Delta Subunit-Containing Gamma-Aminobutyric Acid A Receptor Disinhibits Lateral Amygdala and Facilitates Fear...

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_AR) 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_AR to amygdala inhibition and fear.

By using mice expressing green fluorescent protein in interneurons (INs) and lacking the δ subunit-containing GABA_AR (GABA_A(δ)R), which is exclusively situated in the extrasynaptic membrane, we systematically investigated the role of GABA_A(δ)R in regulating inhibition in the lateral amygdala (LA) and fear learning using the combined approaches of immunohistochemistry, electrophysiology, and behavior.

In sharp contrast to the established role of synaptic GABA_AR in mediating LA inhibition, we found that either pharmacological or physiological recruitment of GABA_A(δ)R resulted in the weakening of GABAergic transmission onto projection neurons in LA while leaving the glutamatergic transmission unaltered, suggesting disinhibition by GABA_A(δ)R. The disinhibition arose from IN-specific expression of GABA_A(δ)R with its activation decreasing the input resistance of local INs and suppressing their activation. Genetic deletion of GABA_A(δ)R attenuated its role in suppressing LA INs and disinhibiting LA. Importantly, the GABA_A(δ)R facilitated long-term potentiation in sensory afferents to LA and permitted the expression of learned fear.

Our findings suggest that GABA_A(δ)R serves as a brake rather than a mediator of GABAergic inhibition in LA. The disinhibition by GABA_A(δ)R may help to prevent excessive suppression of amygdala activity and thus ensure the expression of emotion.