Selective NaV1.1 activation rescues Dravet syndrome mice from seizures and premature death.

Abstract

Dravet syndrome is a catastrophic, pharmacoresistant epileptic encephalopathy. Disease onset occurs in the first year of life, followed by developmental delay with cognitive and behavioral dysfunction and substantially elevated risk of premature death. The majority of affected individuals harbor a loss-of-function mutation in one allele of SCN1A, which encodes the voltage-gated sodium channel NaV1.1. Brain NaV1.1 is primarily localized to fast-spiking inhibitory interneurons; thus the mechanism of epileptogenesis in Dravet syndrome is hypothesized to be reduced inhibitory neurotransmission leading to brain hyperexcitability. We show that selective activation of NaV1.1 by venom peptide Hm1a restores the function of inhibitory interneurons from Dravet syndrome mice without affecting the firing of excitatory neurons. Intracerebroventricular infusion of Hm1a rescues Dravet syndrome mice from seizures and premature death. This precision medicine approach, which specifically targets the molecular deficit in Dravet syndrome, presents an opportunity for treatment of this intractable epilepsy.

• Authors: Kay L Richards, Carol J Milligan, Robert J Richardson, Nikola Jancovski, Morten Grunnet, Laura H Jacobson, Eivind A B Undheim, Mehdi Mobli, Chun Yuen Chow, Volker Herzig, Agota Csoti, Gyorgy Panyi, Christopher A Reid, Glenn F King, Steven Petrou
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 115 Issue 34 Pg. E8077-E8085 (08 21 2018) ISSN: 1091-6490 [Electronic] United States
• PMID: 30076230 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 the Author(s). Published by PNAS.

Chemical References

• NAV1.1 Voltage-Gated Sodium Channel
• Scn1a protein, mouse
• Spider Venoms

Topics

• Animals
• CHO Cells
• Cricetulus
• Epilepsies, Myoclonic (drug therapy, genetics, metabolism, pathology)
• HEK293 Cells
• Humans
• Interneurons (metabolism, pathology)
• Mice
• Mice, Mutant Strains
• Mutation
• NAV1.1 Voltage-Gated Sodium Channel (genetics, metabolism)
• Spider Venoms (pharmacology)
• Synaptic Transmission (drug effects)