Parvalbumin participates in epilepsy-associated cognitive impairment by regulating CaMKIIα–GluN1 interaction

More than 60% of patients with epilepsy experience cognitive impairment, yet the underlying mechanisms remain unclear. Parvalbumin (PV)-positive inhibitory neurons express the NMDA receptor subunit GluN1, and the interaction between GluN1 and CaMKIIα is closely linked to both cognitive function and epilepsy. Our study aimed to investigate the mechanism of the PV-GluN1–CaMKIIα pathway in epilepsy-associated cognitive impairment (ECI), providing a new theoretical framework for therapeutic intervention. Utilizing a pentylenetetrazol (PTZ)-induced chronic epileptic mouse model, we first explored behavioral cognitive deficits and hippocampal histopathological changes. We then modulated PV and PV-positive neurons via adeno-associated virus (AAV)-mediated overexpression, RNA interference-mediated silencing, and chemogenetic activation to elucidate the precise role of the PV-GluN1–CaMKIIα pathway in ECI. Chronic epileptic mice exhibited significant cognitive impairment accompanied by significant hippocampal neuronal loss. Western blot showed significantly decreased levels of PV, GluN1, and CaMKIIα in the epileptic mice. Moreover, the pCaMKIIα level was significantly reduced in the ECI group compared with the epilepsy group. Immunofluorescence staining revealed colocalization of PV with both GluN1 and CaMKIIα. Localized hippocampal delivery of AAV demonstrated that PV status directly regulates the expression of GluN1 and CaMKIIα. Furthermore, PV overexpression reduced seizure susceptibility, ameliorated cognitive impairment, and rescued neuronal damage in epileptic mice, whereas PV silencing yielded contrasting findings. Finally, chemogenetic activation of PV-positive neurons in PV‑silenced epileptic mice restored pCaMKIIα levels, enhanced the molecular binding between GluN1 and CaMKIIα, and rescued cognitive impairment. PV mediates ECI by regulating CaMKIIα autophosphorylation and its interaction with GluN1. Accordingly, overexpressing PV or selectively activating PV-positive neurons alleviated ECI, thereby providing a potential therapeutic target.