GABAA receptor subtypes: Therapeutic potential in down syndrome, affective disorders, schizophrenia, and autism

Uwe Rudolph, Hanns Möhler

Research output: Contribution to journalReview articlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)483-507
Number of pages25
JournalAnnual Review of Pharmacology and Toxicology
Volume54
DOIs
StatePublished - Jan 2014
Externally publishedYes

Keywords

  • Anxiolytics
  • Autism
  • Cognition enhancer
  • Depression
  • Down syndrome
  • Schizophrenia

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

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