Tonic inhibition in principal cells of the amygdala: a central role for α3 subunit-containing GABAA receptors.
GABAergic inhibition in the amygdala is essential in regulating fear and anxiety. Although fast "phasic" inhibition arising through the activation of postsynaptic GABA(A) receptors (GABA(A)Rs) has been well described in the amygdala, much less is known about extrasynaptic GABA(A)Rs mediating persistent or tonic inhibition and regulating neuronal excitability. Here, we recorded tonic currents in the basolateral (BLA) nucleus and the lateral (LA) nucleus of the amygdala. While all BLA principal cells expressed a robust GABAergic tonic current, only 70% of LA principal cells showed a tonic current. Immunohistochemical stainings revealed that the α3 GABA(A)R subunit is expressed moderately in the LA and strongly throughout the BLA nucleus, where it is located mostly at extrasynaptic sites. In α3 subunit KO mice, tonic currents are significantly reduced in BLA principal cells yet not in LA principal cells. Moreover, the α3 GABA(A)R-selective benzodiazepine site agonist and anxiolytic compound TP003 increases tonic currents and dampens excitability markedly in wild-type BLA principal cells but fails to do so in α3KO BLA cells. Interneurons of the LA and BLA nuclei also express a tonic current, but TP003-induced potentiation is seen in only a small fraction of these cells, suggesting that primarily other GABA(A)R variants underlie tonic inhibition in this cell type. Together, these studies demonstrate that α3 GABA(A)R-mediated tonic inhibition is a central component of the inhibitory force in the amygdala and that tonically activated α3 GABA(A)Rs present an important target for anxiolytic or fear-reducing compounds.
Institute of Pharmacology and Toxicology, University of Zurich, CH-8057 Zurich, Switzerland. marowsky@pharma.uzh.ch
Anne
A
Marowsky
Uwe
U
Rudolph
Jean-Marc
JM
Fritschy
Michael
M
Arand
D000679:Amygdala / Q000166:cytology* / Q000187:drug effects; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D001569:Benzodiazepines / Q000494:pharmacology; D003627:Data Interpretation, Statistical; D003975:Diazepam / Q000494:pharmacology; D055724:Electrophysiological Phenomena; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005260:Female; D018755:GABA Agonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D005838:Genotype; D007150:Immunohistochemistry; D007395:Interneurons / Q000378:metabolism / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011963:Receptors, GABA-A / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D017981:Receptors, Neurotransmitter / Q000187:drug effects
D014151:Anti-Anxiety Agents; D018755:GABA Agonists; D018756:GABA Antagonists; C546258:Gabra3 protein, mouse; D011963:Receptors, GABA-A; D017981:Receptors, Neurotransmitter; D001569:Benzodiazepines; D003975:Diazepam