Altered Markers of Tonic Inhibition in the Dorsolateral Prefrontal Cortex of Subjects With Schizophrenia
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OBJECTIVE: Cognitive impairments in schizophrenia are associated with lower expression of markers of gamma-aminobutyric acid (GABA) synthesis in the prefrontal cortex. The effects of GABA are mediated by GABA(A) receptors that mediate either phasic or tonic inhibition. The authors assessed the expression of GABA(A) receptor alpha4 and delta subunits, which coassemble to form receptors mediating tonic inhibition, in schizophrenia. METHOD: The authors used in situ hybridization to quantify expression patterns of GABA(A) receptor alpha4 and delta subunits in prefrontal cortex from 23 matched pairs of schizophrenia and comparison subjects. RESULTS: Levels of delta mRNA were significantly lower in schizophrenia subjects regardless of medication use, whereas alpha4 mRNA levels were lower only in subjects with schizophrenia receiving certain medications at the time of death. To understand the nature of this unexpected dissociation between alpha4 and delta subunit expression in schizophrenia, the authors used similar methods to quantify alpha4 and delta mRNA levels in multiple animal models. During postnatal development of monkey prefrontal cortex, levels of alpha4 mRNA decreased, whereas delta mRNA levels increased. In addition, delta mRNA levels, but not alpha4 mRNA levels, were lower in the medial frontal cortex of mice with a genetic deletion of the GABA(A) receptor alpha1 subunit, and neither delta nor alpha4 mRNA levels were altered in rodent models of altered excitatory neurotransmission. CONCLUSIONS: Since GABA(A) receptor alpha1 subunits also have lower mRNA levels in schizophrenia, show increased expression with age in monkey prefrontal cortex, and can coassemble with delta subunits to form functional GABA(A) receptors, lower delta mRNA levels in schizophrenia might reflect a reduced number of alpha(1)beta(x)delta GABA(A) receptors that could contribute to deficient tonic inhibition and prefrontal cortical dysfunction in schizophrenia.
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Strong data suggesting disinhibition in animal models of schizophrenia parallels the highly replicated observation of interneuron deficits in schizophrenia patients detected in postmortem studies.
“The strong data suggesting disinhibition in animal models of schizophrenia parallels the highly replicated observation of interneuron deficits in schizophrenia patients detected in postmortem studies.78”
From Adolescent Onset of Cortical Disinhibition in Schizophrenia: Insights From Animal Models (2011) · cites this paper as [78]
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- Authors
- Maldonado-Avilés, J. G., Curley, A. A., Hashimoto, T., Morrow, A. L., Ramsey, A. J., O’Donnell, P., Volk, D. W., & Lewis, D. A.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Lewis, David A.
- ORCID
- Venue
- American Journal of Psychiatry
- Published
- 2009-04
- Volume
- 166
- Issue
- 4
- Pages
- 450-459
- ISSN
- 0002-953X (ISSN-L)
- 1535-7228
- PMC
- PMC2887737
- OpenAlex
- W2161166148
- Cited by
- 91
- References
- 39
- Citations by year
- 2026: 3 · 2025: 1 · 2024: 3 · 2023: 4 · 2022: 2 · 2021: 4 · 2020: 1 · 2019: 4 · 2018: 3 · 2017: 7 · 2016: 11 · 2015: 9 · 2014: 8 · 2013: 7 · 2012: 2
- FWCI
- 4.95
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal of Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- D-Scholarship@Pitt (University of Pittsburgh) (acceptedVersion)
- PubMed Central (acceptedVersion)
- ProQuest Demo Repository (submittedVersion)
- Funders
- Bristol-Myers Squibb
- Eli Lilly and Company
- Pfizer
- F. Hoffmann-La Roche
- National Institutes of Health (MH043784, MH084053)
- National Institute of Mental Health (P50MH084053, MH084053, R01MH043784, MH057683, R56MH057683, F31MH079732, R01MH057683, MH079732, 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, tonic inhibition, GABAA receptor, GABA-A receptor alpha1 subunit, dorsolateral prefrontal cortex, GABA synthesis, cognitive impairment, postnatal development, antipsychotic drugs
- MeSH terms
- Adult, Aged, Animals, Cognition Disorders, Disease Models, Animal, Female, Humans, Macaca fascicularis, Macaca mulatta, Male, Memory, Short-Term, Middle Aged, Neural Inhibition, Synaptic Transmission, Receptors, GABA-A, RNA, Messenger, Schizophrenia, Gene Expression, Prefrontal Cortex, Mice, Knockout, Mice, Rats
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