GABAA Receptor Endocytosis in the Basolateral Amygdala Is Critical to the Reinstatement of Fear Memory Measured by Fear-Potentiated Startle

Reinstatement represents a phenomenon that may be used to model the effects of retraumatization observed in patients with posttraumatic stress disorder (PTSD). In this study, we found intraperitoneal injection of the beta-adrenergic receptor antagonist propranolol (10 mg/kg) 1 h before reinstatement training attenuated reinstatement of fear memory in rats. Conversely, reinstatement was facilitated by intra-amygdalar administration of beta-adrenergic receptor agonist isoproterenol (Iso; 2 mu g per side) 30 min before reinstatement training. The frequency and amplitude of the miniature IPSC (mIPSC) and the surface expression of the beta 3 and gamma 2 subunits of the GABA(A) receptor (GABA(A)R) were significantly lower in reinstated than in extinction rats, whereas the AMPA/NMDA ratio and the surface expression of GluR1 and GluR2 in the amygdala did not differ between groups. In amygdala slices, Iso-induced decrease in the surface beta 3 subunit of GABA(A) receptor was blocked by a Tat-conjugated dynamin function-blocking peptide (Tat-P4) pretreatment (10 mu M for 30 min). By contrast, Tat-scramble peptide had no effect. Intravenous injection (3 mu mol/kg) or intra-amygdalar infusion (30 pmol per side) of Tat-P4 interfered with reinstatement. Reinstatement increased the association between protein phosphatase 2A (PP2A) and the beta 3 subunit of the GABA(A)R, which was abolished by PP1/PP2A inhibitors okadaic acid and calyculin A. These results suggest the involvement of beta-adrenergic receptor activation and GABA(A) receptor endocytosis in the amygdala for the reinstatement in fear memory.