The Small GTPase Racl Contributes to Extinction of Aversive Memories of Drug Withdrawal by Facilitating GABAA Receptor Endocytosis in the vmPFC.

Extinction of aversive memories has been a major concern in neuropsychiatric disorders, such as anxiety disorders and drug addiction. However, the mechanisms underlying extinction of aversive memories are not fully understood. Here, we report that extinction of conditioned place aversion (CPA) to naloxone-precipitated opiate withdrawal in male rats activates Rho GTPase Racl in the ventromedial prefrontal cortex (vmPFC) in a BDNF-dependent manner, which determines GABA_A receptor (GABA_AR) endocytosis via triggering synaptic translocation of activity-regulated cytoskeleton-associated protein (Arc) through facilitating actin polymerization. Active Racl is essential and sufficient for GABA_AR endocytosis and CPA extinction. Knockdown of Racl expression within the vmPFC of rats using Racl -shRN A suppressed GABA_AR endocytosis and CP A extinction, whereas expression of a constitutively active form of Rac 1 accelerated GABA_AR endocytosis and CPA extinction. The crucial role of GABA_AR endocytosis in the LTP induction and CPA extinction is evinced by the findings that blockade of GABA_AR endocytosis by a dynamin function-blocking peptide (Myr-P4) abolishes LTP induction and CPA extinction. Thus, the present study provides first evidence that Racl-dependent GABA_AR endocytosis plays a crucial role in extinction of aversive memories and reveals the sequence of molecular events that contribute to learning experience modulation of synaptic GABA_AR endocytosis. [ABSTRACT FROM AUTHOR]