Lower Expression of Glutamic Acid Decarboxylase 67 in the Prefrontal Cortex in Schizophrenia: Contribution of Altered Regulation by Zif268
Open accessAbstract
OBJECTIVE: Cognitive deficits of schizophrenia may be due at least in part to lower expression of the 67-kDa isoform of glutamic acid decarboxylase (GAD67), a key enzyme for GABA synthesis, in the dorsolateral prefrontal cortex of individuals with schizophrenia. However, little is known about the molecular regulation of lower cortical GAD67 levels in schizophrenia. The GAD67 promoter region contains a conserved Zif268 binding site, and Zif268 activation is accompanied by increased GAD67 expression. Thus, altered expression of the immediate early gene Zif268 may contribute to lower levels of GAD67 mRNA in the dorsolateral prefrontal cortex in schizophrenia. METHOD: The authors used polymerase chain reaction to quantify GAD67 and Zif268 mRNA levels in dorsolateral prefrontal cortex area 9 from 62 matched pairs of schizophrenia and healthy comparison subjects, and in situ hybridization to assess Zif268 expression at laminar and cellular levels of resolution. The effects of potentially confounding variables were assessed in human subjects, and the effects of antipsychotic treatments were tested in antipsychotic-exposed monkeys. The specificity of the Zif268 findings was assessed by quantifying mRNA levels for other immediate early genes. RESULTS: GAD67 and Zif268 mRNA levels were significantly lower and were positively correlated in the schizophrenia subjects. Both Zif268 mRNA-positive neuron density and Zif268 mRNA levels per neuron were significantly lower in the schizophrenia subjects. These findings were robust to the effects of the confounding variables examined and differed from other immediate early genes. CONCLUSIONS: Deficient Zif268 mRNA expression may contribute to lower cortical GAD67 levels in schizophrenia, suggesting a potential mechanistic basis for altered cortical GABA synthesis and impaired cognition in schizophrenia.
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Each of these factors could affect the excitability of parvalbumin neurons and contribute to lower expression of activity-dependent genes, such as Zif268 and GAD67, in parvalbumin neurons.
“Each of these factors could affect the excitability of PV neurons and contribute to lower expression of activity-dependent genes, such as Zif268 and GAD67 (Kimoto et al, 2014), in PV neurons.”
From Reduced Labeling of Parvalbumin Neurons and Perineuronal Nets in the Dorsolateral Prefrontal Cortex of Subjects with Schizophrenia (2016) · cites this paper as Kimoto et al, 2014
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- Authors
- Kimoto, S., Bazmi, H. H., & Lewis, D. A.
- Affiliations
- University of Pittsburgh (US)
- Corresponding author
- Lewis, David A.
- Venue
- American Journal of Psychiatry
- Published
- 2014-09
- Volume
- 171
- Issue
- 9
- Pages
- 969-978
- ISSN
- 0002-953X (ISSN-L)
- 1535-7228
- PMC
- PMC4376371
- OpenAlex
- W2137313711
- Cited by
- 91
- References
- 42
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 6 · 2023: 6 · 2022: 6 · 2021: 7 · 2020: 4 · 2019: 6 · 2018: 8 · 2017: 9 · 2016: 9 · 2015: 18 · 2014: 2
- FWCI
- 9.66
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal of Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Bristol-Myers Squibb
- Pfizer
- Sunovion
- Concert Pharmaceuticals
- Nara Medical University
- National Institutes of Health (MH043784, MH084053)
- National Institute of Mental Health (P50MH084053, MH084053, R01MH043784, R37MH043784, MH043784)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- schizophrenia, GAD67, Zif268, immediate early genes, dorsolateral prefrontal cortex, GABA synthesis, GABAergic neurons, cognitive impairment, antipsychotic effects, gene expression regulation, neuronal density
- MeSH terms
- Adult, Animals, Autopsy, Cognition Disorders, Disease Models, Animal, Female, gamma-Aminobutyric Acid, Glutamate Decarboxylase, Humans, Isoenzymes, Macaca fascicularis, Male, Middle Aged, Promoter Regions, Genetic, Schizophrenia, Antipsychotic Agents, Gene Expression Regulation, Enzymologic, Confounding Factors, Epidemiologic, Drug Monitoring, Prefrontal Cortex
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