Remarkable alterations of Nav1.6 in reactive astrogliosis during epileptogenesis.

Hongyan Zhu,Weide Lin,Ziyi Wang,Yuxiao Zhao,Jiahui Jin,Yonghua Ji,Hao Wu,Nan Jiang

doi:10.1038/srep38108

Abstract

Voltage-gated sodium channels (VGSCs) play a vital role in controlling neuronal excitability. Nav1.6 is the most abundantly expressed VGSCs subtype in the adult central nervous system and has been found to contribute to facilitate the hyperexcitability of neurons after electrical induction of status epilepticus (SE). To clarify the exact expression patterns of Nav1.6 during epileptogenesis, we examined the expression of Nav1.6 at protein and mRNA levels in two distinct animal models of temporal lobe epilepsy (TLE) including a post-SE model induced by kainic acid (KA) intrahippocampal injection and a kindling model evoked by pentylenetetrazole (PTZ). A prominent, seizure intensity-dependent increase of Nav1.6 expression in reactive astrocytes was observed in ipsilateral hippocampus of post-SE rats, reaching the peak at 21 days after SE, a time point during the latent stage of epileptogenesis. However, Nav1.6 with low expression level was selectively expressed in the hippocampal neurons rather than astrocytes in PTZ-kindled animals. This seizure-related increase of a VGSCs subtype in reactive astrocytes after SE may represent a new mechanism for signal communication between neuron and glia in the course of epileptogenesis, facilitating the neuronal hyperexcitability.

Highlights

Epilepsy is one of the most common neurological diseases with a prevalence of 0.5–2% of the population worldwide, which is characterized by the periodic and unprovoked occurrence of seizures that manifest neuronal hypersynchrony and hyperexcitability[1]
We found that the expression of Nav1.6 in the hippocampus after status epilepticus (SE) was remarkably increased in reactive astrocytes rather than neuron or other glial cells during epileptogenesis, which is related to the severity of SE induced kainic acid (KA)
SE was characterized by continuous limbic seizures which consisted of head bobbing, wet dog shakes and rearing that started 19.6 ± 1.35 min after intrahippocampal kainic acid injection

Summary

Introduction

Epilepsy is one of the most common neurological diseases with a prevalence of 0.5–2% of the population worldwide, which is characterized by the periodic and unprovoked occurrence of seizures that manifest neuronal hypersynchrony and hyperexcitability[1]. Increasing evidences demonstrate that the abnormal expression or function of VGSCs leading to neural network hyperexcitability could be associated with the generation of seizure activities[5,6]. Recent studies demonstrate that Nav1.6 is a key determinant of neuronal network hyperexcitability and spontaneous epileptiform activity in animal models of Alzheimer disease (AD)[21,22]. The expression of Nav1.6 has been reported to be persistently reduced during epileptogenesis in post status epilepticus (SE) animals induced by pilocarpine and kainic acid[13,14]. We found that the expression of Nav1.6 in the hippocampus after SE was remarkably increased in reactive astrocytes rather than neuron or other glial cells during epileptogenesis, which is related to the severity of SE induced KA. These findings suggest that the increased expression of Nav1.6 is an important molecular change in the progression of reactive astrogliosis during epileptogenesis

Methods

Results

Conclusion