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 GABA 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, α-subunit-containing GABA receptors permit the bidirectional modulation of cognitive processes, and a partial inverse agonist acting at the α-subunit-containing GABA 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 α- and α-subunit-containing GABA 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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  • Article Type: Review Article
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