Investigation of microRNA-134 as a target against seizures and SUDEP in a mouse model of Dravet syndrome

Abstract

Dravet Syndrome (DS) is a catastrophic form of paediatric epilepsy mainly caused by non-inherited mutations in the SCN1A gene. DS patients suffer severe and life-threatening focal and generalised seizures which are often refractory to available anti-seizure medication. Antisense oligonucleotides (ASOs) based approaches may offer treatment opportunities in DS. MicroRNAs are short non-coding RNAs that play a key role in brain structure and function by post-transcriptionally regulating gene expression, including ion channels. Inhibiting microRNA-134 (miR-134) using an antimiR ASO (Ant-134) has been shown to reduce evoked seizures in juvenile and adult mice and reduce epilepsy development in models of focal epilepsy. The present study investigated the levels of miR-134 and whether Ant-134 could protect against hyperthermia-induced seizures, spontaneous seizures and mortality (SUDEP) in F1.Scn1a(+/-)^tm1kea mice. At P17, animals were intracerebroventricular injected with 0.1 – 1 nmol of Ant-134 and subject to a hyperthermia challenge at P18. A second cohort of P21 F1.Scn1a(+/-)^tm1kea mice received Ant-134 and were followed by video and EEG monitoring until P28 to track the incidence of spontaneous seizures and SUDEP. Hippocampal and cortical levels of miR-134 were similar between wildtype and F1.Scn1a(+/-)^tm1keamice. Moreover, Ant-134 had no effect on hyperthermia-induced seizures, spontaneous seizures and SUDEP incidence were unchanged in Ant-134 treated DS mice. These findings suggest that targeting miR-134 does not have therapeutic applications in DS.

Significance Statement

Several preclinical models of epilepsy have implicated miR-134 as a therapeutic target for seizure control and anti-epileptogenesis. The present study here explored whether targeting miR-134 has effects on seizures and mortality in a mouse model of Dravet Syndrome. The results indicate that suppression of miR-134 using an antimiR did not protect against hyperthermia-induced seizures, spontaneous seizures or SUDEP in F1.Scn1a(+/-)^tm1kea mice. The findings suggest that miR-134 is not a therapeutic target in DS.