GABA receptor subunit distribution and FMRP-mGluR5 signaling abnormalities in the cerebellum of subjects with schizophrenia, mood disorders, and autism

S H Fatemi, Timothy D. Folsom

Research output: Contribution to journalReview articlepeer-review

57 Scopus citations

Abstract

Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the brain. GABAergic receptor abnormalities have been documented in several major psychiatric disorders including schizophrenia, mood disorders, and autism. Abnormal expression of mRNA and protein for multiple GABA receptors has also been observed in multiple brain regions leading to alterations in the balance between excitatory/inhibitory signaling in the brain with potential profound consequences for normal cognition and maintenance of mood and perception. Altered expression of GABAA receptor subunits has been documented in fragile X mental retardation 1 (FMR1) knockout mice, suggesting that loss of its protein product, fragile X mental retardation protein (FMRP), impacts GABAA subunit expression. Recent postmortem studies from our laboratory have shown reduced expression of FMRP in the brains of subjects with schizophrenia, bipolar disorder, major depression, and autism. FMRP acts as a translational repressor and, under normal conditions, inhibits metabotropic glutamate receptor 5 (mGluR5)-mediated signaling. In fragile X syndrome (FXS), the absence of FMRP is hypothesized to lead to unregulated mGluR5 signaling, ultimately resulting in the behavioral and intellectual impairments associated with this disorder. Our laboratory has identified changes in mGluR5 expression in autism, schizophrenia, and mood disorders. In the current review article, we discuss our postmortem data on GABA receptors, FMRP, and mGluR5 levels and compare our results with other laboratories. Finally, we discuss the interactions between these molecules and the potential for new therapeutic interventions that target these interconnected signaling systems.

Original languageEnglish (US)
Pages (from-to)42-56
Number of pages15
JournalSchizophrenia Research
Volume167
Issue number1-3
DOIs
StatePublished - Sep 1 2015

Bibliographical note

Funding Information:
Grant support by the National Institute of Child Health and Human Development (# 5R01HD052074-01A2 and 3R01HD052074-03S1 ), the National Institute of Mental Health (# 1R01MH086000-01A2 ), the Winston and Maxine Wallin Neuroscience Discovery Fund , and the Ewald Bipolar Disease Research Fund to SHF is gratefully acknowledged. S.H. Fatemi is also supported by the Bernstein Endowed Chair in Adult Psychiatry .

Funding Information:
Funding for this study was provided by the National Institute of Child Health and Human Development (NICHD), grant #5R01HD052074-01A2 and 3R01HD052074-03S1, the National Institute of Mental Health (NIMH), grant #5R01MH086000-01A2, the Winston and Maxine Wallin Neuroscience Discovery Fund, and the Ewald Bipolar Disease Research Fund (SHF). NICHD, NIMH, the Winston and Maxine Wallin Neuroscience Discovery Fund and the Ewald Bipolar Disease Research Fund had no further role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

Publisher Copyright:
© 2014 Elsevier B.V..

Keywords

  • Bipolar disorder
  • Cerebellum
  • FMRP
  • GABA
  • MGluR5
  • Schizophrenia

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