Assemblies of glutamate receptor subunits with post-synaptic density proteins and their alterations in Parkinson’s disease

A. Bjorklund and M. A. Cenci (Eds.)

Progress in Brain Research, Vol. 183

ISSN: 0079-6123

Copyright � 2010 Elsevier B.V. All rights reserved.

CHAPTER 9

Assemblies of glutamate receptor subunits with post-synaptic density proteins and their alterations in Parkinson’s disease Fabrizio Gardoni†, Veronica Ghiglieri‡, Monica di Luca† and Paolo Calabresi
,‡,§ †

Department of Pharmacological Sciences, University of Milano, Milano, Italy

‡ Fondazione Santa Lucia IRCCS, Rome, Italy

§ Clinica Neurologica, Università degli Studi di Perugia, Ospedale S. Maria della Misericordia, Perugia, Italy

Abstract: N-methyl-D-aspartate (NMDA) receptors have been implicated as a mediator of neuronal injury associated with many neurological disorders including ischemia, epilepsy, brain trauma, dementia and neurodegenerative disorders such as Parkinson’s disease (PD) and Alzheimer’s disease. To this, non­ selective NMDA receptor antagonists have been tried and have been shown to be effective in many experimental animal models of disease, and some of these compounds have moved into clinical trials. However, the initial enthusiasm for this approach has waned, because the therapeutic index for most NMDA antagonists is quite poor, with significant adverse effects at clinically effective doses, thus limiting their utility. More recently, the concept that the exact pathways downstream NMDA receptor activation could represent a key variable element among neurological disorders has been put forward. In particular, variations in NMDA receptor subunit composition could be important in different disorders, both in the pathophysiological mechanisms of cell death and in the application of specific symptomatic therapies. As to PD, NMDA receptor complex has been shown to be altered in experimental models of parkinsonism and in PD in humans. Further, it has become increasingly evident that the NMDA receptor complex is intimately involved in the regulation of corticostriatal long-term potentiation, which is altered in experimental parkinsonism. The following sections will examine the modifications of specific NMDA receptor subunits as well as post-synaptic associated signalling complex including kinases and scaffolding proteins in experimental parkinsonism. These findings may allow the identification of specific molecular targets whose pharmacological or genetic manipulation might lead to innovative therapies for PD.




Corresponding author.

Tel.: þ39-075 5784230; Fax: þ39-075 5784229;

E-mail: [email protected]

DOI: 10.1016/S0079-6123(10)83009-2

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Keywords: Striatum; Synaptic plasticity; NMDA receptor; Post-synaptic density; Experimental parkinsonism

Molecular and functional interactions between glutamate receptors and dopamine (DA) receptors regulate an incredible variety of functions in the brain and, when abnormal, they contribute to and underlie numerous central nervous system (CNS) diseases. Cross-talk between DA and glutamate signalling is relevant in a variety of different functions as motor control, cognition and memory, neurodegenerative disorders, schizophrenia and addiction. On this view, a huge number of studies have been performed in the last decade in the attempt of understanding the molecular and functional mechanisms coordinating functions of glutamate and DA receptors. There is a general agreement that an integrated interplay between DA and glutamate is essential to drive correct motor behaviours. In the striatum, dopaminergic terminals from the substantia nigra pars compacta converge with glutamatergic signals from the cortex on dendritic spines of striatal medium spiny projecting GABAergic neurons. Therefore, the striatum is thought to be a primary substrate for numerous forms of learning and memory and for controlling behavioural output. This critical role of striatum in basal ganglia relies also on the close interactions between medium spiny neurons and several subtypes of interneur­ ons, including three subtypes of GABAergic neu­ rons and large aspiny cholinergic interneurons that receive a powerful excitatory input from cor­ tex and exert a modulatory action on striatal synaptic transmission through pre- and post­ synaptic mechanisms and thus also affecting the function of glutamatergic system (Brown and Arbuthnott, 1983; Centonze et al., 2001; Cepeda et al., 1993; Garcia-Munoz et al., 1991; Kerkerian et al., 1987; Mitchell and Doggett, 1980; Rowlands and Roberts, 1980) Thus, the integrative action exerted by striatal projection neurons on the con­ verging information arising from the cortex, nigral DA neurons and interneurons shapes the activity

of neurons throughout the entire basal ganglia circuitry. It is well known that Parkinson’s disease (PD) is a neurodegenerative disorder characterized by a mas­ sive degeneration of the dopaminergic neurons of the substantia nigra pars compacta. The progressive neurodegeneration of nigrostriatal terminals leads to a depletion of DA in the striatum altering the above-described basal ganglia functioning and is subsequently responsible for most of the PD motor symptoms such as akinesia, rigidity and tre­ mor. The degeneration of the nigrostriatal pathway in PD leads also to significant morphological and functional modifications in the striatal neuronal circuitry such as over-activity of the corticostriatal glutamatergic pathway (Centonze et al., 2005). At molecular level, the sub-cellular organization and the functional interactions of glutamate receptors within the striatum appear to be crucial in the patho­ genesis of PD (Picconi et al., 2004) as well as in the development of L-DOPA-induced dyskinesia (Gardoni and Di Luca, 2006; Hallett et al., 2006). In particular, alterations of N-methyl-D-aspartate (NMDA)-type glutamate receptors localization in striatum have been described in DA-denervated rats (Picconi et al., 2004), as well as in L-DOPA­ treated dyskinetic rats and monkeys (Gardoni and Di Luca, 2006; Hallett et al., 2006). Accordingly, it has been suggested that the normalization of corticostriatal glutamatergic transmission in the PD brain could potentially prevent functional alterations at the dendritic spines of striatal project­ ing neurons (Gardoni et al., 2009a).

Alterations of the NMDA receptor complex in experimental PD The NMDA-type glutamate receptors are abun­ dant, ubiquitously distributed throughout the CNS, fundamental to excitatory glutamatergic

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transmission and critical for normal brain func­ tion. NMDA receptors are oligomeric complexes formed by the co-assembly of members of three receptor subunit families: NR1, NR2 subfamily and NR3. NMDA receptors are enriched in the post-synaptic density (PSD) of the glutamatergic synapse, an electron dense and highly differen­ tiated structure associated with the post-synaptic membrane. The PSD consists of numerous scaffolding cytoskeletal and signalling proteins, some of which are in close contact with the cyto­ plasmic domain of glutamate ionotropic receptors in the post-synaptic membrane. This accumulation of NMDA receptors at the post-synaptic sites ensures a rapid response to neurotransmitter release and provides a molecular mechanism for linking the transmembrane ion flux to the signal­ ling machinery responsible for specific second messenger pathways. In the last decade, the increasing knowledge of the structure and func­ tion of the excitatory glutamatergic PSD (Gardoni et al., 2009a) has led to the identification of key protein families, such as PSD-MAGUKs (membrane-associated guanylate kinases), that play a fundamental role in governing NMDA receptor localization at synapse and, consequently, glutamate receptor function (Gardoni et al., 2009a). Thus, understanding the molecular mechanisms regulating the correct assembly of the NMDA receptors at synapses is a challenge in our comprehension of the strength of glutamater­ gic synapse in physiological and pathological con­ ditions. In other words, the localization of NMDA receptors in the PSD has a key role in the modula­ tion of the response of the post-synaptic neuron to different stimuli, both in activity-dependent synap­ tic plasticity and in cell death (Gardoni, 2008). CNS diseases are often characterized, at least in the early stages of the disease, by alterations in synaptic function/plasticity at the excitatory gluta­ matergic synapse without the concomitant occur­ rence of massive neuronal cell death. These alterations represent a key initial pathogenic event especially in some neurodegenerative disor­ ders such as Alzheimer’s disease (AD) and PD. Of

relevance, modifications of synaptic plasticity par­ alleled by alterations of NMDA receptor complex, molecular composition and function have been recently described in several CNS disorders such as AD, PD, Huntington’s disease (HD) and epi­ lepsy. Concerning to PD, it has become increas­ ingly evident that in striatal spiny neurons, NMDA receptor complex is intimately involved in the reg­ ulation of corticostriatal long-term potentiation (LTP) (Calabresi et al., 1996) and is altered in experimental parkinsonism (Dunah et al., 2000; Ingham et al., 1998; Ulas and Cotman, 1996). Early studies evaluated NMDA receptor abun­ dance, composition and phosphorylation in the rat lesioned with 6-hydroxydopamine (6-OHDA) as a model of parkinsonism. Dunah and co-workers (2000) found in the lesioned striatum a decrease of the abundance of NR1 and NR2B subunits of NMDA receptor in striatal membranes compared to the unlesioned striatum; conversely, the abun­ dance of NR2A was unchanged (Dunah et al., 2000; Ingham et al., 1998). Further studies in the 6-OHDA model showed similar results and corre­ lated the alteration of NMDA receptor composition at synapses with the reduction of corticostriatal synaptic plasticity (Gardoni et al., 2006; Picconi et al., 2003, 2004). In particular, NR2B subunit was specifically reduced in synaptic fraction purified from 6-OHDA rats when compared with sham­ lesioned rats in the absence of parallel alterations of NR1 and NR2A (see Fig. 1) (Gardoni et al., 2006). Intriguingly, molecular modifications of NMDA receptor at synaptic sites have been further con­ firmed in the primate model of PD (Hallett et al., 2005). In fact, it was showed that in the striatum of macaques lesioned with 1-methyl-4-phenyl-1,2,3,6­ tetrahydropyridine (MPTP) DA depletion induces substantial alterations in the abundance of striatal NMDA receptor proteins, namely a reduction in the abundance of NR1 and NR2B but not NR2A subunit in the synaptic membrane fractions. In the PSD, it has been demonstrated that NMDA-type receptors are bound to scaffolding and signalling proteins, which regulate NMDA receptor clustering at synaptic sites and,

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NR1 NR2A NR2B Synaptic NMDA receptors

MAGUK

Synaptic NMDA receptors

Extrasynaptic NMDA receptors

Physiological

Parkinson’s disease

Fig. 1. Diagrammatic representation of the structural rearrangement of glutamatergic synapse in parkinsonian animals. Sub-cellular redistribution of NMDA receptors containing the NR2B subunit from synaptic to extra-synaptic sites represents the key element in the modifications of the glutamatergic synapse in 6-OHDA-lesioned animals compared with controls. These events are paralleled, and most probably triggered, by modifications of NMDA receptor NR2B subunit association with members of the MAGUKs protein family.

consequently, the strength of synaptic transmission (Gardoni et al., 2009a). In particular, C-tails of the NR2A and NR2B subunits of NMDA receptor bind to PDZ domain of members of the PSD-MAGUK family. Maintenance of the PDZ interaction is a critical element in keeping NMDA receptors at the synapse and disrupting this interaction may be the first step in the removal of the receptor (Gardoni et al., 2009b). Interestingly, alterations of NMDA receptor interaction with PSD-MAGUK proteins have been recently put forward as a common event in several neurological disorders such as epilepsy, HD and ischemia (Gardoni et al., 2009b). On this line, in the denervated striatum of parkinsonian animals the alteration of NMDA receptor subunit localization at synaptic sites is accompanied by a decreased recruitment of PSD-95 to NR2A–NR2B subunits; these events are paralleled by an increased activation of the pool of alphaCaMKII associated to the NMDA receptor complex (Picconi et al., 2004). Further, other studies reported that experimental parkinson­ ism in rats appears to be associated with decreased synaptic membrane localization and increased vesi­ cular localization of PSD-95 and SAP97 members of the PSD-MAGUK family (Lee et al., 2008; Nash

et al., 2005) that could account for dysregulation of NMDA receptors at synapses.

Alterations of AMPA receptors in experimental PD Functions of glutamate are also mediated by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropio­ nic acid (AMPA) receptors, tetrameric proteins composed of subunits GluR1-4 that cluster at the PSD. Upon binding with glutamate, synaptic AMPA receptors induce membrane depolariza­ tion and consequently remove magnesium (Mg2þ) block from NMDA, reducing the thresh­ old to induce long-term increases of the synaptic responses. AMPA receptor-dependent depolari­ zation also opens L-type calcium (Ca2þ) channels and lead to activation of CRE elements that, bind­ ing to specific promoter regions, are responsible for gene transcription. It has been put forward that the levels of AMPA receptors at synaptic sites are very dynamic. Con­ sequently, the understanding of the cellular machinery that controls AMPA receptor traffick­ ing will be critical for unravelling the molecular and cellular basis of the function of the excitatory

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synapse and its involvement in many neurological diseases (Shepherd and Huganir, 2007). However, even if it is very difficult to ascertain if dysfunction of AMPA receptor is involved in the initial or in the late steps of a disorder, there are many evi­ dence that alterations of AMPA receptor traffick­ ing may be one of the first manifestations of synaptic dysfunction that underlies neurodegene­ ration. On the other hand, although a direct evi­ dence on the role of AMPA receptors in PD has been recently put forward (Lee et al., 2008), there is still no general consensus on the mechanism underlying dysregulation of AMPA receptor sub­ cellular distribution in PD or their pathological changes in subunit composition. Early studies reported that levels of GluR1 sub­ unit were not changed in the neostriatum of par­ kinsonian rats (Bernard et al., 1996; Betarbet et al., 2000) while GluR1 immunoreactivity was seen to be markedly increased in the caudate and putamen of MPTP-lesioned monkeys (Betarbet et al., 2000). More recent works have provided evidence that GluR1 immunoreactivity is decreased in medium spiny neurons (Lai et al., 2003) and in striatal membrane fractions of 6-OHDA-lesioned rats (Ba et al., 2006); on the contrary, no alteration of GluR1 levels in a triton-insoluble synaptic fraction was seen in striatum of 6-OHDA-lesioned rats (Picconi et al., 2004). Although controversial, these data indicate that altered AMPA receptor-mediated transmis­ sion in the basal ganglia network could play a critical contribution to the motor symptoms of PD.

Pathological synaptic plasticity in the striatum: implications for PD Two forms of synaptic plasticity long-term depres­ sion (LTD) and LTP that are thought to underlie cognitive performance have been described at cor­ ticostriatal synapse both in vitro (Calabresi et al., 1992a, 1992b; Charpier and Deniau, 1997; Lovin­ ger et al., 1993; Partridge et al., 2000; Walsh, 1993; Walsh and Dunia, 1993) and in vivo (Charpier and

Deniau, 1997; Mahon et al., 2004; Reynolds and Wickens, 2000). Both LTP and LTD are induced by using an high-frequency stimulation (HFS) pro­ tocol of the corticostriatal fibers (Calabresi et al., 1992a, 1992b; Lovinger et al., 1993) being the type of the long-lasting change critically dependent on the level of membrane depolarization and on the ionotropic glutamate receptor subtype acti­ vated during the HFS. A third form of striatal synaptic plasticity, distinct from LTD and defined synaptic depotentiation, results from the reversal of an established LTP by the application of a lowfrequency stimulation (LFS) of corticostriatal fibers (1–5 Hz) (O’Dell and Kandel, 1994; Picconi et al., 2003). At the molecular level, it has become increasingly evident that the NMDA receptor complex, which is altered in experimental parkin­ sonism (see below), is a dynamic structure involved in the regulation of corticostriatal longterm synaptic changes (Calabresi et al., 1996; Dunah et al., 2000; Hallett et al., 2005; Ingham et al., 1998; Menegoz et al., 1995; Ulas and Cotman, 1996). Of relevance, also DA, function­ ing at D1- and D2-like receptors crucially influ­ ences both the induction and the reversal of neuroplasticity at corticostriatal synapses making the concurrent involvement of glutamatergic and dopaminergic pathways a characteristic of striatal synaptic plasticity. Thus, activation of DA receptors seems to represent a crucial factor in the induction of neuroplasticity at corticostriatal synapse which is lost after pharmacological manip­ ulation or genetic disruption of the DA-mediated signalling pathway. Accordingly, corticostriatal plasticity has been shown to be impaired in striatal spiny neurons of 6-OHDA-lesioned animals (Centonze et al., 1999). Striatal spiny neurons show spontaneous membrane depolarization in coincidence with phasic release of glutamate from corticostriatal glutamatergic terminals (‘up state’). Conversely, they are silent at rest, when membrane potential is hyperpolarized (‘down state’) (Calabresi et al., 2007; Plenz and Kitai, 1998). In the ‘up state’, the membrane depo­ larization relieves the voltage-dependent Mg2þ

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block of NMDA receptor channel. This oscillatory behaviour of membrane potential accounts for the involvement of NMDA receptors in the induction of LTP. Conversely, the NMDA receptor does not play a prominent role in LTD. Moreover, the defective synaptic plasticity induction in the PD rats, which parallels the development of motor abnormalities, is accompanied by an increase in alphaCaMKII autophosphorylation along with a higher recruitment of activated alphaCaMKII to the regulatory NR2 NMDA receptor subunits (Picconi et al., 2004). This evidence suggests that CaMKII may play a critical role in this process, functioning as a signal integrator downstream of DA and glutamate receptors in the PSD.

Alterations of the glutamatergic synapse in L-DOPA-induced dyskinesia While the current DA replacement therapy offers remarkable symptomatic benefits in many PD patients, these treatments are often accompanied by severe side effects, motor fluctuations and wearing-off phenomena. In the unilateral 6-OHDA model of PD in rats, chronic treatment with L-DOPA is able to restore synaptic plasticity (Picconi et al., 2003). However, a consistent number of treated animals experiences a progressive shortening of the motor response to each drug dose, similar to L-DOPA-induced wearing-off fluctuations in PD patients (Lee et al., 2003). Moreover, rats develop abnormal involuntary movements (AIMs) of the limb con­ tralateral to the lesion, the trunk and the orofacial region, resembling human dyskinesias (Lundblad et al., 2002). Strikingly, electrophysiological recordings from dyskinetic rats demonstrated a selective impairment of striatal synaptic depoten­ tiation. Interestingly, however, experimental PD rats or mice with virtually the same degree of nigrostriatal denervation may or may not develop AIMs following chronic therapeutic doses of L-DOPA (Cenci et al., 1998; Lundblad et al., 2004; Picconi et al., 2003). Animals that do not

develop involuntary movements maintain the phy­ siological reversal of synaptic strength after LFS protocol (Picconi et al., 2003). After chronic L-DOPA therapy, the glutamater­ gic signalling from the cortex to the striatum undergoes further adaptive changes; abnormal composition and function of NMDA receptor complex have been suggested to be correlated also with the development of L-DOPA-induced dyskinesia (Gardoni et al., 2006). In particular, it has been recently demonstrated that L-DOPA­ treated dyskinetic rats are characterized by signif­ icantly higher levels of NR2A subunit while expression of NR2B subunit is reduced in the post-synaptic compartment by redistribution in extra-synaptic membranes. These events are accompanied by modifications of NMDA receptor NR2B subunit association with PSD-95, SAP-97 and SAP-102. Notably, it has been demonstrated that these molecular alterations are strictly corre­ lated to abnormal synaptic plasticity and motor behaviour in L-DOPA-treated dyskinetic rats (Gardoni and Di Luca, 2006; Gardoni et al., 2006; Picconi et al., 2003). Treatment of non-dyskinetic animals with a synthetic peptide (TAT2B) able to affect synaptic localization of NR2B, and its bind­ ing to MAGUK proteins, causes a worsening of motor symptoms with appearance of dyskinetic behaviours (Gardoni et al., 2006). These data further support the idea that molecular distur­ bances of the glutamatergic synapse, initially caused by DA denervation, create a pathological substrate that may have a causal role in the devel­ opment of L-DOPA-induced dyskinesia (Gardoni et al., 2006). Conversely, according to Nash and co-workers (2005), L-DOPA-induced dyskinesias are asso­ ciated with increased total levels of PSD-95 and SAP97, reflecting an increase at the synaptic membrane, whereas vesicular levels of both pro­ teins are decreased. Even if there are some dis­ crepancies between the above-mentioned studies, probably related to the different lesioning para­ digms and L-DOPA treatment used, they all con­ firm a central role for PSD-MAGUK proteins in

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modulating NMDA receptor function in experi­ mental parkinsonism as well as in L-DOPA­ induced dyskinesia.

NMDA receptor antagonist in experimental PD and in dyskinesia Several studies in the last decade have exam­ ined the beneficial effects of NMDA receptor antagonists in animal models of PD (Losch­ mann et al., 2004; Nash et al., 2000) and in blocking the development of L-DOPA-induced dyskinesias (Hadj Tahar et al., 2004; Wessell et al., 2004). Overall, there is a general agree­ ment that NMDA receptor blockade attenuates parkinsonian motor symptoms and improves dopaminergic therapy. However, these agents are not well tolerated in primates due to a high number of unwanted side effects. Research has then focused on selective NMDA receptor antagonists in order to achieve anti-parkinso­ nian effects with a reduction in adverse effects. Subtype-specific antagonists might allow block­ ade of a specific subunit of the NMDA com­ plex. This would facilitate cell preservation during excitotoxic processes while not causing complete inhibition of the receptor and there­ fore allowing physiological neurotransmission. The NR2B-selective antagonist ifenprodil and its derivatives seem well suited for this purpose. These agents are effective in cell culture models of excitotoxicity and in anti-ischemic therapy. Ifenprodil has anti-parkinsonian actions in reserpine-treated rats, 6-OHDA-lesioned rats and MPTP-lesioned non-human primates (Nash and Brotchie, 2002; Nash et al., 1999, 2000). However, this agent has affinity for other recep­ tor types such as adrenergic, serotoninergic and sigma receptors. CP-101,606, a derivative of ifenprodil, acts as selective NR2B antagonist over the NR2A, reducing parkinsonian symp­ toms in both haloperidol-treated rats and MPTP-lesioned non-human primates (Nash et al., 2004; Steece-Collier et al., 2000).

In addition, it has been shown that selective NMDA receptor blockers can reduce L-DOPA­ induced dyskinesia in both experimental parkinsonism and PD patients (Del Dotto et al., 2001; Verhagen Metman et al., 1998) with­ out affecting the beneficial effects on parkinso­ nian symptoms. Selective antagonists targeting NMDA receptors composed by the NR1/NR2B subunits are able to prevent L-DOPA-induced dyskinesia in primate models of PD (Hadj Tahar et al., 2004; Morissette et al., 2006). How­ ever, apparently contradictory results have been provided by recent studies on the effects of NR2B-selective NMDA receptor antagonists on L-DOPA-induced dyskinesia in experimental par­ kinsonism (Rylander et al., 2009). Two studies described conflicting results on the effects of CP­ 101,606 on L-DOPA-induced dyskinesias in two different models of experimental parkinsonism (Nash et al., 2000; Wessell et al., 2004). However, all studies agreed that NR2B is a key element both in the experimental parkinsonism and in the devel­ opment of L-DOPA-induced dyskinesias. On the other hand there have been limited studies of NR2A-selective agents. The competitive NR2A­ selective antagonist MDL 100,453 not only increased motor activity in MPTP-lesioned non­ human primates but also increased dyskinesia caused by L-DOPA (Blanchet et al., 1999). Additionally, this agent has proved ineffective in restoring L-DOPA-associated alterations in the 6-OHDA rat (Blanchet et al., 1999).

AMPA receptor modulation in PD therapy Much effort has been recently put into developing of pharmacological agents able to modulate AMPA receptor function in order to get more insights into the mechanisms underlying the pathophysiology of neurodegenerative diseases, including PD (Johnson et al., 2009). Interestingly, if NMDA receptor antagonists have shown promise in reversing motor symptoms and delaying L-DOPA-induced dyskinesias in

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preclinical PD models, drugs targeting AMPA receptors exert more complex effects. In fact, while antagonists of these receptors may be useful in the treatment of L-DOPA-induced dyskinesias (Chase et al., 2000), AMPA receptor potentiators, also known as ampakines, are allosteric modula­ tors that slow desensitization or deactivation of AMPAR ion channels [reviewed in Arai and Kessler (2007)] and represent a promising thera­ peutic approach to contrast neurodegeneration (Johnson et al., 2009). The most interesting aspect of these positive allosteric modulators is linked to their capability to increase the expression of neurotrophic factors. In fact, by enhancing AMPA receptor activation, ampakines stimulate the downstream pathways that regulate brain-derived neurotrophic factor (BDNF) expression. In particular, strong mem­ brane depolarization induces activation of L-type Ca2þ channels leading to activation of CRE ele­ ments that, binding to BDNF promoter region, positively regulate the protein transcription. Among different functions, BDNF is also a key factor in the regulation of neuronal activity and synaptic plasticity and, through its binding with the high-affinity tyrosine kinase-linked receptor, TrkB, it modulates the activity of several receptor systems and molecular pathways of the PSD (Wu et al., 1996; Yoshii and Constantine-Paton, 2007). Many studies have been conducted in hip­ pocampal and cortical preparations to demon­ strate that BDNF, through activation of TrkB receptors, finely modulates the activity of NMDA receptor by inducing phosphorylation of NR1 sub­ unit (Lin et al., 1999; Suen et al., 1997) and NR2B subunit and its binding with protein phosphatases (Lin et al., 1999). Relevant to striatal neurons is the evidence that BDNF regulates maturation and expression of dopamine and cAMP-regulated phosphoprotein 32 (DARPP-32) (Bogush et al., 2007; Ivkovic et al., 1997), which have a key role in the maintenance of long-term plastic changes (Calabresi et al., 2000). It is therefore conceivable that alterations of BDNF signalling may play an important role in PD and dyskinesias.

On this view, recent studies conducted by O’Neill’s group using 6-OHDA and MPTP rodent models of PD suggest that selective potentiators of AMPA receptors may be useful for protection against nigral degeneration (Murray et al., 2003; O’Neill et al., 2004a, 2004b, 2005). Interestingly, these protective effects occur when the nigrostria­ tal lesion is established, suggesting that these com­ pounds exert a neurotrophic effect in animal models of PD-like neurodegeneration. In support of this, some of these compounds cause increases in expression of BDNF in the substantia nigra pars compacta suggesting that enhancing AMPA receptor activation may slow the normal loss of these neurons that occurs with age and perhaps prevent levels of nigral degeneration that cause PD symptoms. In line with these evidences, a recent paper by Jourdy and colleagues demonstrated that by increasing BDNF expression and activating BDNF-dependent signalling pathways, ampakines exert neuroprotective effect against MPP(þ)­ induced toxicity (Jourdi et al., 2009). These results provide a strong support for testing positive AMPA modulators as a new possible therapy for neurodegenerative disorders, including PD.

Functional and molecular cross-talk between D1 and NMDA receptors: role in physiological synaptic transmission, in experimental PD and in L-DOPA-induced dyskinesia DA and glutamate receptors’ functional interac­ tion in the striatum, as well as in other brain structures, has been shown to regulate locomo­ tion, positive reinforcement, attention and work­ ing memory (Cepeda and Levine, 1998). As stated above, dopaminergic terminals from the substantia nigra pars compacta converge with glutamatergic signals from the cortex on dendritic spines of stria­ tal medium spiny projecting GABAergic neurons. Several studies, using different experimental approaches, have shown that in striatal spiny neu­ rons the D1 receptors are located within dendritic

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spines, both in the spine neck and, probably to a lesser extent, in the PSD (Fiorentini et al., 2003); in this way, PSD-associated D1 receptors co-localize in striatal spiny neurons with NMDA receptors. D1 receptor-mediated potentiation of NMDA responses in the striatum has been described in the early 1990s (Cepeda et al., 1992, 1993) and then confirmed in other brain areas (Chen et al., 2004; Wang and O’Donnell, 2001). Notably, D1 receptor-mediated increase of NMDA responses can lead to significant functional consequences. In fact, potentiation of NMDA receptor-mediated responses can enhance glutamate activity up to predisposing to excitotoxicity. On the other hand, as stated also above, activation of D1 recep­ tors in the striatum is required for the induction of LTP (Calabresi et al., 2000; Kerr and Wickens, 2001), suggesting further that activation of D1 receptors is needed for the correct integration of cortical glutamatergic signals to the striatum. Different mechanisms have been proposed to be involved in the functional cross-talk existing in the striatum between D1 and NMDA receptors, ranging from second messenger-mediated phos­ phorylation of NMDA receptor subunits, and con­ sequent regulation of receptor trafficking at synaptic sites, to direct interaction leading to the formation of heteromeric D1/NMDA receptor complexes (Cenci and Lundblad, 2006). Early studies reported that D1 receptor co­ immunoprecipitates with NMDA receptor subu­ nits from isolated PSD, suggesting that these two receptor types are co-clustered in the post-synaptic compartment (Fiorentini et al., 2003). Further, of key relevance, a direct interaction has been clearly demonstrated between the C-terminal tails of D1 receptor and the NR1 and NR2A sub­ units of NMDA receptor (Lee et al., 2002). These studies also addressed the functional role of the direct D1/NMDA receptor molecular interaction. In particular, D1 interaction with the NR2A subunit is involved in the inhibition of NMDA receptor-gated currents obtained through a decrease in the number of cell surface receptors

(Lee et al., 2002). Moreover, D1/NR1 interaction has been clearly correlated with the attenuation of NMDA receptor-mediated excitotoxicity through a PI-3 kinase-dependent pathway. Recent studies showed that, in striatal neurons, D1 receptor activation leads to rapid trafficking of NMDA receptor subunits, with increased NR1 and NR2B subunits in dendrites and enhanced co-clustering and surface expression of these sub­ units at synaptic sites (Hallett et al., 2006). Inter­ estingly, D1 receptor-mediated NMDA receptor trafficking is blocked by tyrosine kinase inhibi­ tors, while blockers of tyrosine phosphatases also induce NMDA subunit trafficking, but the effect is non-selective and alters both NR2A­ and NR2B-containing receptors. Other signalling cascades have been shown to regulate D1 recep­ tor-dependent enhancement of NMDA responses in the striatum. The most important involves pro­ tein kinase A (PKA) and DARPP-32-regulated phosphorylation of NMDA receptor NR1 subu­ nits (Snyder et al., 1998). Further, NMDA recep­ tor potentiation by phospholipase C-coupled D1­ like receptors has been shown to occur via PKC activation (Chergui and Lacey, 1999). Although much effort has been put into under­ standing the D1/NMDA relationships, a fine reg­ ulation of the interplay between glutamate and DA systems cannot be achieved without the inter­ action of D1 receptor with AMPA receptors. In particular, Wolf and co-workers have demon­ strated that D1 DA receptor stimulation enhances phosphorylation of GluR1 at the PKA site, increases surface expression of AMPA receptors and facilitates their synaptic insertion in several brain areas (Gao et al., 2006; Sun et al., 2005). Notably, in the last few years it has been demon­ strated that alterations of NMDA receptor cluster­ ing with DA receptors can play a central role in the pathogenesis of PD as well as in L-DOPA-induced dyskinesias (Fiorentini et al., 2006). Interestingly, D1/NMDA receptor clusters containing NR2B subunits were decreased in the PSD of 6-OHDA­ lesioned striatum (Fiorentini et al., 2006). Pro­ longed L-DOPA treatment normalizes synaptic

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D1/NMDA receptor complexes in non-dyskinetic rats, but remarkably reduces them in the dyski­ netic group without changing their interaction. Notably, the levels of D1/NMDA receptors com­ plexes are unchanged in total membrane proteins, suggesting that the decrease of these species in the PSD is likely to reflect an altered receptor traffick­ ing (Fiorentini et al., 2006). Modification of these pathways may become an additional therapeutic target for PD and L-DOPA­ induced dyskinesias in which abnormal function of striatal glutamate receptors contributes to the symptoms.

CNS DA HD HFS LTD LTP MAGUKs MPTP NMDA PD PSD

Conclusions In the last decade, the increasing knowledge of the structure and function of the excitatory glutama­ tergic PSD has led to the identification of key protein families, such as PSD-MAGUKs, that play a fundamental role in governing NMDA receptor localization at synapse and, consequently, NMDA receptor function. It has been shown that alterations of NMDA receptor complexes’ locali­ zation in the PSD could represent an important event in different central system disorders (Gardoni et al., 2009a). As to PD, because altera­ tions in NMDA receptor localization at synapse contribute to the clinical features of the experimen­ tal parkinsonism and may underlie the develop­ ment of dyskinesias, therapies targeted to modulate protein–protein interactions between NMDA receptor subunits and PSD-associated scaf­ folding elements able to regulate striatal NMDA receptor trafficking/localization of specific subunits may be useful in the treatment of the disease.

Abbreviations 6-OHDA AD AIMs

AMPA

6-hydroxydopamine Alzheimer’s disease abnormal involuntary movements

alpha-amino-3-hydroxy-5­ methyl-4-isoxazolepropionic acid central nervous system dopamine Huntington’s disease high-frequency stimulation long-term depression long-term potentiation membrane-associated guanylate kinases 1-methyl-4-phenyl-1,2,3,6­ tetrahydropyridine N-methyl-D-aspartate Parkinson’s disease post-synaptic density

References Arai, A. C., & Kessler, M. (2007). Pharmacology of ampakine modulators: From AMPA receptors to synapses and beha­ vior. Current Drug Targets, 8, 583–602. Ba, M., Kong, M., Yang, H., Ma, G., Lu, G., Chen, S., et al. (2006). Changes in subcellular distribution and phosphoryla­ tion of GluR1 in lesioned striatum of 6-hydroxydopamine­ lesioned and l-dopa-treated rats. Neurochemical Research, 31, 1337–1347. Bernard, V., Gardiol, A., Faucheux, B., Bloch, B., Agid, Y., & Hirsch, E. C. (1996). Expression of glutamate receptors in the human and rat basal ganglia: Effect of the dopaminergic denervation on AMPA receptor gene expression in the stria­ topallidal complex in Parkinson’s disease and rat with 6­ OHDA lesion. The Journal of Comparative Neurology, 368, 553–568. Betarbet, R., Porter, R. H., & Greenamyre, J. T. (2000). GluR1 glutamate receptor subunit is regulated differentially in the primate basal ganglia following nigrostriatal dopamine denervation. Journal of Neurochemistry, 74, 1166–1174. Blanchet, P. J., Konitsiotis, S., Whittemore, E. R., Zhou, Z. L., Woodward, R. M., & Chase, T. N. (1999). Differing effects of N-methyl-D-aspartate receptor subtype selective antagonists on dyskinesias in levodopa-treated 1-methyl-4-phenyl-tetra­ hydropyridine monkeys. Journal of Pharmacology and Experimental Therapeutics, 290, 1034–1040. Bogush, A., Pedrini, S., Pelta-Heller, J., Chan, T., Yang, Q., Mao, Z., et al. (2007). AKT and CDK5/p35 mediate brainderived neurotrophic factor induction of DARPP-32 in

179 medium size spiny neurons in vitro. The Journal of Biological Chemistry, 282, 7352–7359. Brown, J. R., & Arbuthnott, G. W. (1983). The electrophysiol­ ogy of dopamine (D2) receptors: A study of the actions of DA on corticostriatal transmission. Neuroscience, 10, 349–355. Calabresi, P., Gubellini, P., Centonze, D., Picconi, B., Bernardi, G., Chergui, K., et al. (2000). Dopamine and cAMP-regulated phosphoprotein 32 kDa controls both striatal long-term depression and long-term potentiation, opposing forms of synaptic plasticity. The Journal of Neuroscience, 20, 8443– 8451. Calabresi, P., Maj, R., Pisani, A., Mercuri, N. B., & Bernardi, G. (1992a). Long-term synaptic depression in the striatum: Physiological and pharmacological characterization. The Journal of Neuroscience, 12, 4224–4233. Calabresi, P., Picconi, B., Tozzi, A., & Di Filippo, M. (2007). Dopamine-mediated regulation of corticostriatal synaptic plasticity. Trends in Neuroscience, 30, 211–219. Calabresi, P., Pisani, A., Mercuri, N. B., & Bernardi, G. (1992b). Long-term potentiation in the striatum is unmasked by removing the voltage-dependent magnesium block of NMDA receptor channels. European Journal of Neuroscience, 4, 929–935. Calabresi, P., Pisani, A., Mercuri, N. B., & Bernardi, G. (1996). The corticostriatal projection: From synaptic plasticity to dysfunctions of the basal ganglia. Trends in Neuroscience, 19, 19–24. Cenci, M. A., & Lundblad, M. (2006). Post-versus presynaptic plasticity in L-DOPA-induced dyskinesia. Journal of Neuro­ chemistry, 99, 381–392. Cenci, M. A., Lee, C. S., & Bjorklund, A. (1998). L-DOPA­ induced dyskinesia in the rat is associated with striatal overexpression of prodynorphin- and glutamic acid decarboxy­ lase mRNA. The European Journal of Neuroscience, 10, 2694–2706. Centonze, D., Gubellini, P., Picconi, B., Calabresi, P., Giacomini, P., & Bernardi, G. (1999). Unilateral dopamine denervation blocks corticostriatal LTP. Journal of Neuro­ physiology, 82, 3575–3579. Centonze, D., Gubellini, P., Rossi, S., Picconi, B., Pisani, A., Bernardi, G., et al. (2005). Subthalamic nucleus lesion reverses motor abnormalities and striatal glutamatergic overactivity in experimental parkinsonism. Neuroscience, 133(3), 831–840. Centonze, D., Picconi, B., Gubellini, P., Bernardi, G., & Calabresi, P. (2001). Dopaminergic control of synaptic plasticity in the dorsal striatum. European Journal of Neuroscience, 13, 1071–1077. Cepeda, C., & Levine, M. S. (1998<). Dopamine and N-methyl­ D-aspartate receptor interactions in the neostriatum. Devel­ opmental Neuroscience, 20, 1–18. Cepeda, C., Buchwald, N. A., & Levine, M. S. (1993). Neuro­ modulatory actions of dopamine in the neostriatum are

dependent upon the excitatory amino acid receptor subtypes activated. Proceedings of the National Academy of Sciences of the United States of America, 90, 9576–9580. Cepeda, C., Radisavljevic, Z., Peacock, W., Levine, M. S., & Buchwald, N. A. (1992). Differential modulation by dopa­ mine of responses evoked by excitatory amino acids in human cortex. Synapse, 11, 330–341. Charpier, S., & Deniau, J. M. (1997). In vivo activity-dependent plasticity at cortico-striatal connections: Evidence for physio­ logical long-term potentiation. Proceedings of the National Academy of Sciences of the United States of America, 94, 7036–7040. Chase, T. N., Oh, J. D., & Konitsiotis, S. (2000). Antiparkinso­ nian and antidyskinetic activity of drugs targeting central glutamatergic mechanisms. Journal of Neurology, 247, II36–II42. Review. Chen, G., Greengard, P., & Yan, Z. (2004). Potentiation of NMDA receptor currents by dopamine D1 receptors in pre­ frontal cortex. Proceedings of the National Academy of Sciences of the United States of America, 101, 2596–2600. Chergui, K., & Lacey, M. G. (1999). Modulation by dopamine D1-like receptors of synaptic transmission and NMDA receptors in rat nucleus accumbens is attenuated by the protein kinase C inhibitor Ro 32-0432. Neuropharmacology, 38, 223–231. Del Dotto, P., Pavese, N., Gambaccini, G., Bernardini, S., Metman, L. V., Chase, T. N., et al. (2001). Intravenous amantadine improves levadopa-induced dyskinesias: An acute double-blind placebo-controlled study. Movement Disorders, 16, 515–520. Dunah, A. W., Wang, Y., Yasuda, R. P., Kameyama, K., Huganir, R. L., Wolfe, B. B., et al. (2000). Alterations in subunit expression, composition, and phosphorylation of striatal N-methyl-D-aspartate glutamate receptors in a rat 6-hydroxydopamine model of Parkinson’s disease. Molecular Pharmacology, 57, 342–352. Fiorentini, C., Gardoni, F., Spano, P., Di Luca, M., & Missale, C. (2003). Regulation of dopamine D1 receptor trafficking and desensitization by oligomerization with glutamate N-methyl­ D-aspartate receptors. The Journal of Biological Chemistry, 278, 20196–20202. Fiorentini, C., Rizzetti, M. C., Busi, C., Bontempi, S., Collo, G., Spano, P., et al. (2006). Loss of synaptic D1 dopa­ mine/N-methyl-D-aspartate glutamate receptor complexes in L-DOPA-induced dyskinesia in the rat. Molecular Pharmacology, 69, 805–812. Gao, C., Sun, X., & Wolf, M. E. (2006). Activation of D1 dopamine receptors increases surface expression of AMPA receptors and facilitates their synaptic incorporation in cul­ tured hippocampal neurons. Journal of Neurochemistry, 98, 1664–1677. Garcia-Munoz, M., Young, S. J., & Groves, P. M. (1991). Term­ inal excitability of the corticostriatal pathway. I. Regulation

180 by dopamine receptor stimulation. Brain Research, 551, 195–206. Gardoni, F. (2008). MAGUK proteins: New targets for phar­ macological intervention in the glutamatergic synapse. Eur­ opean Journal of Pharmacology, 585, 147–152. Gardoni, F., & Di Luca, M. (2006). New targets for pharmaco­ logical intervention in the glutamatergic synapse. European Journal of Pharmacology, 545, 2–10. Gardoni, F., Marcello, E., & Di Luca, M. (2009a). Postsynaptic density-membrane associated guanylate kinase proteins (PSD-MAGUKs) and their role in CNS disorders. Neu­ roscience, 158, 324–333. Gardoni, F., Mauceri, D., Malinverno, M., Polli, F., Costa, C., Tozzi, A., et al. (2009b). Decreased NR2B subunit synaptic levels cause impaired long-term potentiation but not longterm depression. Journal of Neuroscience, 29, 669–677. Gardoni, F., Picconi, B., Ghiglieri, V., Polli, F., Bagetta, V., Bernardi, G., et al. (2006). A critical interaction between NR2B and MAGUK in L-DOPA induced dyskinesia. Jour­ nal of Neuroscience, 26, 2914–2922. Hadj Tahar, A., Gregoire, L., Darre, A., Belanger, N., Meltzer, L., & Bedard, P. J. (2004). Effect of a selective glutamate antago­ nist on L-dopa-induced dyskinesias in drug-naive parkinsonian monkeys. Neurobiology of Disease, 15, 171–176. Hallett, P. J., Dunah, A. W., Ravenscroft, P., Zhou, S., Bezard, E., Crossman, A. R., et al. (2005). Alterations of striatal NMDA receptor subunits associated with the development of dyskine­ sia in the MPTP-lesioned primate model of Parkinson’s disease. Neuropharmacology, 48, 503–516. Hallett, P. J., Spoelgen, R., Hyman, B. T., Standaert, D. G., & Dunah, A. W. (2006). Dopamine D1 activation potentiates striatal NMDA receptors by tyrosine phosphorylation-depen­ dent subunit trafficking. Journal of Neuroscience, 26, 4690–4700. Ingham, C. A., Hood, S. H., Taggart, P., & Arbuthnott, G. W. (1998). Plasticity of synapses in the rat neostriatum after unilateral lesion of the nigrostriatal dopaminergic pathway. Journal of Neuroscience, 18, 4732–4743. Ivkovic, S., Polonskaia, O., Farinas, I., & Ehrlich, M. E. (1997). Brain-derived neurotrophic factor regulates maturation of the DARPP-32 phenotype in striatal medium spiny neurons: Studies in vivo and in vitro. Neuroscience, 79, 509–516. Johnson, K. A., Conn, P. J., & Niswender, C. M. (2009). Glutamate receptors as therapeutic targets for Parkinson’s disease. CNS & Neurological Disorders – Drug Targets, 8, 475–491. Jourdi, H., Hamo, L., Oka, T., Seegan, A., & Baudry, M. (2009). BDNF mediates the neuroprotective effects of posi­ tive AMPA receptor modulators against MPPþ-induced toxicity in cultured hippocampal and mesencephalic slices. Neuropharmacology, 56, 876–885. Kerkerian, L., Dusticier, N., & Nieoullon, A. (1987). Modula­ tory effect of dopamine on high-affinity glutamate uptake in the rat striatum. Journal of Neurochemistry, 48, 1301–1306.

Kerr, J. N., & Wickens, J. R. (2001). Dopamine D-1/D-5 receptor activation is required for long-term potentiation in the rat neostriatum in vitro. Journal of Neurophysiology, 85, 117–124. Lai, S. K., Tse, Y. C., Yang, M. S., Wong, C. K., Chan, Y. S., & Yung, K. K. (2003). Gene expression of glutamate receptors GluR1 and NR1 is differentially modulated in striatal neu­ rons in rats after 6-hydroxydopamine lesion. Neurochemistry International, 43, 639–653. Lee, E. A., Lee, W. Y., Kim, Y. S., & Kang, U. J. (2003). The effects of chronic L-DOPA therapy on pharmacodynamic parameters in a rat model of motor response fluctuations. Experimental Neurology, 184, 304–312. Lee, C. Y., Lee, C. H., Shih, C. C., & Liou, H. H. (2008). Paraquat inhibits postsynaptic AMPA receptors on dopami­ nergic neurons in the substantia nigra pars compacta. Bio­ chemical Pharmacology, 76, 1155–1164. Lee, F. J., Xue, S., Pei, L., Vukusic, B., Chery, N., Wang, Y., et al. (2002). Dual regulation of NMDA receptor functions by direct protein-protein interactions with the dopamine D1 receptor. Cell, 111, 219–230. Lin, S. Y., Wu, K., Len, G. W., Xu, J. L., Levine, E. S., Suen, P. C., et al. (1999). Brain-derived neurotrophic factor enhances asso­ ciation of protein tyrosine phosphatase PTP1D with the NMDA receptor subunit NR2B in the cortical postsynaptic density. Molecular Brain Research, 70, 18–25. Loschmann, P. A., De Groote, C. ,, Smith, L., Wullner, U., Fischer, G., Kemp, J. A., et al. (2004). Antiparkinsonian activity of Ro 25-6981, a NR2B subunit specific NMDA receptor antagonist, in animal models of Parkinson’s disease. Experimental Neurology, 187, 86–93. Lovinger, D. M., Tyler, E. C., & Merritt, A. (1993). Short- and long-term synaptic depression in rat neostriatum. Journal of Neurophysiology, 70, 1937–1949. Lundblad, M., Andersson, M., Winkler, C., Kirik, D., Wierup, N., & Cenci, M. A. (2002). Pharmacological validation of beha­ vioural measures of akinesia and dyskinesia in a rat model of Parkinson’s disease. European Journal of Neuroscience, 15, 120–132. Lundblad, M., Picconi, B., Lindgren, H., & Cenci, M. A. (2004). A model of L-DOPA-induced dyskinesia in 6-hydroxydopa­ mine lesioned mice: Relation to motor and cellular para­ meters of nigrostriatal function. Neurobiology of Disease, 16, 110–123. Mahon, S., Deniau, J. M., & Charpier, S. (2004). Corticostriatal plasticity: Life after the depression. Trends in Neurosciences, 27, 460–467. Menegoz, M., Lau, L. F., Herve, D., Huganir, R. L., & Girault, J. A. (1995). Tyrosine phosphorylation of NMDA receptor in rat striatum: Effects of 6-OH-DA lesions. NeuroReport, 7, 125–128. Mitchell, P. R., & Doggett, N. S. (1980). Modulation of striatal [3h]-glutamic acid release by dopaminergic drugs. Life Science, 26, 2073–2081.

181 Morissette, M., Dridi, M., Calon, F., Hadj Tahar, A., Meltzer, L. T., Bedard, P. J., et al. (2006). Prevention of dyskinesia by an NMDA receptor antagonist in MPTP monkeys: Effect on ade­ nosine A2A receptors. Synapse, 60, 239–250. Murray, T. K., Whalley, K., Robinson, C. S., Ward, M. A., Hicks, C. A., Lodge, D., et al. (2003). LY503430, a novel alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor potentiator with functional, neuroprotective and neurotrophic effects in rodent models of Parkinson’s disease. Journal of Pharmacology and Experimental Therapeutics, 306, 752–762. Nash, J. E., & Brotchie, J. M. (2002). Characterisation of striatal NMDA receptors involved in the generation of parkinsonian symptoms: Intrastriatal microinjection studies in the 6-OHDA-lesioned rat. Movement Disorders, 17, 455–466. Nash, J. E., Fox, S. H., Henry, B., Hill, M. P., Peggs, D., McGuire, S., et al. (2000). Antiparkinsonian actions of ifen­ prodil in the MPTP-lesioned marmoset model of Parkinson’s disease. Experimental Neurology, 165, 136–142. Nash, J. E., Hill, M. P., & Brotchie, J. M. (1999). Antiparkin­ sonian actions of blockade of NR2B-containing NMDA receptors in the reserpine-treated rat. Experimental Neurol­ ogy, 155, 42–48. Nash, J. E., Johnston, T. H., Collingridge, G. L., Garner, C. C., & Brotchie, J. M. (2005). Subcellular redistribution of the synapse-associated proteins PSD-95 and SAP97 in animal models of Parkinson’s disease and L-DOPA-induced dyski­ nesia. The FASEB Journal, 19, 583–585. Nash, J. E., Ravenscroft, P., McGuire, S., Crossman, A. R., Menniti, F. S., & Brotchie, J. M. (2004). The NR2B-selective NMDA receptor antagonist CP-101,606 exacerbates L-DOPA-induced dyskinesia and provides mild potentiation of anti-parkinsonian effects of L-DOPA in the MPTP­ lesioned marmoset model of Parkinson’s disease. Experi­ mental Neurology, 188, 471–479. O’Dell, T. J., & Kandel, E. R. (1994). Low-frequency stimulation erases LTP through an NMDA receptor-mediated activation of protein phosphatases. Learning & Memory, 1, 129–139. O’Neill, M. J., Bleakman, D., Zimmerman, D. M., & Nisenbaum, E. S. (2004a). AMPA receptor potentiators for the treatment of CNS disorders. CNS & Neurological Disorders – Drug Targets, 3, 181–194. O’Neill, M. J., Murray, T. K., Clay, M. P., Lindstrom, T., Yang, C. R., & Nisenbaum, E. S. (2005). LY503430: Pharma­ cology, pharmacokinetics, and effects in rodent models of Parkinson’s disease. CNS & Neurological Disorders, 11, 77–96. O’Neill, M. J., Murray, T. K., Whalley, K., Ward, M. A., Hicks, C. A., Woodhouse, S., et al. (2004b). Neurotrophic actions of the novel AMPA receptor potentiator, LY404187, in rodent models of Parkinson’s disease. European Journal of Pharmacology, 486, 163–174. Partridge, J. G., Tang, K. C., & Lovinger, D. M. (2000). Regional and postnatal heterogeneity of activity-dependent

long-term changes in synaptic efficacy in the dorsal striatum. Journal of Neurophysiology, 84, 1422–1429. Picconi, B., Centonze, D., Hakansson, K., Bernardi, G., Greengard, P., Fisone, G., et al. (2003). Loss of bidirectional striatal synaptic plasticity in L-DOPA-induced dyskinesia. Nature Neuroscience, 6, 501–506. Picconi, B., Gardoni, F., Centonze, D., Mauceri, D., Cenci, M. A., Bernardi, G., et al. (2004). Abnormal Ca2þ-calmodulin-depen­ dent protein kinase II function mediates synaptic and motor deficits in experimental parkinsonism. Journal of Neuroscience, 24, 5283–5291. Plenz, D., & Kitai, S. T. (1998). Up and down states in striatal medium spiny neurons simultaneously recorded with sponta­ neous activity in fast-spiking interneurons studied in cortex­ striatum-substantia nigra organotypic cultures. Journal of Neuroscience, 18, 266–283. Reynolds, J. N., & Wickens, J. R. (2000). Substantia nigra dopamine regulates synaptic plasticity and membrane poten­ tial fluctuations in the rat neostriatum, in vivo. Neuroscience, 99, 199–203. Rowlands, G. J., & Roberts, P. J. (1980). Specific calciumdependent release of endogenous glutamate from rat stria­ tum is reduced by destruction of the cortico-striatal tract. Experimental Brain Research, 39, 239–240. Rylander, D., Recchia, A., Mela, F., Dekundy, A., Danysz, W., & Cenci, M. A. (2009). Pharmacological modulation of glu­ tamate transmission in a rat model of L-DOPA-induced dys­ kinesia: Effects on motor behavior and striatal nuclear signaling. Journal of Pharmacology and Experimental Ther­ apeutics, 330, 227–235. Shepherd, J. D., & Huganir, R. L. (2007). The cell biology of synaptic plasticity: AMPA receptor trafficking. Annual Review of Cell and Developmental Biology, 23, 613–643. Snyder, G. L., Fienberg, A. A., Huganir, R. L., & Greengard, P. (1998). A dopamine/D1 receptor/protein kinase A/dopa­ mine- and cAMP-regulated phosphoprotein (mr 32 kDa)/ protein phosphatase-1 pathway regulates dephosphorylation of the NMDA receptor. Journal of Neuroscience, 18, 10297–10303. Steece-Collier, K., Chambers, L. K., Jaw-Tsai, S. S., Menniti, F. S., & Greenamyre, J. T. (2000). Antiparkinsonian actions of CP­ 101,606, an antagonist of NR2B subunit-containing N-methyl­ D-aspartate receptors. Experimental Neurology, 163, 239–243. Suen, P. C., Wu, K., Levine, E. S., Mount, H. T., Xu, J. L., Lin, S. Y., et al. (1997). Brain-derived neurotrophic factor rapidly enhances phosphorylation of the postsynaptic N-methyl-D-aspartate receptor subunit 1. Proceedings of the National Academy of Sciences of the United States of America, 94, 8191–8195. Sun, X., Zhao, Y., & Wolf, M. E. (2005). Dopamine receptor stimulation modulates AMPA receptor synaptic insertion in prefrontal cortex neurons. Journal of Neuroscience, 25, 7342–7351.

182 Ulas, J., & Cotman, C. W. (1996). Dopaminergic denervation of striatum results in elevated expression of NR2A subunit. NeuroReport, 7, 1789–1793. Verhagen Metman, L., Del Dotto, P., van den Munckhof, P., Fang, J., Mouradian, M. M., & Chase, T. N. (1998). Aman­ tadine as treatment for dyskinesias and motor fluctuations in Parkinson’s disease. Neurology, 50, 1323–1326. Walsh, J. P. (1993). Depression of excitatory synaptic input in rat striatal neurons. Brain Research, 608, 123–128. Walsh, J. P., & Dunia, R. (1993). Synaptic activation of N-methyl-D-aspartate receptors induces short-term potentia­ tion at excitatory synapses in the striatum of the rat. Neu­ roscience, 57, 241–248. Wang, J., & O’Donnell, P. (2001). D(1) dopamine receptors potentiate NMDA-mediated excitability increase in layer V

prefrontal cortical pyramidal neurons. Cerebral Cortex, 11, 452–462. Wessell, R. H., Ahmed, S. M., Menniti, F. S., Dunbar, G. L., Chase, T. N., & Oh, J. D. (2004). NR2B selective NMDA receptor antagonist CP-101,606 prevents levodopa-induced motor response alterations in hemi-parkinsonian rats. Neu­ ropharmacology, 47, 184–194. Wu, K., Xu, J. L., Suen, P. C., Levine, E., Huang, Y. Y., Mount, H. T., et al. (1996). Functional trkB neurotrophin receptors are intrinsic components of the adult brain postsynaptic density. Molecular Brain Research, 43, 286–290. Yoshii, A., & Constantine-Paton, M. (2007). BDNF induces transport of PSD-95 to dendrites through PI3K-AKT signal­ ing after NMDA receptor activation. Nature Neuroscience, 10, 702–711.