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Cortical deficits of glutamic acid decarboxylase 67 expression in schizophrenia: clinical, protein, and cell type-specific features.
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OBJECTIVE: Cognitive deficits in schizophrenia are associated with altered activity of the dorsolateral prefrontal cortex, which has been attributed to lower expression of the 67 kDa isoform of glutamic acid decarboxylase (GAD67), the major γ-aminobutyric acid (GABA)-synthesizing enzyme. However, little is known about the relationship of prefrontal GAD67 mRNA levels and illness severity, translation of the transcript into protein, and protein levels in axon terminals, the key site of GABA production and function. METHOD: Quantitative polymerase chain reaction was used to measure GAD67 mRNA levels in postmortem specimens of dorsolateral prefrontal cortex from subjects with schizophrenia and matched comparison subjects with no known history of psychiatric or neurological disorders (N=42 pairs). In a subset of this cohort in which potential confounds of protein measures were controlled (N=19 pairs), Western blotting was used to quantify tissue levels of GAD67 protein in tissue. In five of these pairs, multilabel confocal immunofluorescence was used to quantify GAD67 protein levels in the axon terminals of parvalbumin-containing GABA neurons, which are known to have low levels of GAD67 mRNA in schizophrenia. RESULTS: GAD67 mRNA levels were significantly lower in schizophrenia subjects (by 15%), but transcript levels were not associated with predictors or measures of illness severity or chronicity. In schizophrenia subjects, GAD67 protein levels were significantly lower in total gray matter (by 10%) and in parvalbumin axon terminals (by 49%). CONCLUSIONS: The findings that lower GAD67 mRNA expression is common in schizophrenia, that it is not a consequence of having the illness, and that it leads to less translation of the protein, especially in the axon terminals of parvalbumin-containing neurons, support the hypothesis that lower GABA synthesis in parvalbumin neurons contributes to dorsolateral prefrontal cortex dysfunction and impaired cognition in schizophrenia.
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“Reduced PV and GAD67 protein levels are also seen in both prefrontal and temporal cortex of post-mortem brain tissues (Beasley and Reynolds, 1997; Curley et al., 2011; Glausier et al., 2014).”
From The Perineuronal ‘Safety’ Net? Perineuronal Net Abnormalities in Neurological Disorders (2018) · cites this paper as Curley et al., 2011
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Metadata
- Authors
- Curley, A. A., Arion, D., Volk, D. W., Asafu-Adjei, J. K., Sampson, A. R., Fish, K. N., & Lewis, D. A.
- Affiliations
- University of Pittsburgh (US)
- Venue
- American Journal of Psychiatry
- Published
- 2011-09
- Volume
- 168
- Issue
- 9
- Pages
- 921-929
- ISSN
- 0002-953X (ISSN-L)
- 1535-7228
- PMC
- PMC3273780
- OpenAlex
- W2159400463
- Cited by
- 283
- References
- 43
- Citations by year
- 2026: 10 · 2025: 13 · 2024: 11 · 2023: 15 · 2022: 13 · 2021: 16 · 2020: 12 · 2019: 22 · 2018: 24 · 2017: 20 · 2016: 23 · 2015: 28 · 2014: 28 · 2013: 23 · 2012: 16
- FWCI
- 16.41
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal of Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Bristol-Myers Squibb
- Pfizer
- AstraZeneca
- SK Life Science
- National Institutes of Health
- National Institute of Mental Health (P50MH084053, MH084053, R21MH085108, MH085108, R01MH043784, MH084016, K08MH084016, 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, glutamic acid decarboxylase 67, GAD67, GABA synthesis, dorsolateral prefrontal cortex, parvalbumin neurons, axon terminals, GABAergic interneurons, cognitive impairment, postmortem brain
- MeSH terms
- Adult, Cognition Disorders, Female, gamma-Aminobutyric Acid, Glutamate Decarboxylase, Humans, Male, Microscopy, Fluorescence, Middle Aged, Neurons, Parvalbumins, Reference Values, RNA, Messenger, Schizophrenia, Blotting, Western, Cohort Studies, Prefrontal Cortex, Presynaptic Terminals
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