]-ketanserin [3H]-ketanserin [3H]-ketanserin [3H]-ketamine [3H]-ketanserin

79 79 78 72 nr 77 82 82 82 74 82

12 nr 13 5 nr 8 7 29 35 7 24

TC – 35, FC – 54, H – 67, A – 60 EC – 42, PC – 65 TC – 58 TC – 57 TC – 57–65, FC – 48–57 PC – 47–54, OC – 60 DG – 48, CA1 – 56, CA3 – 48, EC – 55 Tc – 52 FC – 62*, TC – 48* TC – 54–72 FC, H – no change H – no change

Cross et al. (1984) Perry et al. (1984) Cross et al. (1986) Cross et al. (1988) Procter et al. (1988) Jansen et al. (1990) Cheng et al. (1991) Lai et al. (2005) Tsang et al. (2010) Dewar et al. (1990) Lai et al. (2011)

Positron emission tomography, single photon emission computed tomography and magnetic resonance imaging studies 71 9 TC – 30*, FC – 30*, PC – 45*, OC – 65* PET – [18F]-setoperone PET – [18F]-altanserin 70 9 AnC – 90, PreC – 92, SC – 96 PET – [18F]-altanserin 74 12 OC – 62, PreC – 71 PET – [18F]-deuteroaltanserin 76 9 AnC – 58 SPECT – 123I-5-I-R91150 81 9 Orf – 84, PreC – 85, OC – 92 MRI – [18F]-altanserin 70 16 (aMCI) Neo – 20–30

Blin et al. (1993) Meltzer et al. (1999) Marner et al. (2010a) Santhosh et al. (2009) Versijpt et al. (2003) Hasselbalch et al. (2008)

Immunohistochemical studies 5-HT2A 5-HT2A

Lorke et al. (2006) Yeung et al. (2010)

88 83

6 8

PreC – 67 STN – reduced density

Key: Age: mean age, N: number of AD samples included in the study, BS: binding study, Au: autoradiography, PET: positron emission tomography, SPECT: single photon emission computed tomography, MRI: magnetic resonance imaging, IHC: immunohistochemistry, aMCI: amnesic mild cognitive impairment, FC: frontal cortex, TC: temporal cortex, PC: parietal cortex, PreC: prefrontal cortex, EnC: entrohinal cortex, OC: occipital cortex, Neo: neocortex, Orf: orbitofrontal, SC: somatosensory cortex, SM: sensorymotor, A: amygdala, H: hippocampus, DG: dental gyrus, CA1, CA3: cornus ammonus 1,3 areas of hippocampus, AnC: anterior singulate, STN: sensory trigeminal nuclei, nr: not reported. * Numbers were estimated from the graphs.

progression (measured using MMSE score) (Kepe et al., 2006). Similarly, the severity of decrease in 5-HT1A receptor density in the temporal cortex correlated with aggressive behaviour in AD patients (Lai et al., 2003b). A recent binding study, using 5HT1A/7 receptor agonist [3H]8-OH-DPAT has shown reduced hippocampal 5-HT1A receptors binding sites specifically correlates with the depressive symptoms associated with AD (Lai et al., 2011). Recent immunohistochemical study reports a decrease in 5HT1A receptor immunoreactivity (measured using optical density) in the hippocampus of AD brains (Mizukami et al., 2011), in keeping with the results of previous binding assays and PET imaging studies. In addition, this study supports earlier suggestions that 5-HT1A receptors are affected at the late-stage of AD pathology (Cross et al., 1984), since severe decrease in 5-HT1A receptor immunoreactivity were observed only in patients at Braak stages V–VI (Mizukami et al., 2011). Interestingly, three PET imaging studies with [18F]MPPF as a radioligand reported divergent alterations in 5-HT1A receptor binding sites in patients with mild cognitive impairments (Kepe et al., 2006; Truchot et al., 2008, 2007). The initial report demonstrated a decrease (Kepe et al., 2006), whereas subsequent studies have shown an increase in hippocampal 5-HT1A receptor binding sites in patients with mild cognitive impairment (Truchot et al., 2008, 2007). It is likely that the difference between the reported studies may be due to inclusion of a partial volume effect correction in the latter study to compensate for hippocampus atrophy (Truchot et al., 2007). In addition, the members of the control group used in the initial PET study by Kepe et al. (2006) were of a younger age compared to the patients with mild cognitive impairment (60 years in control vs. 77 years in mild cognitively impaired group), which may account for the difference between studies, especially in view of the previously reported ageassociated decreases in hippocampal 5-HT1A receptor binding (Dillon et al., 1991; Marcusson et al., 1984a). The major problem associated with imaging of the density of receptors is that changes in binding potential (BP) may reflect either

true changes in receptor density (Bmax), changes in receptor affinity (KD) or combination of both (Meltzer et al., 1999). Furthermore, due to limited spatial resolution, the accuracy of binding potentials measured by PET and SPECT imaging techniques can be affected by partial volume effects (Rousset et al., 1998). Partial volume effect should be particularly important in the case of AD, which is associated with severe cortical and hippocampal atrophy (Thompson et al., 2001, 2004). Furthermore, functional imaging fails to distinguish between metabolic changes and brain atrophy in case of neurodegenerative disease such as AD (Truchot et al., 2008). A decrease in 5-HT1A receptor density, associated with AD progression may reflect a compensatory mechanism to balance compromised cholinergic and glutamatergic neurotransmission. Given that cholinergic hypo function is the major pathological hallmark of AD and pharmacological inhibition of 5-HT1A receptors increases ACh release in multiple brain regions concomitant with enhanced cognitive function, AD-related decreases in 5-HT1A receptor density may result in reduction of the inhibitory tone of surviving ACh neurones and maintain the functional activity of ACh projections (Hirst et al., 2008; Kehr et al., 2010; Millan et al., 2004; Rada et al., 1993; Schechter et al., 2005). It is however important to note that reduced 5-HT1A receptor density has not been shown consistently in all post-mortem studies of AD (Table 6). The use of 5-HT1A receptor antagonists has given promising results in preclinical studies in rodents and non-human primates, as well as in the clinical trials of AD patients (Hirst et al., 2008; Luttgen et al., 2005a; Madjid et al., 2006; Millan et al., 2004; Misane and Ogren, 2003). 4.2.2.2. 5-HT2A receptors. Autoradiographic binding studies using 5-HT2A receptor antagonist [3H]-ketanserin have consistently demonstrated reductions in 5-HT2A receptor density in the temporal, frontal and parietal cortex as well as amygdala, entorhinal cortex and in the hippocampus of post-mortem AD brains (Table 7) (Cheng et al., 1991; Cross et al., 1986; Crow et al., 1984; Dewar et al., 1990; Procter et al., 1988). Reduced 5-HT2A

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receptor density has been further confirmed by PET (Blin et al., 1993; Marner et al., 2010a; Meltzer et al., 1999; Santhosh et al., 2009), SPECT (Versijpt et al., 2003) and magnetic resonance imaging (MRI) (Hasselbalch et al., 2008). In addition, AD-related deficits in 5-HT2A receptors were also found using immunohistochemistry with 5-HT2A receptor-specific antibody (Lorke et al., 2006). Decreases in 5-HT2A receptors in the temporal cortex have been correlated with cognitive decline as assessed by MMSE score (Lai et al., 2005). Furthermore, patients with mild cognitive impairment also exhibit a decline in 5-HT2A receptors density of approximately 12% per decade in the neocortex and the striatum (Hasselbalch et al., 2008; Versijpt et al., 2003). In rats, intrahippocampal injections of insoluble Ab1–42 aggregates induce memory impairments associated with a decrease in 5-HT2A receptor protein level as measured by Western blot analysis (Christensen et al., 2008). A recent in vitro autoradiography study with the selective 5-HT2A receptor antagonist [3H]MDL100907 has also reported reduced 5-HT2A receptor binding in the medial prefrontal cortex of the AbPPswe/PS1dE9 double transgenic mouse model of AD with excessive amyloidosis (Holm et al., 2010). Reduced 5-HT2A receptor binding is directly correlated with increased Ab plaque burden in the AbPPswe/PS1dE9 transgenic mouse model of AD, as demonstrated by [11C]PIB binding to Ab plaques (Holm et al., 2010). Taken together, these two preclinical studies suggest that AD-related decreases in 5HT2A receptors are due to neurophatological accumulation of Ab1– 42 deposits (Christensen et al., 2008; Holm et al., 2010). Given that activation of 5-HT2A receptors increases ACh and glutamate release and enhances learning and memory (Harvey, 1996, 2003; Aghajanian and Marek, 1999), decreases in 5-HT2A receptors density may contribute to cognitive deficits associated with AD. Indeed, agonists of 5-HT2A receptors show pro-cognitive effects in different behavioural tasks (Alhaider et al., 1993; Harvey et al., 2004; Meneses and Hong, 1997a; Romano et al., 2010; Welsh et al., 1998). 4.2.2.3. Other 5-HT receptors. The progression of AD is also associated with reduction in densities of 5-HT1B, 5-HT1D and 5HT6 receptors (Garcia-Alloza et al., 2004; Lorke et al., 2006). These

29

receptors are down regulated in frontal, temporal (especially 5HT1B and 5-HT1D) and prefrontal cortex (5-HT6) (Garcia-Alloza et al., 2004; Lorke et al., 2006). Deficits in 5-HT1B and 5-HT1D receptors correlate well with cognitive impairments in AD as assessed by the MMSE score (Garcia-Alloza et al., 2004). No alterations in 5-HT3 receptor binding have been observed in autoradiographic studies of AD brains with the 5-HT3 receptor radioligand [3H](S) zacopride (Barnes et al., 1990). Early in vitro binding studies using the radiolabelled 5-HT4 receptor antagonist [3H]-GR 113808 reported a decrease in 5-HT4 receptor binding sites in the temporal, frontal and prefrontal cortex as well as the hippocampus of AD brain specimens (Reynolds et al., 1995; Wong et al., 1996). On the other hand, a subsequent binding study using the same radioligand reported no decrease in 5-HT4 receptor binding sites in the temporal and frontal cortex (Lai et al., 2003a). A more recent binding study with [3H]-GR 113808 reports decreased 5-HT4 receptor binding sites in the temporal cortex of a relatively small subgroup of AD brains (n = 9) from patients who had been previously diagnosed with hyperphagia, but no changes in AD patients without hyperphagia (n = 26, Tsang et al., 2010). 4.3. Serotonin transporter in AD Significant decreases in serotonin transporter (SERT) binding sites were usually observed in the temporal cortex, frontal cortex and the hippocampus (Table 8). AD patients with an early onset of the disease (50–60 years of age) showed the most prominent decreases in SERT binding sites (Bowen et al., 1983). Imaging studies have confirmed the reductions in SERT binding at early stages of the disease (Ouchi et al., 2009). Reduced SERT density does not appear to correlate with concomitant behavioural symptoms such as anxiety and depression (Tsang et al., 2010). Transmembrane 5-HT transport depends on a functional polymorphism within the promoter region of the SERT gene (Borroni et al., 2006; Seripa et al., 2008). This polymorphism is responsible for the ‘‘short’’ and the ‘‘long’’ variants of the SERT promoter. The transcriptional activity of the ‘‘short’’ variant is significantly reduced compared to the long variant (Assal et al., 2004). The relatively high frequency of the ‘‘short’’ variant of the

Table 8 AD-associated changes in SERT density: binding, PET and animal studies. Radioligand/Marker

Age (years)

N (AD)

Brain region/SERT density % of the control

Reference

Binding studies BS – [3H]-imipramineBS – [3H]-5-HT

69

13

Bowen et al. (1983)

BS – [3H]-paroxetine BS – [3H]-citalopram

81 81

20 22

BS – [3H]-paroxetine BS – [3H]-paroxetine [3H]citalopram BS – [3H]-citalopram

82 74 82 82

14 9 24 35

TC – 72–81 for [3H]-imipramine 62 for [3H]-5-HT FC – 81, TC – 63 FC – 88* TC – 59* FC – 53 FC – 63, TC – 100, PC – 42 H – 70 No change

Positron emission tomography studies PET – [DASB] PET – [18C]DASB

61 74

7 (AD + D) 12

M – 67, NAc – 63, P – 62, T – 68 PreC – 88 OC – 77 mTC – 67

Ouchi et al. (2009) Marner et al. (2010a)

Western blot study SERT

61

7

FC – 102, Ce – 86

Gulesserian et al. (2000)

H – 161 at 3 months, 174 at 18 months

Noristani et al. (2010)

Animal model study IHC – SERT

Transgenic mouse model of AD with Ab and tangle pathology

Chen et al. (1996) Tsang et al. (2003) Thomas et al. (2006) Bowen et al. (2008) Lai et al. (2011) Tsang et al. (2010)

Key: Age: mean age, N: number of AD samples included in the study, BS: binding studies, WB: Western blots, IHC: immunohistochemisrty, TC: temporal cortex, FC: frontal cortex, PreC: prefrontal cortex, PC: parietal cortex, OC: occipital cortex, mTC: mesial temporal cortex, Ce: cerebellum, M: midbrain, NAc: nucleus accumbens, P: putamen, T: thalamus, H: hippocampus. * Numbers were estimated from the graphs.

30

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SERT promoter polymorphism has been suggested to be associated with an increased risk of AD in the Caucasian population (Hu et al., 2000). Low expression of SERT results in abnormal 5-HT homeostasis/transmission in the hippocampus and correlates with the cognitive impairment associated with AD (Hu et al., 2000). Some studies have linked the polymorphism of the SERT promoter with AD-related behavioural symptoms including aggression and psychosis (Borroni et al., 2006; Sukonick et al., 2001). A recent study in the Caucasian population has, however, failed to find any association between polymorphism of the SERT promoter and increased risk of AD (Seripa et al., 2008), as previously found in similar analysis of Latin American and Japanese populations (Forero et al., 2006; Kunugi et al., 2000). 5. Serotonergic neurotransmission in non-AD dementia Vascular dementia (VaD) is another common form of dementia (Geldmacher and Whitehouse, 1996). VaD is a consequence of cerebrovascular injury such as stroke and ischemia (Elliott et al., 2009; Kalaria et al., 2004). Epidemiological studies have reported various incidence rates for VaD depending on the geographical location, ranging between 15% and 20% in Europe and Canada to 27–38% in Asia. Similar to AD, there is a higher prevalence of VaD in people with lower levels of education (Di Carlo et al., 2002; Liu et al., 1998; Ott et al., 1995). However, unlike AD, the incidence of VaD does not increase with advanced age (Brayne et al., 1995; Liu et al., 1998; Ott et al., 1995). Some studies have reported impaired 5-HT neurotransmission in VaD (Elliott et al., 2009; Gottfries, 1990; Tohgi et al., 1995), whilst others reported no difference (Hansson et al., 1996). The level of 5-HT is decreased in the cerebrospinal fluid of patients with VaD (Tohgi et al., 1995). A post-mortem study has reported reduced levels of the 5-HT metabolite (5-HIAA) in the caudate nucleus and the hippocampus of VaD brains (Wallin et al., 1989). An early binding study using [3H]-paroxetine, [3H]8OH-DPAT and [3H]-ketanserin as radioligands reported no changes in SERT, 5-HT1A and 5-HT2A receptor binding sites in the frontal and temporal cortex as well as the caudate nucleus of VaD brains (Hansson et al., 1996). However, a more recent study using (3H)WAY 100635 and [3H]-ketanserin as radioligands demonstrated increased 5-HT1A and 5-HT2A receptor binding sites in the temporal cortex (Elliott et al., 2009). 5-HT1A receptor binding correlated with preserved global cognition and memory function, suggesting that up-regulation of these receptors was associated with preserved cognitive function (Elliott et al., 2009). Frontotemporal lobar degeneration is a progressive form of dementia that is characterised by a relatively selective atrophy of frontotemporal cortex (Garibotto et al., 2010). In frontotemporal lobar degeneration, changes in 5-HT neurotransmission are primarily postsynaptic and include reduced density of cortical 5-HT1A and 5-HT2A receptors (Bowen et al., 2008; Franceschi et al., 2005; Lanctot et al., 2007). Loss of 5-HT1A and 5-HT2A receptors is probably associated with the degeneration of cortical pyramidal neurones (Franceschi et al., 2005). No changes in levels of 5-HT, 5HIAA and SERT expression have been found in frontotemporal lobar degeneration, which could account for the negligible therapeutic effects of paroxetine in the treatment of this disorder (Bowen et al., 2008; Deakin et al., 2004). Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterised by the degeneration of corticospinal, brain stem and spinal cord motor neurones (Rowland and Shneider, 2001). ALS-associated changes in 5-HT neurotransmission include alterations in 5-HT and 5-HIIA concentrations and a decrease in 5-HT receptor binding sites including 5-HT1A and 5HT2A receptors in the spinal cord (for review see Sandyk, 2006).

Contradictory results have been reported regarding ALSassociated alterations in 5-HT and 5-HIAA. Some post-mortem studies did not find any changes in the levels of 5-HT and 5-HIAA in the spinal cord of deceased ALS patients (Forrest et al., 1996; Ohsugi et al., 1987), whereas Bertel et al. (1991) reported no changes in 5-HT concentration, but reduced 5-HIAA concentration; in yet another study Sofic et al. (1991) measured decreases in both 5-HT and 5-HIAA. ALS patients display reduced levels of tryptophan (5-HT precursor) in the plasma and cerebrospinal fluid, which may result in decreased 5-HT synthesis in the brain (Monaco et al., 1979). Quantitative autoradiographic study using [3H]8-OH-DPAT and [3H]-ketanserin as radioligands have shown reduced 5-HT1A/7 and 5-HT2A receptor binding sites in postmortem ALS spinal cords (Forrest et al., 1996). A recent PET study using the selective radioligand [11C]-WAY100635 has also reported reduced 5-HT1A receptor binding sites in the frontotemporal and cingulate cortex as well as midbrain of ALS patients (Turner et al., 2007, 2005). 6. The serotonergic system as a potential therapeutic target in AD The majority of drugs used for the treatment and management of AD act by reducing the cholinergic deficit (Dringenberg, 2000). However, cholinesterases inhibitors (AChEIs) have limited effects in improving cognitive deficits (for reviews see Clegg et al., 2001; Raina et al., 2008; Takeda et al., 2006). Several studies have examined the effects of 5-HT drugs on cognitive function in AD (Table 9). Whereas some clinical studies demonstrated significant improvements in cognitive function following treatment with selective SERT inhibitors (SSRIs) (Mossello et al., 2008; Mowla et al., 2007; Roth et al., 1996; Rozzini et al., 2010; Schneider et al., 1991; Taragano et al., 1997), others failed to detect pro-cognitive effects (Lyketsos et al., 2003; Munro et al., 2004; Nyth and Gottfries, 1990; Rao et al., 2006). Factors accounting for differences in clinical outcome include a great heterogeneity in clinical designs and notably (i) duration of treatment, (ii) number of patients in the trial, (iii) selection of patients at different stages of disease, (iv) drug dosage and (v) concomitant effects of other drugs (de Vasconcelos Cunha et al., 2007). An international double-blind, placebo-control trial showed a protective effect of moclobemide (a reversible monoamine oxidase inhibitor) towards cognitive impairments in AD subjects with depressive symptoms (Roth et al., 1996). Antidepressant treatments also result in improved cognitive function in nondemented elderly-depressed subjects (Butters et al., 2000; Rocca et al., 2005) and in depressed elderly patients with concomitant dementia (Nyth et al., 1992). Clinical trials using SSRIs demonstrated consistent improvement of behavioural symptoms associated with AD, including depression, agitation, irritability, anxiety, affective symptoms and aggressive behaviour (see Table 9). A recent study by Mizukami et al. (2009) also reported improvements of behavioural symptoms associated with AD following treatment with milnacipram (a selective 5-HT and noradrenalin reuptake blocker). Another approach to improve cognitive deficits involves the simultaneous stimulation of cholinergic and 5-HT neurotransmitter systems (Abe et al., 2003; Dringenberg, 2000; Smith et al., 2009; Toda et al., 2003). Combined treatment with inhibitors of acetylcholinesterase (AChE) and SERT increases cerebral metabolism and induces significant improvements in memory and cognition (Finkel et al., 2004; Mossello et al., 2008; Rozzini et al., 2010; Smith et al., 2009). Clinical studies also reported an improvement in the performance of the daily activity in AD patients receiving treatment with cholinesterase inhibitors (AChEIs) and SSRIs (Lyketsos et al., 2003; Mowla et al., 2007;

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31

Table 9 Serotonomimetic drugs in AD treatment. Patients

Drug tested (dose)

Study duration

AD-B

Citalopram, SSRI, (10–30 mg/day) AChEI + MAOI (10 mg/day)

4 weeks

Age (years)

Effect on cognitive function

Effect on other behaviour

Reference

65

77

Improved ADL

Improved behaviour symptoms

Nyth and Gottfries (1990)

4 weeks

14

<60

7 weeks

694

74

Improved agitation and depressive behaviour Improved depressive behaviour

Schneider et al. (1991)

Moclobemide, reversible MAOI, (400 mg/day) Fluoxetine, SSRI (10 mg/day) Setraline, SSRI, (25–100 mg/day) Setraline, SSRI, (25–150 mg/day) Fluoxetine, SSRI (10–40 mg/day) Citalopram, SSRI, (10–20 mg/day) Setraline hydrochloride, SSRI, (25–150 mg/day) Setraline, SSRI, (nr)

Roth et al. (1996)

6 weeks 8 weeks 12 weeks 6 weeks 17 days 12 weeks

18 17 22 41 31 44

72 88 77 70 81 76

Improved episodic memory Reduced cognitive disturbance Improved MMSE nr Less decline in ADL nr nr Improved ADL

Improved Improved Improved Improved Improved Improved

Taragano et al. (1997) Magai et al. (2000) Lyketsos et al. (2000) Petracca et al. (2001) Pollock et al. (2002) Lyketsos et al. (2003)

14 weeks

44

nr

Improved depressive behaviour

Munro et al. (2004)

AD-B

AChEI + setraline, SSRI, (50–200 mg/day)

36 weeks

124

Improved verbal learning in women but not men AD patients nr

Finkel et al. (2004)

AD-D

Escitalopram, SSRI, (10–20 mg/day) Venlafaxine, SNRI, (38–131 mg/day) Rivastigmine, AChEI (6–12 mg/day) + Flouxetine, SSRI, (20 mg/day) AChEIs + SSRI (nr)

8 weeks

15

50–90

Improved irritability, anxiety, aggitaion, affective symptoms and aggressive behaviour Improved depressive behaviour

6 weeks

14

78

12 weeks

41

55–85

9 months

72

78

12 weeks

14

36 weeks 9 months

AD-D AD-D AD-D AD-D AD-D AD-D AD-B AD-D AD-D

AD-D AD

AD-D

AD-D AD-B AD-D

Milnacipram, SNRI, (15–30 mg/day) Citalopram, SSRI, (5–30 mg/day) AChEIs + SSRI, (5-50 mg/day)

N (AD)

>50

No direct improvement in cognition nr

depressive depressive depressive depressive depressive depressive

behaviour behaviour behaviour behaviour behaviour behaviour

Improved depressive behaviour Significant improvement in depressive behaviour

74

Improved MMSE, memory, ADL and global functioning Improved cognitive performance and less cognitive decline nr

34

nr

nr

66

76

Preserved cognitive function

Rao et al. (2006) de Vasconcelos Cunha et al. (2007) Mowla et al. (2007)

Improved depressive behaviour

Mossello et al. (2008)

Improved depressive behaviour

Mizukami et al. (2009)

Improved irritability without sedation Improved depressive behaviour

Siddique et al. (2009) Rozzini et al. (2010)

Key: SSRI: selective serotonin reuptake inhibitor, AChEIs: acetylcholinesterase inhibitors, SNRI: selective serotonin and noradrenaline reuptake inhibitor, AD-D: Alzheimer’s disease patients with depression, AD-B: Alzheimer’s disease patients with behavioural symptoms (irritability, apathy and delusion but without depression), MMSE: MiniMental State Examination, MAOI: monoamine oxidase inhibitor, ADL: activity of daily living, nr: not reported.

Nyth and Gottfries, 1990). Studies by Abe et al. (2003) led to the development of a novel compound for the dual enhancement of cholinergic and 5-HT systems. This drug works by simultaneously inhibiting AChE and SERT in the brain (for recent review see Toda et al., 2010). In mice and rats, simultaneous improvements in memory tasks have been observed following oral administration of this compound (Abe et al., 2003; Toda et al., 2010). It is unclear whether the combined treatments with AChEIs and SSRIs act independently and/or synergistically in AD (Finkel et al., 2004; Lyketsos et al., 2003). There are two main hypotheses to explain the effect of serotonomimetic drugs as cognitive-enhancers in AD (Rozzini et al., 2010): (i) a direct action on neurotransmitter balance, where increased 5-HT interacts with ACh, which subsequently improves cognition and (ii) a decline in depressive symptoms, which then accounts for improvment in cognitive functions (Nyth et al., 1992; Roth et al., 1996). However, other groups found no association between the improved mood and cognitive functions in depressed AD patients treated with tricyclic antidepressants (clomipramine) (Petracca et al., 1996) or the SSRI (sertraline) (Munro et al., 2004). A recent clinical study has clearly shown that treatment with a SSRI resulting in better preservation of cognitive functions acted, independently from its beneficial effects on the reduced depressive symptoms in AD (Mossello et al., 2008). Further randomised clinical trails of adequate design, duration and sample size will be required to justify the use of serotonomimetic drugs in the treatment of AD. In vitro, 5-HT has been shown to stimulate the nonamyloidogenic processing of APP metabolites (APPS) (Nitsch et al., 1996; Robert et al., 2001). Other in vitro studies have

shown that the SSRI paroxetine reduced APP translation and lowered pathogenic Ab peptide secretion (Morse et al., 2004; Payton et al., 2003). Administration of the commonly prescribed SSRI citalopram or the tricyclic antidepressant imipramine facilitates APPS secretion in vitro and might potentially prevent Ab accumulation in AD (Pakaski et al., 2005). These findings are supported by an in vivo study in which chronic administration of the 5-HT2A/2C agonist dexnorfenfluramine (DEXNOR) was found to increase APPS in the CSF and to reduce Ab secretion in primary basal forebrain neuronal culture of guinea pig (Arjona et al., 2002). Given that released APP is no longer available for the amyloidogenic accumulation mediated by the cleavage of b- and gsecretases, increased serotonergic input by SSRI might alleviate AD-related neuropathology (Arjona et al., 2002). Acute administration of SSRIs including fluoxetine, desvenlafaxine and citalopram reduces Ab levels in the brain interstitial fluid in the PS1APP transgenic mouse model of AD (Cirrito et al., 2011). Direct 5-HT infusion into the hippocampus has the same effect decreasing interstitial fluid Ab (Cirrito et al., 2011). Chronic treatment with SSRI (citalopram) reduces Ab plaque burdens in the cortex and in the hippocampus in the PS1APP transgenic mouse model (Cirrito et al., 2011). Furthermore, chronic treatment with SSRI (paroxetine) reduces AD-related histopathology (Ab plaques and NFT) in the cortex and the hippocampus, which is also associated with improved memory performance in the 3xTg-AD mouse model of AD (Nelson et al., 2007). A recent preliminary clinical study has found that exposure to SSRI antidepressants (for a minimum of 5 years) reduced Ab plaque load in cognitively normal individuals (Cirrito et al., 2011). These studies indicate that serotonomimetic

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of the Czech Republic (GACR 309/09/1696) to JJR and (GACR 305/ 08/1381 and GACR 305/08/1384) to AV; the Spanish Government, Plan Nacional de I+D+I 2008-2011 and ISCIII- Subdireccio´n General de Evaluacio´n y Fomento de la investigacio´n (PI10/02738) to JJR and AV and the Government of the Basque Country grant (AE2010-1-28; AEGV10/16) to JJR. The authors would also like to thank BBSRC for PhD studentship to H.N. Noristani. References

Fig. 3. Schematic illustration of the clinical effects of serotonomimetic drugs in Alzheimer’s disease patients with and without behavioural symptoms, respectively. Combined selective 5-HT reuptake inhibitors (SSRI) and acetylcholinestarase inhibitors (AChEI) treatment improves not only behavioural/depressive symptoms but also reduces cognitive decline whilst enhancing learning, memory and improved activity of daily living, just improves cognition in AD patients without any effect on depressive behaviour.

drugs might be useful not only for the treatment of the behavioural disturbances and cognitive impairments associated with AD, but may also alleviate the histopathology of the disease. In summary (Fig. 3), beneficial effects of serotonomimetic drugs include an improvement in behavioural/depressive symptoms, which may subsequently (i) enhance learning and memory, (ii) reduce cognitive decline and (iii) improve the quality of life, ultimately leading to an improved cognitive performance in AD patients. Early indications from in vitro and in vivo studies suggest that serotonomimetic drugs may also influence Ab accumulation. The use of transgenic animal models with AD-related neuropathological characteristics and cognitive impairment will be of critical importance for uncovering the exact link between altered 5-HT neurotransmission and its effect on cognition and AD neuropathology. 7. Conclusion Serotonergic neurotransmission plays an important role in memory, both directly and via modulation of other transmitter systems. A dysfunctional serotonergic system is implicated in the pathophysiology of various mental illnesses including depression, anxiety and schizophrenia. Accumulating evidence emphasises the involvement of the 5-HT system in AD. The link between impaired 5-HT neurotransmission and AD is further supported by imaging studies using PET, SPECT and MRI in living AD patients throughout the progression of the disease. Deficits in serotonergic neurotransmission correlate with clinical symptoms associated with AD including memory impairment. Treatment with serotonomimetic drugs (MAOIs and SSRIs) improves various behavioural and cognitive abnormalities associated with AD. Acknowledgements This work was supported by Alzheimer’s Research Trust Programme Grant (ART/PG2004A/1) to JJR and AV. Grant Agency

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