Decreased synapse-associated proteins are associated with the onset of epileptic memory impairment in endothelial CDK5-deficient mice

Epilepsy accompanying cognitive impairment has been verified by accumulating clinical cases, but the mechanism remains unclear. Here, we discover that persistent epileptic seizures impaired the ability of mice to recognize either novel objects or novel locations at 6 months old but not at 2 months old by utilizing the spontaneous epilepsy model of Cdh5-CreERT2; CDK5f/f mice after tamoxifen treatment. To the best of our knowledge, this is the first report that the levels of synapse-related proteins, such as NMDA receptors (NR1 and NR2B), PSD95, and phosphorylation of CaMKII, are progressively decreased during epileptic seizures in the hippocampus of spontaneous epileptic mice. Notably, we also found that valproate (VPA) augment synapse-related genes and protein expression and ameliorate progressive cognitive impairment. Hence, our study describes a mechanism of cognitive deficits in epilepsy and identifies new effects of VPA on synapses, which provides new insights into preventive or therapeutic interventions for epileptic cognitive deficits. Overall design: Examination of CDK5f/f mice and Cdh5-CreERT2;CDK5f/f mice hiappocampus CA1 region different genes expression