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PMID: 23543703 Published · epublish English Journal Article

NMDA hypofunction as a convergence point for progression and symptoms of schizophrenia.

Frontiers in cellular neuroscience ·Vol. 7 ·2013-00-00 ·Pages 31

Snyder MA, Gao WJ

Abstract

Schizophrenia is a disabling mental illness that is now recognized as a neurodevelopmental disorder. It is likely that genetic risk factors interact with environmental perturbations to affect normal brain development and that this altered trajectory results in a combination of positive, negative, and cognitive symptoms. Although the exact pathophysiology of schizophrenia is unknown, the N-methyl-D-aspartate receptor (NMDAR), a major glutamate receptor subtype, has received great attention. Proper expression and regulation of NMDARs in the brain is critical for learning and memory processes as well as cortical plasticity and maturation. Evidence from both animal models and human studies implicates a dysfunction of NMDARs both in disease progression and symptoms of schizophrenia. Furthermore, mutations in many of the known genetic risk factors for schizophrenia suggest that NMDAR hypofunction is a convergence point for schizophrenia. In this review, we discuss how disrupted NMDAR function leads to altered neurodevelopment that may contribute to the progression and development of symptoms for schizophrenia, particularly cognitive deficits. We review the shared signaling pathways among the schizophrenia susceptibility genes DISC1, neuregulin1, and dysbindin, focusing on the AKT/GSK3β pathway, and how their mutations and interactions can lead to NMDAR dysfunction during development. Additionally, we explore what open questions remain and suggest where schizophrenia research needs to move in order to provide mechanistic insight into the cause of NMDAR dysfunction, as well as generate possible new avenues for therapeutic intervention.

Keywords
NMDA receptors gene neurodevelopment psychiatric disorders schizophrenia
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Snyder Melissa A
Department of Neurobiology and Anatomy, Drexel University College of Medicine Philadelphia, PA, USA.
Gao Wen-Jun
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Article Info
Journal
Frontiers in cellular neuroscience
Abbr.
Front Cell Neurosci
ISSN
1662-5102
DOI
10.3389/fncel.2013.00031
Published
2013-00-00
Epub
2013-00-27
Pages
31
Language
English
Region
Switzerland
NLM ID
101477935
PMCID
PMC3608949
Grants
NIMH NIH HHS · R01 MH085666 · United States
External Links
PubMed source DOI: 10.3389/fncel.2013.00031 PMC Full Text View journal details
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