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

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

MedComm (2022-07-01)
Zheng-Mao Li, Xiu-Xiu Liu, Chen Li, Zhao-Cong Wei, Yi Shi, Heng-Yi Song, Xiang Chen, Yu Zhang, Jia-Wei Li, Rui-Fang Zhu, Ben-Hui Hu, Wei-Feng Ye, Da Huo, Guo-Jun Jiang, Takuya Sasaki, Li Zhang, Feng Han, Ying-Mei Lu
ABSTRACT

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.

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