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