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

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.

Molecular Features Underlying Neurodegeneration Identified through In Vitro Modeling of Genetically Diverse Parkinson’s Disease Patients

“…RBFOX1 has been linked to various neurological disorders including epilepsy, mental retardation, and autism spectrum disorder (Bhalla et al, 2004;Martin et al, 2007;Voineagu et al, 2011;Wen et al, 2015), revealing an important role of alternative splicing events in regulating the homeostasis of neuronal function. Thus, the splicing dysregulation triggered by RBFOX1 in PD progression was further evaluated by RNA-seq.…”

Ginsenoside Rb1 Protects the Brain from Damage Induced by Epileptic Seizure via Nrf2/ARE Signaling

“…Immunofluorescence assay was performed according to previous studies [26]. Briefly, tissue sections underwent dehydration through the ethanol gradient.…”

RBFOX1, encoding a splicing regulator, is a candidate gene for aggressive behavior

“…In line with this, as mentioned above, the knockout mice for Rbfox1 show susceptibility to seizures and increased neuronal excitability (Gehman et al, 2011). Another study observed upregulation of RBFOX1 in patients with malformed cortex and epilepsy, and showed that this upregulation produces an increase in the neuronal activity of rat cortical neurons (Wen et al, 2015).…”

“…Mutant animal models of Rbfox1 exist, but they have not been evaluated for aggressive behavior: a knockdown of rbfox1 in zebrafish was investigated for heart phenotypes and was shown to produce cardiac dysfunction and heart failure (Frese et al, 2015); knockout mice for Rbfox1 (−/−), central nervous system-specific, have been reported to present seizures and increased neuronal excitability (Gehman et al, 2011). Electrophysiological recordings of rat cortical neurons with increased expression of this gene also showed increased neuronal activity (Wen et al, 2015). A very recent study shows that RBFOX1 plays an important role in coordinating the synaptic downscaling of excitatory synapses (Rajman et al, 2017).…”