NMDA receptors and schizophrenia
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).
References (83)
- et al.
Altered cortical glutamate neurotransmission in schizophrenia: evidence from morphological studies of pyramidal neurons
Ann N Y Acad Sci
(2003) - et al.
NMDA receptor subunits: diversity, development and disease
Curr Opin Neurobiol
(2001) - et al.
Specific assembly with the NMDA receptor 3B subunit controls surface expression and calcium permeability of NMDA receptors
J Neurosci
(2003) - et al.
The micromolar zinc-binding domain on the NMDA receptor subunit NR2B
J Neurosci
(2005) - et al.
Neuronal and glial localization of NR1 and NR2A/B subunits of the NMDA receptor in the human cerebral cortex
Cereb Cortex
(1999) - et al.
Expression of NMDA glutamate receptor subunit mRNAs in neurochemically identified projection and interneurons in the striatum of the rat
Brain Res Mol Brain Res
(1999) - et al.
Direct interaction of myosin regulatory light chain with the NMDA receptor
J Neurochem
(2005) - et al.
Receptor compartmentalization and trafficking at glutamate synapses: a developmental proposal
Trends Neurosci
(2004) - et al.
Differential localization and regulation of stargazin-like protein, gamma-8 and stargazin in the plasma membrane of hippocampal and cortical neurons
Neurosci Res
(2006) - et al.
Subunit dependencies of N-methyl-D-aspartate (NMDA) receptor-induced alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor internalization
Mol Pharmacol
(2006)
Tyrosine phosphatases regulate AMPA receptor trafficking during metabotropic glutamate receptor-mediated long-term depression
J Neurosci
Alternative splicing of the C-terminal domain regulates cell surface expression of the NMDA receptor NR1 subunit
J Neurosci
Synaptic targeting of N-methyl-D-aspartate receptor splice variants is regulated differentially by receptor activity
Neuroscience
AMPA receptor binding in the dorsolateral prefrontal cortex of schizophrenics and controls
Schizophr Res
Alterations in phencyclidine and sigma binding sites in schizophrenic brains. Effects of disease process and neuroleptic medication
Schizophr Res
NR2B-containing NMDA receptors are up-regulated in temporal cortex in schizophrenia
Neuroreport
Selective reduction of a PDZ protein, SAP-97, in the prefrontal cortex of patients with chronic schizophrenia
J Neurochem
Asymmetrical reductions of hippocampal NMDAR1 glutamate receptor mRNA in the psychoses
Neuroreport
Altered transcript expression of NMDA receptor-associated postsynaptic proteins in the thalamus of subjects with schizophrenia
Am J Psychiatry
Synapse-associated protein 90/postsynaptic density-95-associated protein (SAPAP) is expressed differentially in phencyclidine-treated rats and is increased in the nucleus accumbens of patients with schizophrenia
Neuropsychopharmacology
Regulation of NMDA receptor subunit messenger RNA levels in the rat brain following acute and chronic exposure to antipsychotic drugs
Brain Res Mol Brain Res
Effects of long-term antipsychotic treatment on NMDA receptor binding and gene expression of subunits
Neurochem Res
Vesl/Homer proteins regulate ryanodine receptor type 2 function and intracellular calcium signaling
Cell Calcium
Sarcosine or D-serine add-on treatment for acute exacerbation of schizophrenia: a randomized, double-blind, placebo-controlled study
Arch Gen Psychiatry
Phenotype of schizophrenia: a review and formulation
Mol Psychiatry
A review of the evidence from family, twin and adoption studies for a genetic contribution to adult psychiatric disorders
Int Rev Psychiatry
Socioeconomic position and major mental disorders
Epidemiol Rev
Schizophrenia: a review of neuropharmacology
Ir J Med Sci
Glutamate and its role in psychiatric illness
Hum Psychopharmacol
Frontal-subcortical neuronal circuits and clinical neuropsychiatry: an update
J Psychosom Res
Molecular biology and ontogeny of glutamate receptors in the mammalian central nervous system
J Child Neurol
Subunit characterization of NMDA receptors
Curr Drug Targets
NMDA receptor pharmacology: perspectives from molecular biology
Curr Drug Targets
NMDA receptor subunit gene expression in the rat brain: a quantitative analysis of endogenous mRNA levels of NR1Com, NR2A, NR2B, NR2C, NR2D and NR3A
Brain Res Mol Brain Res
Modulation of NMDA receptors in the cerebellum. 1. Properties of the NMDA receptor that modulate its function
Cerebellum
Regulation of the NMDA receptor complex and trafficking by activity-dependent phosphorylation of the NR2B subunit PDZ ligand
J Neurosci
Glia-derived D-serine controls NMDA receptor activity and synaptic memory
Cell
A steroid modulatory domain on NR2B controls N-methyl-d-aspartate receptor proton sensitivity
Proc Natl Acad Sci USA
Control of voltage-independent zinc inhibition of NMDA receptors by the NR1 subunit
J Neurosci
Subunit- and site-specific pharmacology of the NMDA receptor channel
Prog Neurobiol
Cited by (206)
The crosstalk between 5-HT<inf>2A</inf>R and mGluR2 in schizophrenia
2023, NeuropharmacologyMusic rhythm perception and production relate to treatment response in schizophrenia
2023, Schizophrenia ResearchAxonal transport deficits in neuropsychiatric disorders
2022, Molecular and Cellular NeuroscienceAdvances in novel molecular targets for antidepressants
2021, Progress in Neuro-Psychopharmacology and Biological PsychiatryPrenatal exposure to environmental insults and enhanced risk of developing Schizophrenia and Autism Spectrum Disorder: focus on biological pathways and epigenetic mechanisms
2020, Neuroscience and Biobehavioral ReviewsKetamine a dissociative anesthetic: Neurobiology and biomolecular exploration in depression
2020, Chemico-Biological Interactions