BDNF dependent Rac1 GTPase activation in the vmPFC contributes to aversive memory extinction by Arc-mediated GABAA receptor endocytosis

Extinction of aversive memories has been a major concern in neuropsychiatric disorders such as anxiety disorders and drug addiction. The ventromedial prefrontal cortex(vmPFC) is important for memory extinction,but the underlying mechanisms are little known. Here,we report that extinction of conditioned place aversion(CPA),a type of aversive memory associated with drug withdrawal,required activation of Rho GTPase Rac1 in the vmPFC in a brain-derived neurotrophic factor(BDNF)-dependent manner,which triggers actin polymerization via Pak1-cofilin signaling pathway,leading to synaptic localization of activity-regulated cytoskeleton-associated protein(Arc) in the vmPFC. The synaptic Arc further determines GABA_Areceptor(GABA_AR) endocytosis that is necessary and sufficient for vmP FC long-term potentiation and CPA extinction. Thus,extinction of an aversive memory associated with drug withdrawal is intriguingly controlled by Rac1-dependent GABA_AR endocytosis in the vmPFC,thereby suggesting therapeutic targets to promote extinction of the unwanted memory.