RT Journal Article
SR Electronic
T1 Investigation of microRNA-134 as a target against seizures and SUDEP in a mouse model of Dravet syndrome
JF eneuro
JO eNeuro
FD Society for Neuroscience
SP ENEURO.0112-22.2022
DO 10.1523/ENEURO.0112-22.2022
A1 Gerbatin, Rogério R.
A1 Augusto, Joana
A1 Morris, Gareth
A1 Campbell, Aoife
A1 Worm, Jesper
A1 Langa, Elena
A1 Reschke, Cristina R.
A1 Henshall, David C.
YR 2022
UL http://www.eneuro.org/content/early/2022/09/07/ENEURO.0112-22.2022.abstract
AB 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 StatementSeveral 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.