Elsevier

Brain Research Bulletin

Volume 83, Issues 3–4, 30 September 2010, Pages 108-121
Brain Research Bulletin

Research report
N-methyl-d-aspartate (NMDA) receptor dysfunction or dysregulation: The final common pathway on the road to schizophrenia?

https://doi.org/10.1016/j.brainresbull.2010.04.006Get rights and content

Abstract

Schizophrenia is a severe mental disorder associated with a characteristic constellation of symptoms and neurocognitive deficits. At present, etiological mechanisms remain relatively unknown, although multiple points of convergence have been identified over recent years. One of the primary convergence points is dysfunction of N-methyl-d-aspartate (NMDAR)-type glutamate receptors. Antagonists of NMDAR produce a clinical syndrome that closely resembles, and uniquely incorporates negative and cognitive symptoms of schizophrenia, along with the specific pattern of neurocognitive dysfunction seen in schizophrenia. Genetic polymorphisms involving NMDAR subunits, particularly the GRIN2B subunit have been described. In addition, polymorphisms have been described in modulatory systems involving the NMDAR, including the enzymes serine racemase and d-amino acid oxidase/G72 that regulate brain d-serine synthesis. Reductions in plasma and brain glycine, d-serine and glutathione levels have been described as well, providing potential mechanisms underlying NMDAR dysfunction. Unique characteristics of the NMDAR are described that may explain the characteristic pattern of symptoms and neurocognitive deficits observed in schizophrenia. Finally, the NMDAR complex represents a convergence point for potential new treatment approaches in schizophrenia aimed at correcting underlying abnormalities in synthesis and regulation of allosteric modulators, as well as more general potentiation of pre- and post-synaptic glutamatergic and NMDAR function.

Section snippets

NMDA receptor dysfunction as a convergence point for schizophrenia

NMDARs are a type of receptor for the neurotransmitter glutamate, which is the primary excitatory neurotransmitter in the brain. Glutamate accounts for 100% of pyramidal neurons, virtually all cortico-cortical neurotransmission and approximately 60% of total brain neurons. Glutamate mediates its neurophysiological effects through both ionotropic and metabotropic receptor types. Ionotropic receptors, which are linked to intrinsic ionic channels, include NMDA-, AMPA- and kainite-type receptors in

Intrinsic functional characteristics of NMDAR

Although all neurotransmitter receptors are unique, some are more unique than others. In the case of NMDAR, several features distinguish them from other ligand-gated channel receptors, and make NMDA receptors particularly unique. Structurally, NMDAR are heteroligomers with multiple subunits surrounding a central pore than serves as an intrinsic ion channel. Subunits are divided into NR1, NR2 and NR3 subtypes, with functional receptors containing an NR1 subunit along with multiple additional NR2

Regulatory features of NMDAR

In addition to the intrinsic characteristics of NMDAR that make them a potential convergence point for theories of schizophrenia, NMDAR are also subject to complex modulatory processes within brain. Thus, even in the absence of intrinsic abnormalities of NMDAR themselves, dysregulation of NMDAR is possible via a number of convergent mechanisms. An emerging story from the genetics of schizophrenia is the potential contribution of numerous genes of small effect size, many of which converge on

Clinical symptoms as a convergence point for NMDAR models

The ability of PCP or ketamine to induce a schizophrenia-like psychosis has by now become well established [64], [78], [93], [99]. Although PCP psychosis is sometimes suggested as a model for negative-symptom schizophrenia, and amphetamine- or LSD-psychosis, as a model for positive symptoms [46], such a clear distinction does not hold up upon closer inspection. In PCP- or ketamine-induced psychosis, the relative proportions of positive and negative symptoms are highly similar to those observed

Neuropsychological deficits as a convergence point for NMDAR models

Glutamatergic models provide a framework from which to view the pattern of the core neuropsychological dysfunction [20], [44] associated with schizophrenia. Unlike dopaminergic models of schizophrenia, which predict mainly prefrontal dysfunction, in studies that have utilized comprehensive neuropsychological batteries, similar levels of deficit have been observed across multiple neurocognitive domains, particularly in learning and declarative memory formation [82].

Because glutamatergic systems

Sensory deficits in schizophrenia

Because NMDAR are located in both sensory and higher cognitive brain regions, a key prediction of NMDAR models is that schizophrenia should be associated with impaired processing within sensory brain regions. Studies over recent years have confirmed such deficits, providing both support for NMDAR models and increased insight into mechanisms underlying cognitive impairment in schizophrenia. To date, studies addressing integrity of sensory systems have been performed primarily in auditory and

Conclusion

Over the last 40 years, the DA model has been the leading neurochemical hypothesis of schizophrenia. This model has proven heuristically valuable, with all current medications for schizophrenia functioning primarily to block DA D2 receptors. Yet it remains unlikely that dopaminergic dysfunction, on its own, can fully account for the wide range of symptoms and neurocognitive deficits seen in schizophrenia.

Glutamatergic models provide an alternate approach for conceptualizing the brain

Conflict of interest

Dr. Javitt holds intellectual property rights for use of glycine, d-serine and glycine transport inhibitors in treatment of schizophrenia and related disorders.

Acknowledgements

Supported in part by USPHS grants R37 MH49334 and R01 DA03383 to DCJ and by the NYU Conte Center (P50 MH086385).

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