Upregulation of RBFOX1 in the malformed cortex of patients with intractable epilepsy and in cultured rat neurons

Wen,Ming; Yan,Yong; Yan,Ning; Chen,Xiao Shan; Liu,Shi Yong; Feng,Zhan Hui

doi:10.3892/ijmm.2015.2061

Upregulation of RBFOX1 in the malformed cortex of patients with intractable epilepsy and in cultured rat neurons

Authors:
- Ming Wen
- Yong Yan
- Ning Yan
- Xiao Shan Chen
- Shi Yong Liu
- Zhan Hui Feng
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Affiliations: Department of Neurology, The First Afﬁliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing 400016, P.R. China, Department of Neurology, University‑Town Hospital of Chongqing Medical University, Chongqing 401331, P.R. China, Department of Neurology, Xi'an Central Hospital, Xi'an 710003, P.R. China, Department of Neurosurgery, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, P.R. China, Department of Neurology, Afﬁliated Hospital of Guiyang Medical University, Guiyang 550004, P.R. China
Published online on: January 5, 2015 https://doi.org/10.3892/ijmm.2015.2061
Pages: 597-606
Copyright: © Wen et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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Abstract

Mutations in RNA‑binding Fox 1 (RBFOX1) are known to be associated with neurodevelopmental disorders including epilepsy, mental retardation and autism spectrum disorder. The deletion of the Rbfox1 gene in mice has been shown to result in heightened susceptibility to seizures. However, other studies have revealed mutations or the downregulation of RBFOX1 in specimens obtained from patients with epilepsy or malformations of cortical development (MCD). Generally, the expression of RBFOX1 varies according to tissue type. In this study, we demonstrated the upregulation of RBFOX1 protein in the cortex of patients with MCD and intractable epilepsy. Electrophysiological recordings of cultured rat cortical neurons with increased Rbfox1 expression also revealed a significantly increased amplitude of action potential (AP) and Na+ current density. Some of these neurons (26.32%) even displayed spontaneous, recurrent, epileptiform discharges (SREDs). Additionally, certain Rbfox1 target transcripts associated with epilepsy, including glutamate receptor, ionotropic, N-methyl D-aspartate 1 [Grin1, also known as N-methyl-D-aspartate receptor subunit NR1 (NMDAR1)], synaptosomal-associated protein, 25 kDa (SNAP‑25 or Snap25) and sodium channel, voltage gated, type VIII, alpha subunit (Scn8a, also known as Nav1.6) were identified to be upregulated in these cultured cortical neurons with an upregulated Rbfox1 expression. These data suggest that the upregulation of RBFOX1 contributes to neuronal hyperexcitation and seizures. The upregulation of NMDAR1 (Grin1), SNAP‑25 (Snap25) and Scn8a may thus be involved in Rbfox1‑related neuronal hyperexcitation.

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