NMDA receptors and schizophrenia

NMDA receptors and schizophrenia Lars V Kristiansen, Ibone Huerta, Monica Beneyto and James H Meador-Woodruff The pathophysiology of schizophrenia is poorly understood but is likely to involve alterations in excitatory glutamatergic signaling molecules in several areas of the brain. Clinical and experimental evidence has shown that expression of the Nmethyl-D-asparate (NMDA) receptor and intracellular NMDA receptor-interacting proteins of the glutaminergic synapse appear to be dysregulated in schizophrenia. It has been suggested that schizophrenia involves molecular changes in the glutamatergic pathways that mediate excitatory communication between multiple brain regions. Recent data also implicate abnormalities in cellular functions such as receptor trafficking and synaptic targeting. Addresses University of Alabama at Birmingham, Department of Psychiatry and Behavioral Neurobiology, SC560, 1530 3rd Avenue South, Birmingham, AL 35294-0017, USA Corresponding author: Kristiansen, Lars V ([email protected])

Current Opinion in Pharmacology 2007, 7:48–55 This review comes from a themed issue on Neurosciences Edited by Karima Chergui, Bertil Fredholm and Per Svenningsson

additional risk factor for schizophrenia, possibly owing to increased prenatal and early childhood stress [3]. Several neurotransmitter systems have been implicated in the pathophysiology of schizophrenia [4]. The ‘glutamate hypothesis of schizophrenia’ emerged in the early 1980s as an alternative to the prevailing theory of altered dopamine neurotransmission. It is based on studies showing that non-competitive antagonists of the N-methyl-Dasparate (NMDA) subtype of glutamate receptors, such as phencyclicine (PCP), ketamine and MK-801, induce in healthy individuals a psychosis resembling both the positive and negative symptoms of schizophrenia and, when administered to patients with schizophrenia, can worsen these symptoms [5]. Together, these observations suggest diminished function of the NMDA receptor in this disorder. Evidence from morphological, clinical and neuroimaging studies have also provided support for a glutamate component to the pathophysiology of schizophrenia by mapping cognitive impairment, alterations in blood flow and changes in neuronal morphology to particular brain areas, including the frontal and cingulate cortices, both of which are areas with extensive excitatory glutamatergic neurotransmission [6,7].

Available online 9th November 2006 1471-4892/$ – see front matter # 2006 Elsevier Ltd. All rights reserved. DOI 10.1016/j.coph.2006.08.013

Introduction Schizophrenia is a chronic debilitating psychiatric illness characterized by positive, negative and cognitive symptoms that affects approximately 1% of the population [1]. Positive symptoms of schizophrenia include hallucinations, delusions and disorganized speech and behavior, whereas negative symptoms include flattened or restricted affect and lack of motivation. Cognitive symptoms involve compromised working memory, learning and symptoms associated with cortical processing. The etiology of schizophrenia is unknown, but there is epidemiological evidence to suggest that increased vulnerability is associated with environmental factors and developmental insults, superimposed on genetic predisposition. The likelihood of a genetic component in schizophrenia is illustrated by the significantly higher incidence of the disorder in affected families, especially in monozygotic twins, for which concordance rates reach 50% [2]. Interestingly, whereas ethnicity appears to be a largely independent factor, socioeconomic status is an Current Opinion in Pharmacology 2007, 7:48–55

In this review, we present the most recent evidence for abnormal expression and regulation of the NMDA receptor and its interacting molecules of the postsynaptic density (PSD) in schizophrenia. We primarily focus on evidence from studies using postmortem brain, and discuss current attempts to use the NMDA receptor complex as a target for the treatment of symptoms associated with schizophrenia.

The NMDA receptor complex Stoichiometry of the NMDA receptor

From their function as selective ion channels or mediators of G-protein-activated second messenger systems, glutamate receptors can be divided into ionotropic or metabotropic glutamate receptors [8]. The ionotropic NMDA receptor is a multimeric assembly of at least one obligatory NR1 subunit in combination with different constellations of NR2 and/or NR3 subunits. Through alternative splicing of the NR1 gene, which gives rise to eight different NR1 isoforms, and by forming different combinations with NR2 (NR2A, NR2B, NR2C and NR2D) and NR3 subunits (NR3A and NR3B), a multitude of different NMDA receptors — with differing pharmacological properties — are expressed in a tissue- and developmentspecific manner [9–13]. An additional level of NMDA receptor complexity is achieved through differential www.sciencedirect.com

NMDA receptors and schizophrenia Kristiansen et al. 49

post-translational modifications, including phosphorylation, glycosylation and ubiquitination, which influence both function and cellular localization of the receptor [14,15]. The importance of these parameters, especially in relation to their possible dysregulation in psychiatric illnesses, is only starting to emerge.

compounds have been identified, including MK801, ketamine, PCP, 2-amino-5-phosphonopentanoic acid and 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid, which all are antagonists of the NMDA receptor.

NMDA receptor regulation

Although the NMDA receptor is expressed in glia, its expression is principally located to dendritic spines where, through subunit-specific interactions, it connects to intracellular molecules of the postsynaptic multi-protein network known as the PSD [22,23]. These proteins include signaling and structural proteins such as neuronal intermediate filament (NF-L), myosin regulatory light chain, and proteins of the actin cytoskeleton [24–26,27]. These interactions probably help stabilize the NMDA receptor in the PSD [28,29]. Additionally, a set of NMDA-interacting PSD proteins belonging to the large group of membrane-associated guanylate kinase proteins, including PSD-95/SAP90, PSD-93/chapsin-110 and SAP102/hDLG3, have received special attention

The NMDA receptor is a highly permeable ligand-gated Ca2+ channel, which is regulated by voltage-dependent Mg2+ blockade. Receptor activation, characterized by slow channel kinetics and dependency on a-amino-3hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated depolarization of the postsynaptic membrane, requires, in addition to glutamate binding, concordant binding of D-serine to its NR1-associated binding site [16] (Figure 1). The channel properties of the NMDA receptor are further modulated by allosteric receptor binding sites for zinc, protons and the polyamines spermidine and spermine [17–21]. In addition, several artificially derived NMDA receptor modulatory

NMDA receptor-interacting proteins of the postsynaptic density

Figure 1

NMDA receptor organization. Schematic presentation of the NMDA receptor, with superimposed tertiary structures for the NR1 and NR2 subunits demonstrating N-terminal binding sites for glycine/D-serine and glutamate agonists, as well as binding sites for modulatory endogenous and exogenous ligands. Binding of PSD proteins to the C-termini of NR1 (NF-L) and NR2 (PSD-95, PSD-93 and SAP102) subunits is illustrated by arrows. Alternative splicing of the C1/C2/C2’ cassettes in the NR1 subunit, indicated by black and green boxes, determine binding to intracellular proteins such as NF-L. Retention and export motifs in the C-terminus of the NR1 subunit (amino acid sequences RRR and STVV, respectively), as well as the NR2-associated motif for PDZ recognition (amino acid sequence ESDV), are also shown. www.sciencedirect.com

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owing to their function as mediators of NMDA receptor signaling [30–32]. PSD-95 also links NMDA receptors to AMPA receptors through its binding to stargazin, and to group I metabotropic glutamate receptors via interactions with the scaffolding proteins GKAP (guanylate kinaseassociated protein), Shank and Homer [33,34]. Thus, postsynaptic glutamate receptors are organized into functional units that permit cooperation between different receptor types, thereby forming an integrated postsynaptic signaling complex [35,36,37,38].

have further complicated analysis of the available data. Thus, although no alterations in transcript expression for the NR1 subunit have been described in the frontal pole or parieto-temporal cortex in schizophrenia [42], increased transcript expression has been reported in the dorsolateral prefrontal cortex (DLPFC), occipital cortex [43] and superior temporal gyrus [44]. Other studies, however, have found decreased NR1 transcript expression in the DLPFC [45] and superior temporal regions [46]. Analyses of NR2 transcripts have shown an increased contribution of the NR2D subunit to the total pool of NR2 subunits, and a small but significant decrease of NR2C [42] in the prefrontal cortex. No changes have been reported for transcripts encoding NR2B in the DLPFC and occipital cortex, whereas a small increase in NR2A transcripts was seen in the occipital cortex [43]. One study found transcripts for NR3A significantly increased in a subfield of the DLPFC, with unaltered expression in the inferior temporal cortex [47]. Taken together, transcriptional changes of NMDA subunit expression in cortical areas appear to be associated with specific regions and, overall, might indicate altered stoichiometry of the NMDA receptor in schizophrenia, possibly owing to alterations in cortical glutamatergic neurotransmission.

In addition to their functions as PSD scaffolding proteins, PSD-95 and SAP102 are involved in dendritic trafficking of newly synthesized NMDA receptors and their subsequent targeting to the PSD. Early in the synthesis pathway, while still in the endoplasmatic reticulum, either PSD-95 or SAP102 binds to the newly assembled NMDA receptor and facilitates its interaction with transporting complexes [39–41]. Abnormalities in expression of these molecules could, in addition to resulting in receptor signaling disturbances, interfere with NMDA receptor trafficking and targeting, and thus affect excitatory neurotransmission.

Postmortem studies in schizophrenia In addition to studies of transcript expression, recent efforts have focused on analysis of protein levels of these subunits. Total cortical NR1 protein expression was unchanged both in the orbitofrontal cortex, as measured by immunoautoradiography [48], and in the superior temporal cortex, DLPFC and anterior cingulate cortex (ACC),

Cerebral cortex

Studies of cortical NMDA receptor expression in schizophrenia have found variable changes in transcript and protein expression depending upon the cortical area and receptor subunit examined (Table 1). In addition, differences in detection methodology and cohorts investigated Table 1

Summary of studies of NMDA receptor abnormalities in schizophrenia using postmortem brain samples. Brain Region

Subarea

Cortex

Frontal pole DLPFC

NR1

NR2B

NR2C

NR2D

&

&

#

"

Temporal

Refs

"

[42,48] [43,45,47,49]

& "

NF-L

PSD-95

PSD-93

SAP102

&

&

&

&

& "

& &

&

&

Hippocampus

&

Thalamus

Thalamus

&

#"

&

Refs [48] [43,49, 59,60] [49]

[49]

Hippocampus

Basal ganglia

NR3A

a

ACC Parietal lobe Occipital

NR2A

[44,46,47,50] [42] [43]

[43,60]

&

&

[48,61,62,63, 64]

&

#&

&

[65,66]

#"

[48,59,60, 61] #"

#"

Dorsomedial

[67]

[65,68, 69] [67]

Ventral

[67]

[67]

Striatum Accumbens

&

&

&

&

&

Substantia nigra

"

&

&

&

&

&

&

[70]

&

#

&

#

[73] [74]

[72]

&

&

&

&

[72]

Table summarizing studies in postmortem brain of NMDA receptor subunit and PSD protein expression in cortex, hippocampus, thalamus and basal ganglia. Black symbols indicate transcript and red symbols represent protein data. Open boxes represent unpublished transcript data. Increased and decreased expression is indicated by arrows (up and down, respectively). Unchanged expression is represented by a box). a Selective increase of one NR1 isoform but no change in total NR1 expression.

Current Opinion in Pharmacology 2007, 7:48–55

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NMDA receptors and schizophrenia Kristiansen et al. 51

as shown by Western blot analysis [49,50]. Interestingly, although no change in total NR1 protein expression was found, one study reported increased expression of the NR1-C2’ isoform in the ACC [49]. As distinct C-terminal NR1 isoforms associate with different pathways for synaptic trafficking and targeting, differential expression of these splice variants might lead to abnormal NMDA receptor trafficking [51,52]. The identification of specific cellular processes, such as receptor trafficking and targeting, that might be involved in schizophrenia suggests subtle perturbations of cell biology of this illness, permitting the generation of new hypotheses concerning specific aspects of cellular dysfunction, and of novel targets for new drug discovery. In addition to direct quantification of the individual NMDA receptor subunits, receptor autoradiography has identified differences in NMDA receptor expression in the cortex in schizophrenia. [3H]MK-801 binding has been reported to be increased in the ACC [53], but unchanged in frontal or temporal cortices [54,55]. However, binding of [3H]TCP [N-(1-[thienyl] cyclohexyl)piperidine], a ligand for the intrachannel PCP site also recognized by MK-801, was found to be increased only in the orbitofrontal cortex, and unchanged in other cortical areas [56,57]. Interestingly, increased glycine/D-serine site ([3H]L 689 560) and polyamine site ([3H]ifenprodil) binding has been reported in temporal, but not in motor and prefrontal, cortices [50,58]. In summary, typically modest and occasionally contradictory transcript and protein expression patterns of NMDA receptors have been reported in the cortex, suggesting that other components of the receptor signaling complex might be affected in schizophrenia. Expression of several NMDA receptor-associated proteins of the PSD have been evaluated and found to be significantly altered in schizophrenia. In a recent study, NF-L transcript expression was increased in the DLPFC, whereas NF-L protein expression was decreased [49]. Considering its function in NMDA receptor anchoring and cytoskeletal stability, abnormalities in NF-L expression might be associated with altered synaptic NMDA receptor localization. Decreased PSD-95 transcript expression has been found in the DLPFC [59], whereas expression was increased in the occipital cortex [43]. Increased transcript but decreased protein expression have been reported for both PSD-93 and PSD-95 in the ACC [49]. Such alterations of transcript and protein levels in opposite directions could suggest abnormal cellular processing of the NMDA receptor, including transcript and protein synthesis and/or protein stability. Protein expression of PSD-95, PSD-93 and SAP102 in the occipital cortex is not altered [60]. Finally, expression of SAP102 has consistently been reported to be unchanged in the DLPFC, ACC and occipital cortex in schizophrenia [49,60]. www.sciencedirect.com

Hippocampus

Studies of NMDA receptor subunit expression in schizophrenia have also been performed in the hippocampus. These studies have reported unchanged expression of transcripts for all receptor subunits [61], decreased transcripts encoding NR1, increased expression of NR2B transcripts, or unchanged NR2A transcript expression [62,63]. Receptor subunit protein expression, as evaluated by NR1 immunoautoradiography, however, is unchanged [48]. NMDA receptor autoradiography is not altered for [H3]-glutamate, [H3]MK801 or [H3]CGP39653 binding [61,63]. Few studies have investigated the expression of NMDAassociated PSD molecules in the hippocampus in schizophrenia. However, NF-L, PSD-95, PSD-93 and SAP-102 transcript expression does not appear to be altered in the hippocampus [59,61]. Levels of protein expression has been reported to be decreased for PSD-95 and SAP102, whereas PSD-93 expression is not altered [48,60]. Thalamus

An initial study found no changes in NR1 and NR2A transcript expression in thalamic nuclei in a small sample (n = 5) in schizophrenia [64]. Differences in the expression of transcripts encoding different NMDA receptor subunits in two different and larger cohorts have subsequently been reported. In a younger group of subjects, increased expression of NR2B transcripts was found [65], whereas thalamic expression of transcripts for NR1, NR2B and NR2C were decreased in a study of older subjects [66]. NR2A and NR2D expression levels were unchanged in both studies. Taken together, these results suggest that different NMDA receptor-related cellular processes might be compromised as a function of the progression of the disorder, emphasizing the importance of subject characteristics such as age when interpreting data. Increased NR2B protein expression was found in the dorsomedial, but not ventral thalamic, nuclei in schizophrenia, and no change in NR1 and NR2A expression were seen [67]. Interestingly, although binding to the glycine/D-serine ([3H]MDL105, 519) and polyamine sites ([3H]-ifenprodil) was decreased in the thalamus, as measured by receptor autoradiography, [3H]MK-801 binding was unchanged [66]. These data on transcript expression, binding and protein expression suggest that, although the total number of thalamic NMDA receptors might remain normal, receptor stoichiometry appears to be altered [67]. Similar to thalamic expression of NMDA receptor subunits, age-related differences in the expression of NMDA receptor-interacting PSD molecules have been described. Decreased NF-L transcript expression was observed in younger subjects [68], but was increased in an older group [69]. PSD-95 and SAP102 showed similar cohort-dependent alterations in transcript expression levels, with Current Opinion in Pharmacology 2007, 7:48–55

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decreased expression associated with younger subjects and increased expression in those who were older [65,69].

Figure 2

Increased PSD-95 protein expression has been reported in the dorsomedial, but not ventral, thalamus in schizophrenia [67]. SAP102, PSD-95 and NF-L protein expression levels were unchanged [67]. Consistent with studies in the cortex, abnormal expression of NMDA-associated PSD proteins in thalamus suggests altered postsynaptic receptor trafficking and signaling in schizophrenia. Basal ganglia

No changes have been reported in the expression of any NMDA receptor subunit transcript in the striatum in schizophrenia [70], although increased [3H]MK-801 and [3H]L-689 560 binding have been detected in the putamen but not in the caudate or nucleus accumbens, indicating increased receptor density in certain areas of the striatum [54,71]. In the substantia nigra, increased NR1, but unchanged NR2A-D and NR3A, mRNA expression was identified [72]. Consistent with other brain regions, striatal expression of NMDA receptorinteracting PSD proteins is altered in schizophrenia. One study reported decreased PSD-95 and SAP102 transcript expression, with unchanged NF-L and PSD-93 transcripts, in the striatum [73]. Another study, however, demonstrated increased PSD-95 protein expression in the nucleus accumbens of an unmedicated group of schizophrenia patients [74]. No changes in these proteins have been found in the substantia nigra [72]. Summary of postmortem findings

Taken together, altered expression of the NMDA receptor complex in schizophrenia affects many of the major brain glutamatergic pathways (Figure 2). Interestingly, the most consistent changes are found in brain areas interconnected by specific projections (i.e. the prefrontal and anterior cingulate cortices, which are reciprocally connected with the dorsomedial and anterior thalamic nuclei). In addition, combined results from several recent postmortem studies indicate that alterations associated with the NMDA receptor in schizophrenia involve more complex cellular changes than previously assumed. These new insights into specific alterations of cellular function in schizophrenia could potentially provide new pharmaceutical targets for drug discovery.

Effects of antipsychotic drugs on NMDA subunits and related proteins Previous reports have demonstrated effects of both acute [75] and chronic antipsychotic treatment [76–78] on the expression of NMDA receptor subunits in rats. Not haloperidol, clozapine nor sulpiride has been found to influence NR1 transcript levels in the frontal cortex [75,77]. However, in a different study, clozapine Current Opinion in Pharmacology 2007, 7:48–55

Simplified diagram of the main neurochemical pathways implicated in the pathophysiology of schizophrenia. The intricate interconnections between cortical and subcortical structures are, in addition to glutamate, modulated by the g-aminobutyric acid (GABA)ergic and dopaminergic systems that also have been reported to be altered in schizophrenia. GP, globus pallidus; PFC, prefrontal cortex; Ret, reticular formation; SN, substantia nigra; VTA, ventral tegmental area.

downregulated NR1 and NR2A mRNA expression in the frontal cortex, without affecting [3H]MK801 binding, whereas chronic haloperidol treatment reduced only frontal NR2A transcript expression. None of these drugs had any effect on the expression of NR2B, NR2C or NR2D subunits [78]. Riva et al. [76], however, found a reduction in NR2C mRNA levels following three weeks of clozapine treatment, and decreased levels of NR2B transcript following acute, but not chronic, administration of haloperidol [75,79]. Toyoda et al. [75] found that NR2A and NR2B transcript levels were decreased after acute administration of sulpiride, whereas expression of NR2A and NR2B were increased following chronic administration. From these animal studies, it is clear that evaluation of antipsychotic medication status is highly dependent upon the type and length of antipsychotic treatment, emphasizing the importance of including these measures when interpreting findings from postmortem studies. www.sciencedirect.com

NMDA receptors and schizophrenia Kristiansen et al. 53

Therapeutic approaches involving the NMDA receptor complex NMDA receptor dysfunction in schizophrenia has resulted in attempts to alleviate the associated symptoms in patients. Negative and cognitive symptoms of schizophrenia are only modestly responsive to conventional antipsychotic medications. When given in combination with antipsychotic drugs, positive modulators of the glycine/D-serine site of the NMDA receptor, such as Dserine, glycine or D-alanine, significantly improve symptoms in patients with schizophrenia [80,81]. Interestingly, inhibition of glycine reuptake by sarcosine, an antagonist of the glycine transporter 1, was more effective at reducing both positive and negative symptoms than was direct activation of the glycine/D-serine site by D-serine [82]. Together with direct activators of the NMDA receptor, future treatments are likely to include drugs that enhance the production of endogenous modulators of the NMDA receptor, such as serine racemase, an astrocytic enzyme synthesizing D-serine. Interestingly, expression of this enzyme was recently reported to be altered in schizophrenia [83]. The potential to target activity and expression of a multitude of synaptic and extrasynaptic molecules involved in synthesis and control of NMDA receptor function could produce new drugs with enhanced efficacy in patients with schizophrenia.

Conclusions Observations from postmortem studies, as well as from other lines of research into the pathophysiology of this disorder, reflect the complexity of schizophrenia. Molecular abnormalities in the glutamatergic circuitry, especially those involving the NMDA receptor complex, are likely to be involved in the pathophysiology of schizophrenia, and are potential relevant targets for drug treatment. The current knowledge of molecular regulation of the NMDA receptor complex should help guide future research into this disorder.

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This work was supported by grants from NIH (MH53327 and MH70895) and The Stanley Foundation (Dr Meador-Woodruff) as well as NARSAD (Dr Beneyto).

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