NMDA receptors and schizophrenia

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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.

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 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-d-asparate (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].

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.

Section snippets

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

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 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],

Effects of antipsychotic drugs on NMDA subunits and related proteins

Previous reports have demonstrated effects of both acute [75] and chronic antipsychotic treatment [76, 77, 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

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 D-serine, glycine or D-alanine, significantly improve symptoms in patients with schizophrenia [80, 81]. Interestingly, inhibition

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

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

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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