Roscovitine alleviates PTSD-like cognitive impairment by inhibiting CDK5-mediated Tau hyperphosphorylation.

BACKGROUND

Post-Traumatic Stress Disorder (PTSD) is a complex cognitive disorder triggered by severe traumatic experiences, currently, lacks effective pharmacological treatments. Recent research has emphasized the pivotal role of hippocampal damage in the initiation and development of PTSD. However, the underlying mechanisms remain largely elusive.

METHODS

A modified single prolonged stress and electric foot shock model (SPS&S) was employed to induce PTSD-like behaviors in mice. The phosphorylation levels of Tau protein and the activity of cyclin-dependent kinase 5 (CDK5) in the hippocampus were analyzed at dif-ferent time points within the SPS&S paradigm. Mice were subjected to early Roscovitine (Rosc) treatment (initiating on day 3 post-stress, at a dose of 50 mg/kg) to evaluate its impacts on hippocampal Tau phosphorylation levels, neurogenesis, dendritic complexity, and behaviors.

RESULTS

SPS&S mice exhibited CDK5-driven Tau hyperphosphorylation at Ser202/Thr205 (AT8) sites. Early Rosc administration inhibited CDK5 activity, reduced Tau phosphorylation, and preserved neurogenesis. Structurally, Rosc restored the den-dritic complexity in dentate gyrus (DG) and CA1 neurons. Behaviorally, it alleviated PTSD-related fear memory and anxiety behaviors.

CONCLUSIONS

CDK5-mediated hy-perphosphorylation of Tau at Ser202/Thr205 (AT8) in the hippocampus represents a cru-cial pathological cascade contributing to PTSD cognitive impairments. Early intervention with Rosc shows promising therapeutic potential of PTSD by targeting CDK5.