Hippocampal Zkscan4 confers resilience to chronic stress–induced depression-like behaviors

作者：Kai Gao, Yang Yang, Xiaoxuan Sun, Jinxin Wang, Xiaqin Sun, Tianlan Lu, Lifang Wang, Ming Li, Weihua Yue, Hesheng Liu, Dai Zhang, Jun Li · 发表于：Science Advances · 年份：2025 · DOI：10.1126/sciadv.adr2291 · 被引用次数：8 · 研究领域：Neuroscience and Neuropharmacology Research、Tryptophan and brain disorders、Genetics, Aging, and Longevity in Model Organisms

Major depression is a prevalent and devastating psychiatric disorder. However, our understanding of the underlying molecular mechanisms is limited. Here, we found reduced expression of zinc finger protein with Krüppel-associated box and SCAN domains 4 (Zkscan4) in the hippocampi of patients with major depressive disorder and stress-susceptible mice. Zkscan4 disruption ( Zkscan4 −/− ) was sufficient to induce depression-like behaviors following subthreshold social stress. Zkscan4 regulated excitatory synaptic transmission mainly through direct interaction with the Htr2a promoter and the recruitment of glucocorticoid receptors for the transcriptional repression of 5-hydroxytryptamine receptor 2a (Htr2a). Reduced excitatory synaptic transmission in the hippocampus and stress susceptibility in Zkscan4 −/− mice were restored by pharmacological inhibition, genetic knockdown of Htr2a, or overexpression of the amino-terminal SCAN domain of Zkscan4 (Zkscan4 1–133 ) in cornus ammonis region 3. Our findings demonstrate an essential role of Zkscan4 in promoting stress resilience, suggesting a potential antidepressant effect of Zkscan4 1–133 .