Tonic inhibition in principal cells of the amygdala: A central role for α3 subunit-containing GABA _A 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 _ARs) has been well described in the amygdala, muchless is known about extrasynaptic GABA _ARs 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, only70%ofLAprincipal cells showed a tonic current. Immunohistochemical stainings revealed that the α3GAB _AA Rsubunit is expressed moderately in the LA and strongly throughout the BLA nucleus, where it is located mostly at extrasynaptic sites. In 3 subunit KO mice, tonic currents are significantly reduced in BLA principal cells yet not in LA principal cells. Moreover, the α3 GABA _AR-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 _AR variants underlie tonic inhibition in this cell type. Together, these studies demonstrate that α3 GABAAR-mediated tonic inhibition is a central component of the inhibitory force in the amygdala and that tonically activated α3 GABA _ARs present an important target for anxiolytic or fear-reducing compounds.