Block of γ-Aminobutyric Acid-A Receptor Insertion in the Amygdala Impairs Extinction of Conditioned Fear

Background: Extinction is a complex phenomenon but generally is regarded as a new inhibitory learning that suppresses the original memory. However, how or from where the inhibition originates remains to be determined. In the present study, we examine whether increase in the expression of gamma-aminobutyric acid (GABA), receptors in the amygdala is required for extinction by employing cell-permeable TAT-conjugated peptide (TAT)-GABA receptor-associated protein (GABARAP) inhibitory peptide to block GABA(A) receptor insertion. Methods: Retention of fear memory was assessed with fear-potentiated startle paradigm. Whole cell patch clamp recordings were performed to record miniature inhibitory postsynaptic current (mIPSC). Western blotting analysis was used to measure the expression of gephyrin, beta 2, and gamma 2 subunits of GABA(A) receptor. Results: Fear conditioning decreased frequency and amplitude of mIPSC and surface protein levels of beta 2 and gamma 2 subunits of GABA(A) receptor. Extinction training, by contrast, reversed the decreased frequency and amplitude of mIPSC and surface protein levels of gephyrin and beta 2 subunit of GABA(A) receptor. Disruption of GABARAP-GABA(A) receptor interaction in the amygdala with GABARAP inhibitory peptide blocked N-methyl-D-aspartate-mediated GABA(A) receptor insertion in the amygdala. Importantly, it also blocked extinction-induced increase in the frequency and amplitude of mIPSCs, and the reduction of fear-potentiated startle. Conclusions: GABA(A) receptor insertion in the amygdala contributes a significant part to the extinction of fear memory.