Pyk2-PSD95 activation alleviates cognitive dysfunction by modulation of hippocampal synaptic structural plasticity...

Neuropathic pain is frequently accompanied by cognitive impairments, which exacerbate the quality of life for chronic pain patients. Previous studies have demonstrated that the hippocampus as a key region involved in cognitive dysfunction. In this study, we discovered that cognitive impairments in neuropathic pain mice were associated with decreased hippocampal expression of PTK2B (which encodes Pyk2) and PSD-95, as revealed by RNA sequencing. Further analysis of the results of RNA sequencing indicated that differentially expressed genes (DEGs) were primarily enriched in postsynaptic specialization cellular components and calcium signaling pathways. These findings suggest that synaptic alterations are closely related to cognitive impairments in neuropathic pain mice. We also observed a reduction in the density of dendritic spines on hippocampal synapses in mice suffering from neuropathic pain with cognitive deficits. Notably, modulating PTK2B expression in the bilateral hippocampus through stereotactic injection can influence cognitive function and alter PSD-95 expression in neuropathic pain mice. Overexpression of PTK2B in the dorsal hippocampus of these mice alleviated cognitive dysfunction by modifying the synaptic cleft and restoring the diminished density of dendritic spines, while enhancing PSD-95 and NMDAR2A expression, but not NMDAR2B. Additionally, co-immunoprecipitation (Co-IP) experiments demonstrated a direct interaction between Pyk2 and PSD-95, which modulates the glutamate receptor NMDAR2A. In conclusion, our findings suggest that the Pyk2-PSD95 interaction modulates synaptic structural plasticity via NMDAR2A and contributes to cognitive impairment in chronic neuropathic pain, offering potential molecular targets for therapeutic intervention.