A schizophrenia-related sensorimotor deficit links α3-containing GABA A receptors to a dopamine hyperfunction
Open accessAbstract
Overactivity of the dopaminergic system in the brain is considered to be a contributing factor to the development and symptomatology of schizophrenia. Therefore, the GABAergic control of dopamine functions was assessed by disrupting the gene encoding the alpha3 subunit of the GABA(A) receptor. alpha3 knockout (alpha3KO) mice exhibited neither an obvious developmental defect nor apparent morphological brain abnormalities, and there was no evidence for compensatory up-regulation of other major GABA(A)-receptor subunits. Anxiety-related behavior in the elevated-plus-maze test was undisturbed, and the anxiolytic-like effect of diazepam, which is mediated by alpha2-containing GABA(A) receptors, was preserved. As a result of the loss of alpha3 GABA(A) receptors, the GABA-induced whole-cell current recorded from midbrain dopamine neurons was significantly reduced. Spontaneous locomotor activity was slightly elevated in alpha3KO mice. Most notably, prepulse inhibition of the acoustic startle reflex was markedly attenuated in the alpha3KO mice, pointing to a deficit in sensorimotor information processing. This deficit was completely normalized by treatment with the antipsychotic D2-receptor antagonist haloperidol. The amphetamine-induced hyperlocomotion was not altered in alpha3KO mice compared with WT mice. These results suggest that the absence of alpha3-subunit-containing GABA(A) receptors induces a hyperdopaminergic phenotype, including a severe deficit in sensorimotor gating, a common feature among psychiatric conditions, including schizophrenia. Hence, agonists acting at alpha3-containing GABA(A) receptors may constitute an avenue for an effective treatment of sensorimotor-gating deficits in various psychiatric conditions.
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α5GABAARs have been implicated most consistently in memory, with knockdown, knockout, or pharmacological suppression of α5GABAARs leading to improvements in learning and memory.
“α5GABAARs, which are expressed most intensively in the hippocampus and deep layers of cortex, have been implicated most consistently in memory, with knockdown, knockout, or pharmacological suppression of α5GABAARs leading to improvements in learning and memory [56-61].”
From An emerging circuit pharmacology of GABAA receptors (2018) · cites this paper as [57]
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- Authors
- Yee, B. K., Keist, R., von Boehmer, L., Studer, R., Benke, D., Hagenbuch, N., Dong, Y., Malenka, R. C., Fritschy, J.-M., Bluethmann, H., Feldon, J., Möhler, H., & Rudolph, U.
- Affiliations
- University of Zurich (CH)
- Institute of Pharmacology and Toxicology, University of Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland; Laboratory of Behavioral Neurobiology and Department of Chemistry and Applied Biosciences and Collegium Helveticum, Swiss Federal Institute of Technology Zürich, Schorenstrasse 16, CH-8603 Schwerzenbach, Switzerland; Nancy Pritzker Laboratory, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, MSLS P104, Stanford, CA 94305-5485; and Roche Center...
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2005-11-11
- Volume
- 102
- Issue
- 47
- Pages
- 17154-17159
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC1288020
- OpenAlex
- W2147434999
- Cited by
- 201
- References
- 45
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 2 · 2023: 1 · 2022: 6 · 2021: 14 · 2020: 4 · 2019: 4 · 2018: 12 · 2017: 4 · 2016: 4 · 2015: 5 · 2014: 11 · 2013: 15 · 2012: 12
- FWCI
- 11.23
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Science Foundation
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- 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, prepulse inhibition, sensorimotor gating, acoustic startle response, dopaminergic neurons, haloperidol, diazepam, locomotor activity, GABA-A receptor agonists
- MeSH terms
- Amphetamine, Animals, Diazepam, Disease Models, Animal, Dopamine, Electrophysiology, Haloperidol, Immunohistochemistry, Motor Activity, Receptors, GABA-A, Schizophrenia, Anti-Anxiety Agents, Ion Channel Gating, Mice, Knockout, Gene Targeting, GABA Modulators, Protein Subunits, Mice
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