Pan Han-Qing, Liu Wei-Zhu, Yang Cui-Zhu, Jiang Si-Ying, Zhang Mao-Xue, Hu Ping, Yang Hao-Tian, Wang Yun-Yun, Li Ya-Qing, Tu Jiang-Long, Chen Wen-Bing, Liu Lumin, Pan Bing-Xing, Zhang Wen-Hua
Department of Neurology, The Second Affiliated Hospital, School of Basic Medical Sciences and Institute of Biomedical Innovation, Jiangxi Medical College, Nanchang University, Nanchang, China.
Department of Pathology and Jiangxi Institute of Respiratory Disease, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China.
Sci Adv. 2025 May 23;11(21):eadt3163. doi: 10.1126/sciadv.adt3163.
Chronic stress exposure is a primary contributor to the development of anxiety disorders, closely associated with hippocampal dysfunction. However, the underlying molecular mechanism remains poorly understood. Here, using a mouse model of chronic restraint stress (CRS), we observed a notable increase in the activity, rather than its overall expression level, of hippocampal Rap1, a small guanosine triphosphatase belonging to the Ras superfamily. Pharmacological inhibition of Rap1 activity in the ventral hippocampus (vHPC) effectively mitigated CRS-induced anxiety. Cell type-specific manipulation of Rap1 activity revealed that Rap1 dysfunction in vHPC pyramidal neurons (PNs), but not in astrocytes or interneurons, contributed to CRS-induced anxiety-like behaviors. Mechanistically, the heightened Rap1 activity in vHPC PNs augmented their intrinsic excitability through Kv4.2 phosphorylation at the Thr site, which contributes to the onset of anxiety-like behaviors in mice following CRS. Overall, our study reveals a previously undescribed anxiogenic effect of Rap1 and highlights it as a potential target for therapeutic intervention in stress-related mental disorders.
长期暴露于应激状态是焦虑症发生的主要因素，与海马功能障碍密切相关。然而，其潜在的分子机制仍知之甚少。在此，我们使用慢性束缚应激（CRS）小鼠模型，观察到属于Ras超家族的小GTP酶海马Rap1的活性显著增加，而非其整体表达水平。对腹侧海马（vHPC）中Rap1活性进行药理抑制可有效减轻CRS诱导的焦虑。对Rap1活性进行细胞类型特异性调控显示，vHPC锥体神经元（PNs）而非星形胶质细胞或中间神经元中的Rap1功能障碍导致了CRS诱导的焦虑样行为。机制上，vHPC PNs中增强的Rap1活性通过Thr位点的Kv4.2磷酸化增加了它们的内在兴奋性，这促成了CRS后小鼠焦虑样行为的发生。总体而言，我们的研究揭示了Rap1以前未被描述的致焦虑作用，并突出其作为应激相关精神障碍治疗干预潜在靶点的地位。
