Delta Subunit-Containing Gamma-Aminobutyric Acid A Receptor Disinhibits Lateral Amygdala and Facilitates Fear Expression in Mice

BACKGROUND: Maintaining gamma-aminobutyric acidergic (GABAergic) inhibition in the amygdala within a physiological range is critical for the appropriate expression of emotions such as fear and anxiety. The synaptic GABA type A receptor (GABA(A)R) is generally known to mediate the primary component of amygdala inhibition and prevent inappropriate expression of fear. However, little is known about the contribution of the extrasynaptic GABA(A)R to amygdala inhibition and fear. METHODS: By using mice expressing green fluorescent protein in interneurons (INs) and lacking the delta subunit-containing GABA(A)R (GABA(A)(delta)R), which is exclusively situated in the extrasynaptic membrane, we systematically investigated the role of GABA(A)(delta)R in regulating inhibition in the lateral amygdala (LA) and fear learning using the combined approaches of immunohistochemistry, electrophysiology, and behavior. RESULTS: In sharp contrast to the established role of synaptic GABA(A)R in mediating LA inhibition, we found that either pharmacological or physiological recruitment of GABA(A)(delta)R resulted in the weakening of GABAergic transmission onto projection neurons in LA while leaving the glutamatergic transmission unaltered, suggesting disinhibition by GABA(A)(delta)R. The disinhibition arose from IN-specific expression of GABA(A)(delta)R with its activation decreasing the input resistance of local INs and suppressing their activation. Genetic deletion of GABA(A)(delta)R attenuated its role in suppressing LA INs and disinhibiting LA. Importantly, the GABA(A)(delta)R facilitated long-term potentiation in sensory afferents to LA and permitted the expression of learned fear. CONCLUSIONS: Our findings suggest that GABA(A)(delta)R serves as a brake rather than a mediator of GABAergic inhibition in LA. The disinhibition by GABA(A)(delta)R may help to prevent excessive suppression of amygdala activity and thus ensure the expression of emotion.