期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 103, 期 41, 页码 15230-15235出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0604304103
关键词
tonic inhibition; THIP; analgesia; sedative/hypnotic
资金
- NIAAA NIH HHS [AA13646, R01 AA013004, R37 AA007680, R01 AA007680, AA13004, R01 AA013646, AA07680] Funding Source: Medline
- NIDCR NIH HHS [DE14184, K08 DE014184] Funding Source: Medline
- NIGMS NIH HHS [GM45129, R01 GM045129] Funding Source: Medline
- NINDS NIH HHS [P01 NS035985, NS35985] Funding Source: Medline
- BLRD VA [I01 BX000404] Funding Source: Medline
The neurotransmitter GABA mediates the majority of rapid inhibition in the CNS. inhibition can occur via the conventional mechanism, the transient activation of subsynaptic GABA(A) receptors (GABA(A)-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 GABA(A)-R alpha 4 subunit is expressed at high levels in the dentate gyrus and thalamus and is suspected to contribute to extrasynaptic GABA(A)-R-mediated tonic inhibition. Mice were engineered to lack the alpha 4 subunit by targeted disruption of the Gabra4 gene. alpha 4 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 GABA(A)-Rs containing the alpha 4 subunit and that gaboxadol achieves its effects via the activation of this GABA(A)-R subtype.
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