There remains an urgent need for new
therapies for treatment-resistant
epilepsy.
Sodium channel blockers are effective for seizure control in common forms of
epilepsy, but loss of
sodium channel function underlies some genetic forms of
epilepsy. Approaches that provide bidirectional control of
sodium channel expression are needed.
MicroRNAs (
miRNA) are small noncoding RNAs which negatively regulate gene expression. Here we show that genome-wide
miRNA screening of hippocampal tissue from a rat
epilepsy model, mice treated with the antiseizure medicine
cannabidiol, and plasma from patients with treatment-resistant
epilepsy, converge on a single target-miR-335-5p. Pathway analysis on predicted and validated miR-335-5p targets identified multiple
voltage-gated sodium channels (VGSCs). Intracerebroventricular injection of
antisense oligonucleotides against miR-335-5p resulted in upregulation of Scn1a, Scn2a, and Scn3a in the mouse brain and an increased action potential rising phase and greater excitability of hippocampal pyramidal neurons in brain slice recordings, consistent with VGSCs as functional targets of miR-335-5p. Blocking miR-335-5p also increased voltage-gated
sodium currents and SCN1A, SCN2A, and SCN3A expression in human induced pluripotent stem cell-derived neurons. Inhibition of miR-335-5p increased susceptibility to
tonic-clonic seizures in the
pentylenetetrazol seizure model, whereas adeno-associated virus 9-mediated overexpression of miR-335-5p reduced seizure severity and improved survival. These studies suggest modulation of miR-335-5p may be a means to regulate VGSCs and affect neuronal excitability and
seizures. Changes to miR-335-5p may reflect compensatory mechanisms to control excitability and could provide
biomarker or therapeutic strategies for different types of treatment-resistant
epilepsy.