6043747 nmda receptors and schizophrenia

NMDA receptors and schizophreniaLars V Kristiansen, Ibone Huerta, Monica Beneyto andJames 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 N-

methyl-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

Available online 9th November 2006

1471-4892/$ – see front matter

# 2006 Elsevier Ltd. All rights reserved.

DOI 10.1016/j.coph.2006.08.013

IntroductionSchizophrenia is a chronic debilitating psychiatric illness

characterized by positive, negative and cognitive symp-

toms that affects approximately 1% of the population

[1��]. Positive symptoms of schizophrenia include hallu-

cinations, delusions and disorganized speech and beha-

vior, whereas negative symptoms include flattened or

restricted affect and lack of motivation. Cognitive symp-

toms involve compromised working memory, learning

and symptoms associated with cortical processing. The

etiology of schizophrenia is unknown, but there is epi-

demiological evidence to suggest that increased vulner-

ability is associated with environmental factors and

developmental insults, superimposed on genetic predis-

position. The likelihood of a genetic component in schi-

zophrenia 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


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 ‘gluta-

mate hypothesis of schizophrenia’ emerged in the early

1980s as an alternative to the prevailing theory of altered

dopamine neurotransmission. It is based on studies show-

ing that non-competitive antagonists of the N-methyl-D-

asparate (NMDA) subtype of glutamate receptors, such as

phencyclicine (PCP), ketamine and MK-801, induce in

healthy individuals a psychosis resembling both the posi-

tive 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 dis-

order. Evidence from morphological, clinical and neuroi-

maging 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].

In this review, we present the most recent evidence for

abnormal expression and regulation of the NMDA recep-

tor and its interacting molecules of the postsynaptic

density (PSD) in schizophrenia. We primarily focus on

evidence from studies using postmortem brain, and dis-

cuss current attempts to use the NMDA receptor complex

as a target for the treatment of symptoms associated with

schizophrenia.

The NMDA receptor complexStoichiometry of the NMDA receptor

From their function as selective ion channels or mediators

of G-protein-activated second messenger systems, gluta-

mate receptors can be divided into ionotropic or metabo-

tropic 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 prop-

erties — are expressed in a tissue- and development-

specific manner [9–13]. An additional level of NMDA

receptor complexity is achieved through differential

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NMDA receptors and schizophrenia Kristiansen et al. 49

post-translational modifications, including phosphoryla-

tion, 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.

NMDA receptor regulation

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-3-

hydroxy-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 polya-

mines spermidine and spermine [17–21]. In addition,

several artificially derived NMDA receptor modulatory

Figure 1

NMDA receptor organization. Schematic presentation of the NMDA recepto

demonstrating N-terminal binding sites for glycine/D-serine and glutamate a

exogenous ligands. Binding of PSD proteins to the C-termini of NR1 (NF-L)

by arrows. Alternative splicing of the C1/C2/C2’ cassettes in the NR1 subun

intracellular proteins such as NF-L. Retention and export motifs in the C-ter

respectively), as well as the NR2-associated motif for PDZ recognition (amin


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-interacting proteins of the

postsynaptic density

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-pro-

tein 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

r, with superimposed tertiary structures for the NR1 and NR2 subunits

gonists, as well as binding sites for modulatory endogenous and

and NR2 (PSD-95, PSD-93 and SAP102) subunits is illustrated

it, indicated by black and green boxes, determine binding to

minus of the NR1 subunit (amino acid sequences RRR and STVV,

o acid sequence ESDV), are also shown.


50 Neurosciences

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 kinase-

associated protein), Shank and Homer [33,34]. Thus,

postsynaptic glutamate receptors are organized into func-

tional units that permit cooperation between different

receptor types, thereby forming an integrated postsynap-

tic signaling complex [35,36�,37,38].

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 subse-

quent targeting to the PSD. Early in the synthesis path-

way, 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 neu-

rotransmission.

Postmortem studies in schizophreniaCerebral cortex

Studies of cortical NMDA receptor expression in schizo-

phrenia have found variable changes in transcript and

protein expression depending upon the cortical area and

receptor subunit examined (Table 1). In addition, differ-

ences in detection methodology and cohorts investigated

Table 1

Summary of studies of NMDA receptor abnormalities in schizophreni

Brain

Region

Subarea NR1 NR2A NR2B NR2C NR2D N

Cortex Frontal pole & & # "DLPFC "

ACC a

Temporal & & & & &

Parietal lobe & & & & &

Occipital " " &

Hippo-

campus

Hippocampus & & &

Thalamus Thalamus & #" #& &

Dorsomedial

Ventral

Basal

ganglia

Striatum & & & & &

Accumbens

Substantia nigra " & & & & &

Table summarizing studies in postmortem brain of NMDA receptor subunit a

ganglia. Black symbols indicate transcript and red symbols represent protein

decreased expression is indicated by arrows (up and down, respectively).a Selective increase of one NR1 isoform but no change in total NR1 expre


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 super-

ior temporal gyrus [44]. Other studies, however, have found

decreased NR1 transcript expression in the DLPFC [45]

and superior temporal regions [46]. Analyses of NR2 tran-

scripts 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 signifi-

cantly increased in a subfield of the DLPFC, with unal-

tered 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 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 tem-

poral cortex, DLPFC and anterior cingulate cortex (ACC),

a using postmortem brain samples.

R3A Refs NF-L PSD-95 PSD-93 SAP102 Refs

[42,48] [48]

[43,45,47,49�] [43,49�,

59,60]

[49�] [49�]

[44,46,47,50]

[42]

[43] [43,60]

[48,61,62,63,

64]

& [48,59,60,

61]

[65,66] #" #" & #" [65,68,

69]

[67�] [67�]

[67�] [67�]

[70] & # & # [73]

[74]

[72] & & & & [72]

nd PSD protein expression in cortex, hippocampus, thalamus and basal

data. Open boxes represent unpublished transcript data. Increased and

Unchanged expression is represented by a box).

ssion.



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 synap-

tic 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 per-

turbations 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]. How-

ever, binding of [3H]TCP [N-(1-[thienyl] cyclohexyl)pi-

peridine], 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 cor-

tical areas [56,57]. Interestingly, increased glycine/D-ser-

ine 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 com-

ponents of the receptor signaling complex might be

affected in schizophrenia.

Expression of several NMDA receptor-associated pro-

teins 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 expres-

sion 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].


Hippocampus

Studies of NMDA receptor subunit expression in schizo-

phrenia have also been performed in the hippocampus.

These studies have reported unchanged expression of

transcripts for all receptor subunits [61], decreased tran-

scripts 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 NMDA-

associated PSD molecules in the hippocampus in schizo-

phrenia. 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 expres-

sion of transcripts encoding different NMDA receptor

subunits in two different and larger cohorts have subse-

quently 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 expres-

sion 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 sub-

units, 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-depen-

dent alterations in transcript expression levels, with


52 Neurosciences

Figure 2

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.

decreased expression associated with younger subjects

and increased expression in those who were older [65,69].

Increased PSD-95 protein expression has been reported

in the dorsomedial, but not ventral, thalamus in schizo-

phrenia [67�]. SAP102, PSD-95 and NF-L protein expres-

sion 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 puta-

men 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 receptor-

interacting PSD proteins is altered in schizophrenia.

One study reported decreased PSD-95 and SAP102 tran-

script 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 schizo-

phrenia 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 recep-

tor 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 post-

mortem studies indicate that alterations associated with

the NMDA receptor in schizophrenia involve more com-

plex cellular changes than previously assumed. These

new insights into specific alterations of cellular function

in schizophrenia could potentially provide new pharma-

ceutical targets for drug discovery.

Effects of antipsychotic drugs on NMDAsubunits and related proteinsPrevious 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


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, administra-

tion 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 post-

mortem studies.



Therapeutic approaches involving theNMDA receptor complexNMDA receptor dysfunction in schizophrenia has

resulted in attempts to alleviate the associated symptoms

in patients. Negative and cognitive symptoms of schizo-

phrenia are only modestly responsive to conventional

antipsychotic medications. When given in combination

with antipsychotic drugs, positive modulators of the gly-

cine/D-serine site of the NMDA receptor, such as D-

serine, glycine or D-alanine, significantly improve symp-

toms in patients with schizophrenia [80,81]. Interestingly,

inhibition of glycine reuptake by sarcosine, an antagonist

of the glycine transporter 1, was more effective at redu-

cing 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 schizo-

phrenia [83]. The potential to target activity and expres-

sion 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.

ConclusionsObservations from postmortem studies, as well as from

other lines of research into the pathophysiology of this

disorder, reflect the complexity of schizophrenia. Mole-

cular abnormalities in the glutamatergic circuitry, espe-

cially those involving the NMDA receptor complex, are

likely to be involved in the pathophysiology of schizo-

phrenia, and are potential relevant targets for drug treat-

ment. The current knowledge of molecular regulation of

the NMDA receptor complex should help guide future

research into this disorder.

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

References and recommended readingPapers of particular interest, published within the period of review,have been highlighted as:

� of special interest�� of outstanding interest

1.��

Tamminga CA, Holcomb HH: Phenotype of schizophrenia: areview and formulation. Mol Psychiatry 2005, 10:27-39.

This is a thorough review of the clinical features and molecular patho-physiology of schizophrenia.

2. Shih RA, Belmonte PL, Zandi PP: A review of the evidence fromfamily, twin and adoption studies for a genetic contribution toadult psychiatric disorders. Int Rev Psychiatry 2004, 16:260-283.

3. Muntaner C, Eaton WW, Miech R, O’Campo P: Socioeconomicposition and major mental disorders. Epidemiol Rev 2004,26:53-62.


4. Lyne J, Kelly BD, O’Connor WT: Schizophrenia: a review ofneuropharmacology. Ir J Med Sci 2004, 173:155-159.

5. Belsham B: Glutamate and its role in psychiatric illness.Hum Psychopharmacol 2001, 16:139-146.

6. Tekin S, Cummings JL: Frontal-subcortical neuronal circuitsand clinical neuropsychiatry: an update. J Psychosom Res2002, 53:647-654.

7. Lewis DA, Glantz LA, Pierri JN, Sweet RA: Altered corticalglutamate neurotransmission in schizophrenia: evidence frommorphological studies of pyramidal neurons. Ann N Y Acad Sci2003, 1003:102-112.

8. Simeone TA, Sanchez RM, Rho JM: Molecular biology andontogeny of glutamate receptors in the mammaliancentral nervous system. J Child Neurol 2004, 19:343-360,discussion 361.

9. Stephenson FA: Subunit characterization of NMDA receptors.Curr Drug Targets 2001, 2:233-239.

10. Lynch DR, Guttmann RP: NMDA receptor pharmacology:perspectives from molecular biology. Curr Drug Targets 2001,2:215-231.

11. Goebel DJ, Poosch MS: NMDA receptor subunit geneexpression in the rat brain: a quantitative analysis ofendogenous mRNA levels of NR1Com, NR2A, NR2B, NR2C,NR2D and NR3A. Brain Res Mol Brain Res 1999, 69:164-170.

12. Cull-Candy S, Brickley S, Farrant M: NMDA receptor subunits:diversity, development and disease. Curr Opin Neurobiol 2001,11:327-335.

13. Matsuda K, Fletcher M, Kamiya Y, Yuzaki M: Specific assemblywith the NMDA receptor 3B subunit controls surfaceexpression and calcium permeability of NMDA receptors.J Neurosci 2003, 23:10064-10073.

14. Llansola M, Sanchez-Perez A, Cauli O, Felipo V: Modulation ofNMDA receptors in the cerebellum. 1. Properties of the NMDAreceptor that modulate its function. Cerebellum 2005,4:154-161.

15. Chung HJ, Huang YH, Lau LF, Huganir RL: Regulation of theNMDA receptor complex and trafficking by activity-dependentphosphorylation of the NR2B subunit PDZ ligand.J Neurosci 2004, 24:10248-10259.

16.�

Panatier A, Theodosis DT, Mothet JP, Touquet B, Pollegioni L,Poulain DA, Oliet SH: Glia-derived D-serine controls NMDAreceptor activity and synaptic memory. Cell 2006, 125:775-784.

This paper demonstrates that astrocytic D-serine, not glycine, is theprimary ligand for the glycine modulatory site in the NMDA receptor.

17. Rachline J, Perin-Dureau F, Le Goff A, Neyton J, Paoletti P:The micromolar zinc-binding domain on the NMDA receptorsubunit NR2B. J Neurosci 2005, 25:308-317.

18. Jang MK, Mierke DF, Russek SJ, Farb DH: A steroid modulatorydomain on NR2B controls N-methyl-D-aspartate receptorproton sensitivity. Proc Natl Acad Sci USA 2004, 101:8198-8203.

19. Traynelis SF, Burgess MF, Zheng F, Lyuboslavsky P, Powers JL:Control of voltage-independent zinc inhibition of NMDAreceptors by the NR1 subunit. J Neurosci 1998, 18:6163-6175.

20. Yamakura T, Shimoji K: Subunit- and site-specificpharmacology of the NMDA receptor channel. Prog Neurobiol1999, 59:279-298.

21. Huggins DJ, Grant GH: The function of the amino terminaldomain in NMDA receptor modulation. J Mol Graph Model 2005,23:381-388.

22. Conti F, Barbaresi P, Melone M, Ducati A: Neuronal and gliallocalization of NR1 and NR2A/B subunits of the NMDAreceptor in the human cerebral cortex. Cereb Cortex 1999,9:110-120.

23. Standaert DG, Friberg IK, Landwehrmeyer GB, Young AB, PenneyJB Jr: Expression of NMDA glutamate receptor subunitmRNAs in neurochemically identified projection andinterneurons in the striatum of the rat. Brain Res Mol Brain Res1999, 64:11-23.


54 Neurosciences

24. Ehlers MD, Fung ET, O’Brien RJ, Huganir RL: Splice variant-specific interaction of the NMDA receptor subunit NR1 withneuronal intermediate filaments. J Neurosci 1998, 18:720-730.

25. Amparan D, Avram D, Thomas CG, Lindahl MG, Yang J, Bajaj G,Ishmael JE: Direct interaction of myosin regulatory light chainwith the NMDA receptor. J Neurochem 2005, 92:349-361.

26. Wyszynski M, Lin J, Rao A, Nigh E, Beggs AH, Craig AM, Sheng M:Competitive binding of alpha-actinin and calmodulin to theNMDA receptor. Nature 1997, 385:439-442.

27.�

Collins MO, Husi H, Yu L, Brandon JM, Anderson CN,Blackstock WP, Choudhary JS, Grant SG: Molecularcharacterization and comparison of the components andmultiprotein complexes in the postsynaptic proteome.J Neurochem 2006, 97(Suppl 1):16-23.

Proteomic analysis of NR1/NR2-associated PSD complexes from themouse central nervous system.

28. Nakagawa T, Engler JA, Sheng M: The dynamic turnover andfunctional roles of alpha-actinin in dendritic spines.Neuropharmacology 2004, 47:734-745.

29. Ratnam J, Teichberg VI: Neurofilament-light increases the cellsurface expression of the N-methyl-D-aspartate receptor andprevents its ubiquitination. J Neurochem 2005, 92:878-885.

30. Aoki C, Miko I, Oviedo H, Mikeladze-Dvali T, Alexandre L,Sweeney N, Bredt DS: Electron microscopicimmunocytochemical detection of PSD-95, PSD-93, SAP-102,and SAP-97 at postsynaptic, presynaptic, and nonsynapticsites of adult and neonatal rat visual cortex. Synapse 2001,40:239-257.

31. van Zundert B, Yoshii A, Constantine-Paton M: Receptorcompartmentalization and trafficking at glutamate synapses:a developmental proposal. Trends Neurosci 2004, 27:428-437.

32. Tao YX, Rumbaugh G, Wang GD, Petralia RS, Zhao C, Kauer FW,Tao F, Zhuo M, Wenthold RJ, Raja SN et al.: Impaired NMDAreceptor-mediated postsynaptic function and bluntedNMDA receptor-dependent persistent pain in mice lackingpostsynaptic density-93 protein. J Neurosci 2003,23:6703-6712.

33. Tu JC, Xiao B, Naisbitt S, Yuan JP, Petralia RS, Brakeman P,Doan A, Aakalu VK, Lanahan AA, Sheng M et al.: Coupling ofmGluR/Homer and PSD-95 complexes by the Shank family ofpostsynaptic density proteins. Neuron 1999, 23:583-592.

34. Inamura M, Itakura M, Okamoto H, Hoka S, Mizoguchi A,Fukazawa Y, Shigemoto R, Yamamori S, Takahashi M:Differential localization and regulation of stargazin-likeprotein, gamma-8 and stargazin in the plasma membraneof hippocampal and cortical neurons. Neurosci Res 2006,55:45-53.

35. Lindemeyer K, Leemhuis J, Loffler S, Grass N, Norenberg W,Meyer DK: Metabotropic glutamate receptors modulate theNMDA- and AMPA-induced gene expression in neocorticalinterneurons. Cereb Cortex 2006, 16:1662-1677.

36.�

Tigaret CM, Thalhammer A, Rast GF, Specht CG, Auberson YP,Stewart MG, Schoepfer R: Subunit dependencies ofN-methyl-D-aspartate (NMDA) receptor-induced alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)receptor internalization. Mol Pharmacol 2006, 69:1251-1259.

This paper demonstrates subtype-dependent functional interactionsbetween NMDA and AMPA receptors.

37. Moult PR, Gladding CM, Sanderson TM, Fitzjohn SM, Bashir ZI,Molnar E, Collingridge GL: Tyrosine phosphatases regulateAMPA receptor trafficking during metabotropic glutamatereceptor-mediated long-term depression. J Neurosci 2006,26:2544-2554.

38. Mangiavacchi S, Wolf ME: Stimulation of N-methyl-D-aspartatereceptors, AMPA receptors or metabotropic glutamatereceptors leads to rapid internalization of AMPA receptors incultured nucleus accumbens neurons. Eur J Neurosci 2004,20:649-657.

39. Guillaud L, Setou M, Hirokawa N: KIF17 dynamics and regulationof NR2B trafficking in hippocampal neurons. J Neurosci 2003,23:131-140.


40. Setou M, Nakagawa T, Seog DH, Hirokawa N: Kinesinsuperfamily motor protein KIF17 and mLin-10 in NMDAreceptor-containing vesicle transport. Science 2000,288:1796-1802.

41. Sans N, Prybylowski K, Petralia RS, Chang K, Wang YX, Racca C,Vicini S, Wenthold RJ: NMDA receptor trafficking through aninteraction between PDZ proteins and the exocyst complex.Nat Cell Biol 2003, 5:520-530.

42. Akbarian S, Sucher NJ, Bradley D, Tafazzoli A, Trinh D, Hetrick WP,Potkin SG, Sandman CA, Bunney WE Jr, Jones EG: Selectivealterations in gene expression for NMDA receptor subunits inprefrontal cortex of schizophrenics. J Neurosci 1996, 16:19-30.

43. Dracheva S, Marras SA, Elhakem SL, Kramer FR, Davis KL,Haroutunian V: N-methyl-D-aspartic acid receptor expressionin the dorsolateral prefrontal cortex of elderly patients withschizophrenia. Am J Psychiatry 2001, 158:1400-1410.

44. Le Corre S, Harper CG, Lopez P, Ward P, Catts S: Increasedlevels of expression of an NMDARI splice variant in thesuperior temporal gyrus in schizophrenia. Neuroreport 2000,11:983-986.

45. Sokolov BP: Expression of NMDAR1, GluR1, GluR7, and KA1glutamate receptor mRNAs is decreased in frontal cortex of‘neuroleptic-free’ schizophrenics: evidence on reversibleup-regulation by typical neuroleptics. J Neurochem 1998,71:2454-2464.

46. Humphries C, Mortimer A, Hirsch S, de Belleroche J: NMDAreceptor mRNA correlation with antemortem cognitiveimpairment in schizophrenia. Neuroreport 1996, 7:2051-2055.

47. Mueller HT, Meador-Woodruff JH: NR3A NMDA receptor subunitmRNA expression in schizophrenia, depression and bipolardisorder. Schizophr Res 2004, 71:361-370.

48. Toro C, Deakin JF: NMDA receptor subunit NRI andpostsynaptic protein PSD-95 in hippocampus andorbitofrontal cortex in schizophrenia and mood disorder.Schizophr Res 2005, 80:323-330.

49.�

Kristiansen LV, Beneyto M, Haroutunian V, Meador-Woodruff JH:Changes in NMDA receptor subunits and interacting PSDproteins in dorsolateral prefrontal and anterior cingulatecortex indicate abnormal regional expression inschizophrenia. Mol Psychiatry 2006, 11:737-747.

This paper reported alterations in the expression of NMDA receptorsubunits and related PSD proteins in the cortex in schizophrenia by bothin situ hybridization and Western blot analysis.

50. Nudmamud-Thanoi S, Reynolds GP: The NR1 subunit of theglutamate/NMDA receptor in the superior temporal cortex inschizophrenia and affective disorders. Neurosci Lett 2004,372:173-177.

51. Okabe S, Miwa A, Okado H: Alternative splicing of theC-terminal domain regulates cell surface expression of theNMDA receptor NR1 subunit. J Neurosci 1999, 19:7781-7792.

52. Pauly T, Schlicksupp A, Neugebauer R, Kuhse J: Synaptictargeting of N-methyl-D-aspartate receptor splice variants isregulated differentially by receptor activity. Neuroscience 2005,131:99-111.

53. Zavitsanou K, Ward PB, Huang XF: Selective alterations inionotropic glutamate receptors in the anterior cingulatecortex in schizophrenia. Neuropsychopharmacology 2002,27:826-833.

54. Kornhuber J, Mack-Burkhardt F, Riederer P, Hebenstreit GF,Reynolds GP, Andrews HB, Beckmann H: [3H]MK-801 bindingsites in postmortem brain regions of schizophrenic patients.J Neural Transm 1989, 77:231-236.

55. Noga JT, Hyde TM, Bachus SE, Herman MM, Kleinman JE: AMPAreceptor binding in the dorsolateral prefrontal cortex ofschizophrenics and controls. Schizophr Res 2001, 48:361-363.

56. Weissman AD, Casanova MF, Kleinman JE, London ED, DeSouza EB: Selective loss of cerebral cortical sigma, but not PCPbinding sites in schizophrenia. Biol Psychiatry 1991, 29:41-54.

57. Simpson MD, Slater P, Royston MC, Deakin JF: Alterations inphencyclidine and sigma binding sites in schizophrenic



brains. Effects of disease process and neurolepticmedication. Schizophr Res 1991, 6:41-48.

58. Grimwood S, Slater P, Deakin JF, Hutson PH: NR2B-containingNMDA receptors are up-regulated in temporal cortex inschizophrenia. Neuroreport 1999, 10:461-465.

59. Ohnuma T, Kato H, Arai H, Faull RL, McKenna PJ, Emson PC:Gene expression of PSD95 in prefrontal cortex andhippocampus in schizophrenia. Neuroreport 2000,11:3133-3137.

60. Toyooka K, Iritani S, Makifuchi T, Shirakawa O, Kitamura N,Maeda K, Nakamura R, Niizato K, Watanabe M, Kakita A et al.:Selective reduction of a PDZ protein, SAP-97, in the prefrontalcortex of patients with chronic schizophrenia. J Neurochem2002, 83:797-806.

61. McCullumsmith R, Kristiansen LV, Beneyto M, Scarr E, Dean B,Meador-Woodruff JH. Decreased NR1, NR2A, and SAP102transcript expression in the hippocampus in bipolar disorder.Brain Res 2006, in press.

62. Law AJ, Deakin JF: Asymmetrical reductions of hippocampalNMDAR1 glutamate receptor mRNA in the psychoses.Neuroreport 2001, 12:2971-2974.

63. Gao XM, Sakai K, Roberts RC, Conley RR, Dean B, Tamminga CA:Ionotropic glutamate receptors and expression of N-methyl-D-aspartate receptor subunits in subregions of humanhippocampus: effects of schizophrenia. Am J Psychiatry 2000,157:1141-1149.

64. Popken GJ, Leggio MG, Bunney WE, Jones EG: Expression ofmRNAs related to the GABAergic and glutamatergicneurotransmitter systems in the human thalamus: normal andschizophrenic. Thalamus and Related Systems 2002, 1:349-369.

65. Clinton SM, Meador-Woodruff JH: Abnormalities of the NMDAreceptor and associated intracellular molecules in thethalamus in schizophrenia and bipolar disorder.Neuropsychopharmacology 2004, 29:1353-1362.

66. Ibrahim HM, Hogg AJ Jr, Healy DJ, Haroutunian V, Davis KL,Meador-Woodruff JH: Ionotropic glutamate receptor bindingand subunit mRNA expression in thalamic nuclei inschizophrenia. Am J Psychiatry 2000, 157:1811-1823.

67.�

Clinton SM, Haroutunian V, Meador-Woodruff JH: Up-regulationof NMDA receptor subunit and post-synaptic density proteinexpression in the thalamus of elderly patients withschizophrenia. J Neurochem 2006, 98:1114-1125.

First study showing abnormalities in protein level expression of NMDA-interacting molecules in the thalamus in schizophrenia.

68. Clinton SM, Abelson S, Haroutunian V, Davis KL, Meador-Woodruff JH: Neurofilament subunit protein abnormalities inthe thalamus in shizophrenia. Thalamus and Related Systems2004, 2:265-272.

69. Clinton SM, Haroutunian V, Davis KL, Meador-Woodruff JH:Altered transcript expression of NMDA receptor-associatedpostsynaptic proteins in the thalamus of subjects withschizophrenia. Am J Psychiatry 2003, 160:1100-1109.

70. Meador-Woodruff JH, Hogg AJ Jr, Smith RE: Striatal ionotropicglutamate receptor expression in schizophrenia, bipolardisorder, and major depressive disorder. Brain Res Bull 2001,55:631-640.


71. Aparicio-Legarza MI, Davis B, Hutson PH, Reynolds GP:Increased density of glutamate/N-methyl-D-aspartatereceptors in putamen from schizophrenic patients.Neurosci Lett 1998, 241:143-146.

72. Mueller HT, Haroutunian V, Davis KL, Meador-Woodruff JH:Expression of the ionotropic glutamate receptor subunits andNMDA receptor-associated intracellular proteins in thesubstantia nigra in schizophrenia. Brain Res Mol Brain Res 2004,121:60-69.

73. Kristiansen LV, Meador-Woodruff JH: Abnormal striatalexpression of transcripts encoding NMDA interacting PSDproteins in schizophrenia, bipolar disorder and majordepression. Schizophr Res 2005, 78:87-93.

74. Kajimoto Y, Shirakawa O, Lin XH, Hashimoto T, Kitamura N,Murakami N, Takumi T, Maeda K: Synapse-associatedprotein 90/postsynaptic density-95-associated protein(SAPAP) is expressed differentially in phencyclidine-treatedrats and is increased in the nucleus accumbens of patientswith schizophrenia. Neuropsychopharmacology 2003,28:1831-1839.

75. Toyoda H, Takahata R, Inayama Y, Sakai J, Matsumura H,Yoneda H, Asaba H, Sakai T: Effect of antipsychotic drugs onthe gene expression of NMDA receptor subunits in rats.Neurochem Res 1997, 22:249-252.

76. Riva MA, Tascedda F, Lovati E, Racagni G: Regulation of NMDAreceptor subunit messenger RNA levels in the rat brainfollowing acute and chronic exposure to antipsychotic drugs.Brain Res Mol Brain Res 1997, 50:136-142.

77. Hanaoka T, Toyoda H, Mizuno T, Kikuyama H, Morimoto K,Takahata R, Matsumura H, Yoneda H: Alterations in NMDAreceptor subunit levels in the brain regions of rats chronicallyadministered typical or atypical antipsychotic drugs.Neurochem Res 2003, 28:919-924.

78. Schmitt A, Zink M, Muller B, May B, Herb A, Jatzko A, Braus DF,Henn FA: Effects of long-term antipsychotic treatment onNMDA receptor binding and gene expression of subunits.Neurochem Res 2003, 28:235-241.

79. Westhoff JH, Hwang SY, Scott Duncan R, Ozawa F, Volpe P,Inokuchi K, Koulen P: Vesl/Homer proteins regulate ryanodinereceptor type 2 function and intracellular calcium signaling.Cell Calcium 2003, 34:261-269.

80. Tsai GE, Yang P, Chang YC, Chong MY: D-alanine added toantipsychotics for the treatment of schizophrenia. BiolPsychiatry 2006, 59:230-234.

81. Heresco-Levy U, Javitt DC, Ebstein R, Vass A, Lichtenberg P,Bar G, Catinari S, Ermilov M: D-serine efficacy as add-onpharmacotherapy to risperidone and olanzapine fortreatment-refractory schizophrenia. Biol Psychiatry 2005,57:577-585.

82. Lane HY, Chang YC, Liu YC, Chiu CC, Tsai GE: Sarcosineor D-serine add-on treatment for acute exacerbationof schizophrenia: a randomized, double-blind, placebo-controlled study. Arch Gen Psychiatry 2005, 62:1196-1204.

83. Steffek AE, Haroutunian V, Meador-Woodruff JH: Serineracemase protein expression in cortex and hippocampus inschizophrenia. Neuroreport 2006, 17:1181-1185.


6043747 nmda receptors and schizophrenia

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