Open AccessGABA A receptor α4 subunits mediate extrasynaptic inhibition in thalamus and dentate gyrus and the action of gaboxadol
Author(s) -
Dev Chandra,
Jia Fan,
Jing Liang,
Zebo Peng,
Asha Suryanarayanan,
David F. Werner,
Igor Spigelman,
Carolyn R. Houser,
Richard W. Olsen,
Neil L. Harrison,
Gregg E. Homanics
Publication year - 2006
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.0604304103
Subject(s) - dentate gyrus , gabaa receptor , neuroscience , knockout mouse , thalamus , pharmacology , gamma aminobutyric acid , biology , gabaa rho receptor , chemistry , receptor , hippocampus , biochemistry
The neurotransmitter GABA mediates the majority of rapid inhibition in the CNS. Inhibition can occur via the conventional mechanism, the transient activation of subsynaptic GABAA receptors (GABAA -Rs), or via continuous activation of high-affinity receptors by low concentrations of ambient GABA, leading to “tonic” inhibition that can control levels of excitability and network activity. The GABAA -R α4 subunit is expressed at high levels in the dentate gyrus and thalamus and is suspected to contribute to extrasynaptic GABAA -R-mediated tonic inhibition. Mice were engineered to lack the α4 subunit by targeted disruption of theGabra4 gene. α4 Subunit knockout mice are viable, breed normally, and are superficially indistinguishable from WT mice. In electrophysiological recordings, these mice show a lack of tonic inhibition in dentate granule cells and thalamic relay neurons. Behaviorally, knockout mice are insensitive to the ataxic, sedative, and analgesic effects of the novel hypnotic drug, gaboxadol. These data demonstrate that tonic inhibition in dentate granule cells and thalamic relay neurons is mediated by extrasynaptic GABAA -Rs containing the α4 subunit and that gaboxadol achieves its effects via the activation of this GABAA -R subtype.