Cited by 319Neuroscience and Neuropharmacology ResearchReceptor Mechanisms and SignalingNicotinic Acetylcholine Receptors Study

GABA A Receptor Subtypes: Therapeutic Potential in Down Syndrome, Affective Disorders, Schizophrenia, and Autism

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Rudolph, Uwe, Möhler, Hanns·2014·Annual Review of Pharmacology and Toxicology

Abstract

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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Research works printed but not linked: 5

  1. [13]Glykys J Mann EO Mody I Which GABAA receptor subunits are necessary for tonic inhibition in the hippocampus? J. Neurosci 2008 28 1421 -26 18256262 PMC6671570
  2. Crestani F Keist R Fritschy JM Benke D Vogt K Trace fear conditioning involves hippocampal α5 GABAA receptors. Proc. Natl. Acad. Sci. USA 2002 99 8980 -85 12084936 PMC124409
  3. [58]McGaugh JL Time-dependent processes in memory storage. Science 1966 153 1351 -58 5917768
  4. [94]Atack JR Wafford KA Tye SJ Cook SM Sohal B TPA023, an agonist selective for α2- and α3-containing GABAA receptors, is a non-sedating anxiolytic in rodents and primates. J. Pharm. Exp. Ther 2006 316 410 -22 16183706
  5. Lüscher B Fuchs T Kilpatrick CL GABAA receptor trafficking-mediated plasticity of inhibitory synapses. Neuron 2011 70 385 -409 21555068 PMC3093971

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Authors
Rudolph, U., & Möhler, H.
Affiliations
  • Harvard University (US)
  • University of Zurich (CH)
Venue
Annual Review of Pharmacology and Toxicology
Published
2014-01-06
Volume
54
Issue
1
Pages
483-507
ISSN
  • 0362-1642 (ISSN-L)
  • 1545-4304
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
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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