GABA A Receptor Subtypes: Therapeutic Potential in Down Syndrome, Affective Disorders, Schizophrenia, and Autism
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The γ-aminobutyric acid (GABA) system plays a pivotal role in orchestrating the synchronicity of local networks and the functional coupling of different brain regions. Here we review the impact of the GABAA receptor subtypes on cognitive and emotional behavior, paying particular attention to five disease states: cognitive dysfunction and Down syndrome, anxiety disorders, depression, schizophrenia, and autism. Through the bidirectional modulation of tonic inhibition, α5-subunit-containing GABAA receptors permit the bidirectional modulation of cognitive processes, and a partial inverse agonist acting at the α5-subunit-containing GABAA receptor is in a clinical trial in individuals with Down syndrome. With regard to anxiety disorders, the viability of nonsedative anxiolytics based on the modulation of α2- and α3-subunit-containing GABAA receptors has been established in clinical proof-of-concept trials. Regarding the remaining three disease states, the GABA hypothesis of depression offers new options for antidepressant drug development; cognitive symptoms in schizophrenia are attributed to a cortical GABAergic deficit, and dysfunctional GABAergic inhibition is increasingly understood to contribute to the pathophysiology of autism spectrum disorders.
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α2GABAARs are densely expressed in the central amygdala.
“α2-GABAARs are densely expressed in the central amygdala [35, 36, 40], but their precise cellular location and function are still unknown.”
From An emerging circuit pharmacology of GABAA receptors (2018) · cites this paper as [40]
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Hippocampal α5 subunit-containing GABAA receptors modulate the expression of prepulse inhibition
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Functional mapping of GABAA receptor subtypes in the amygdala
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The use of cognitive enhancers in animal models of fear extinction.
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Molecular Basis for the GABAA Receptor-Mediated Tonic Inhibition in Rat Somatosensory Cortex
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Antidepressant-like properties of α2-containing GABAA receptors
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Resolving differences in GABAA receptor mutant mouse studies
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Mouse Models for Down Syndrome-Associated Developmental Cognitive Disabilities
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The yin and yang of cortical layer 1
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Self-citationGABAA Receptor α Subunits Differentially Contribute to Diazepam Tolerance after Chronic Treatment
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Gerdjikov, T. V., Rudolph, U., Keist, R., Möhler, H., Feldon, J., & Yee, B. K. (2008) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2007.06.003 · Cited by 43 · see citing works
Self-citationReversal of Ketamine-Induced Working Memory Impairments by the GABAAα2/3 Agonist TPA023
Castner, S. A., Arriza, J. L., Roberts, J. C., Mrzljak, L., Christian, E. P., & Williams, G. V. (2010) · Biological Psychiatry · doi:10.1016/j.biopsych.2010.01.001 · Cited by 37 · see citing works
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Diazepam and cocaine potentiate brain stimulation reward in C57BL/6J mice
Straub, C. J., Carlezon, W. A., & Rudolph, U. (2009) · Behavioural Brain Research · doi:10.1016/j.bbr.2009.08.025 · Cited by 33 · see citing works
Self-citationModulation of α5 Subunit‐Containing GABAA Receptors Alters Alcohol Drinking by Rhesus Monkeys
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Efficacy and Safety of Zopiclone and Eszopiclone in the Treatment of Primary and Comorbid Insomnia
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Flagged first, then by citations
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- Authors
- Rudolph, U., & Möhler, H.
- Affiliations
- Harvard University (US)
- University of Zurich (CH)
- ORCID
- Rudolph, Uwe
- Venue
- Annual Review of Pharmacology and Toxicology
- Publisher
- Annual Reviews
- Published
- 2014-01-06
- Volume
- 54
- Issue
- 1
- Pages
- 483-507
- ISSN
- 0362-1642 (ISSN-L)
- 1545-4304
- PMC
- PMC3997216
- OpenAlex
- W2128784337
- Cited by
- 319
- References
- 149
- Citations by year
- 2026: 16 · 2025: 17 · 2024: 14 · 2023: 13 · 2022: 25 · 2021: 20 · 2020: 26 · 2019: 34 · 2018: 39 · 2017: 31 · 2016: 30 · 2015: 30 · 2014: 23
- FWCI
- 2.82
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Annual Review of Pharmacology and Toxicology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute of Mental Health (R01MH095905, R01MH080006, MH094834, MH095905, R03MH094834, MH080006)
- National Institute on Drug Abuse (DA033491, R03DA033491)
- National Institute of General Medical Sciences (R01GM086448, GM086448)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
- Keywords
- GABAA receptor subtypes, GABA system, Down syndrome, cognitive impairment, anxiety disorders, depression, schizophrenia, autism spectrum disorder, inverse agonists, tonic inhibition
- MeSH terms
- Animals, Autistic Disorder, Brain, Clinical Trials as Topic, Cognition, Disease Models, Animal, Down Syndrome, Humans, Memory, Receptors, GABA-A, Schizophrenia, Mood Disorders, Molecular Targeted Therapy
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