CB1R dysfunction of inhibitory synapses in the ACC drives chronic social isolation stress-induced social impairments in male mice.

Neuron 2024 Feb 07

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Social isolation is a risk factor for multiple mood disorders. Specifically, social isolation can remodel the brain, causing behavioral abnormalities, including sociability impairments. Here, we investigated social behavior impairment in mice following chronic social isolation stress (CSIS) and conducted a screening of susceptible brain regions using functional readouts. CSIS enhanced synaptic inhibition in the anterior cingulate cortex (ACC), particularly at inhibitory synapses of cholecystokinin (CCK)-expressing interneurons. This enhanced synaptic inhibition in the ACC was characterized by CSIS-induced loss of presynaptic cannabinoid type-1 receptors (CB1Rs), resulting in excessive axonal calcium influx. Activation of CCK-expressing interneurons or conditional knockdown of CB1R expression in CCK-expressing interneurons specifically reproduced social impairment. In contrast, optogenetic activation of CB1R or administration of CB1R agonists restored sociability in CSIS mice. These results suggest that the CB1R may be an effective therapeutic target for preventing CSIS-induced social impairments by restoring synaptic inhibition in the ACC. Copyright © 2023 Elsevier Inc. All rights reserved.

Citation

Baolin Guo, Kaiwen Xi, Honghui Mao, Keke Ren, Haoxiang Xiao, Nolan D Hartley, Yangming Zhang, Junjun Kang, Yingying Liu, Yuqiao Xie, Yongsheng Zhou, Yuanyuan Zhu, Xia Zhang, Zhanyan Fu, Jiang-Fan Chen, Hailan Hu, Wenting Wang, Shengxi Wu. CB1R dysfunction of inhibitory synapses in the ACC drives chronic social isolation stress-induced social impairments in male mice. Neuron. 2024 Feb 07;112(3):441-457.e6