GABAA(δ) receptor hypofunction in the amygdala-hippocampal circuit underlies stress-induced anxiety

• 作者: Xia Qin Han-Qing Pan Shou-He Huang Jia-Xin Zou Zhi-Heng Zheng Xiao-Xuan Liu Wen-Jie You Zhi-Peng Liu Jun-Li Cao Wen-Hua Zhang Bing-Xing Pan
• 来源期刊: 科学通报（英文版）
• 年，卷（期）: 2022,（1）
• 所属期刊栏目: Life Sciences
• 页码范围: 97-110
• 页数: 14页
• 语种: 英文

摘要

Dysregulated GABAergic inhibition in the amygdala has long been implicated in stress-related neuropsy-chiatric disorders.However,the molecular and circuit mechanisms underlying the dysregulation remain elusive.Here,by using a mouse model of chronic social defeat stress (CSDS),we observed that the dys-regulation varied drastically across individual projection neurons (PNs) in the basolateral amygdala(BLA),one of the kernel amygdala subregions critical for stress coping.While persistently reducing the extrasynaptic GABAA receptor (GABAAR)-mediated tonic current in the BLA PNs projecting to the ventral hippocampus (BLA → vHPC PNs),CSDS increased the current in those projecting to the anterodorsal bed nucleus of stria terminalis (BLA → adBNST PNs),suggesting projection-based dysregulation of tonic inhi-bition in BLA PNs by CSDS.Transcriptional and electrophysiological analysis revealed that the opposite CSDS influences were mediated by loss-and gain-of-function of δ-containing GABAARs (GABAA(δ)Rs) in BLA → vHPC and BLA → adBNST PNs,respectively.Importantly,it was the lost inhibition in the former population but not the augmentation in the latter population that correlated with the increased anxiety-like behavior in CSDS mice.Virally mediated maintenance of GABAA(δ)R currents in BLA → vHPC PNs occluded CSDS-induced anxiety-like behavior.These findings clarify the molecular sub-strate for the dysregulated GABAergic inhibition in amygdala circuits for stress-associated psychopathology.