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

• Published in: MedComm (2020) Vol. 3; no. 3; pp. e128 - n/a
• Main Authors: Li, Zheng‐Mao, Liu, Xiu‐Xiu, Li, Chen, Wei, Zhao‐Cong, Shi, Yi, Song, Heng‐Yi, Chen, Xiang, Zhang, Yu, Li, Jia‐Wei, Zhu, Rui‐Fang, Hu, Ben‐Hui, Ye, Wei‐Feng, Huo, Da, Jiang, Guo‐Jun, Sasaki, Takuya, Zhang, Li, Han, Feng, Lu, Ying‐Mei
• Format: Journal Article
• Language: English
• Published: China John Wiley & Sons, Inc 01.09.2022; John Wiley and Sons Inc; Wiley
• Subjects: Convulsions & seizures; endothelial CDK5; Epilepsy; mechanism; Memory; memory impairment; Original; Phosphorylation; spontaneous epilepsy; synapse‐related proteins; synapse‐related proteins; endothelial CDK5; mechanism; memory impairment; spontaneous epilepsy
• ISSN: 2688-2663; 2688-2663
• DOI: 10.1002/mco2.128

Accumulating evidence indicates that epilepsy has a higher risk of inducing memory impairment and dementia. However, the underlying onset mechanism remains unclear. Here, we found that mice with spontaneous epilepsy induced by endothelial CDK5 deficiency exhibited hippocampal‐dependent memory impairment at 6 months of age, but not at 2 months of age. Moreover, the persistent epileptic seizures induce aberrant changes in phosphorylation of CaMKII protein in the hippocampus of spontaneous epileptic mice. Using genome‐wide RNA sequencing and intergenic interaction analysis of STRING, we found that in addition to epilepsy‐related genes, there are changes in synaptic organization pathway node genes, such as Bdnf and Grin1. The synapse‐related proteins by Western blot analysis, such as NMDA receptors (NR1 and NR2B), PSD95, and the phosphorylation of synapsin1, are progressively decreased during epileptic seizures in Cdh5‐CreERT2;CDK5f/f mice. Notably, we found that valproate (VPA) and phenytoin (PHT) augment mRNA expression and protein levels of synapse‐related genes and ameliorate memory impairment in Cdh5‐CreERT2;CDK5f/f mice. Our study elucidates a potential mechanism of memory deficits in epilepsy, and pharmacological reversal of synaptic pathology targeting might provide a new therapeutic intervention for epileptic memory deficits. The mechanism of cognitive deficits in epilepsy remains unclear. Here, we found that persistent epileptic seizures induce cognitive deficits by cognitional behavior analysis. Accordingly, changes of synapse‐related gene (Phka1, Btaf1, Magt1, and Grin1) and aberrant alternation of NMDA receptors, PSD95, phosphorylation of CaMKII were found in the hippocampus of spontaneous epilepsy mice. More importantly, antiepileptic drugs treatment increased synaptic protein expression and partly ameliorated cognitive dysfunction.