Enhanced Rap1 small GTPase activity in the ventral hippocampus drives stress-induced anxiety

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 607 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.