The impact of Vav1 on epileptogenesis and neuronal apoptosis: insights from Sirt1 activation

Epilepsy is a chronic brain disorder characterized by recurrent epileptic seizures, which are caused by abnormal discharges of neurons in the brain. The Vav guanine nucleotide exchange factor (Vav1) has been reported to modulate inflammation and neuronal apoptosis; however, its role in epilepsy remains elusive. This study aimed to investigate the specific function of Vav1 in epileptogenesis and its underlying molecular mechanisms. Rats were challenged with lithium chloride-pilocarpine (LiCl-Pilo) treatment to induce epilepsy model. It was found a high expression of Vav1 in hippocampal tissue of epileptic rats. Vav1 knockdown reduced seizure frequency and mortality in epileptic rats. Besides, LiCl-Pilo treatment-induced spontaneous recurrent seizures was inhibited by Vav1 downregulation, as well as epileptic activity and abnormal sprouting of mossy fibers. We also showed that interfering with the expression of Vav1 alleviates seizure-induced cognitive impairment. Vav1 knockdown restrained neuronal damage and degeneration. Moreover, Sirtuin 1 (Sirt1) was found to regulate the histone acetylation of Vav1 promotor. Sirt1 activation increased the neuronal activity and decreased the neuronal apoptosis, while Vav1 overexpression reversed it. Additionally, the results of mRNA-seq indicated that Vav1 is related to neuronal function and apoptosis regulation. Our study demonstrated that Vav1 accelerates the development of epilepsy, and neuronal damage might be the critical event. These findings could provide a novel direction for epilepsy therapy.