Selective Na V 1.1 activation rescues Dravet syndrome mice from seizures and premature death

TY - JOUR

T1 - Selective Na V 1.1 activation rescues Dravet syndrome mice from seizures and premature death

AU - Richards, Kay L.

AU - Milligan, Carol J.

AU - Richardson, Robert J.

AU - Jancovski, Nikola

AU - Grunnet, Morten

AU - Jacobson, Laura H.

AU - Undheim, Eivind A. B.

AU - Mobli, Mehdi

AU - Chow, Chun Yuen

AU - Herzig, Volker

AU - Csoti, Agota

AU - Panyi, Gyorgy

AU - Reid, Christopher A.

AU - King, Glenn F.

AU - Petrou, Steven

PY - 2018/8/21

Y1 - 2018/8/21

N2 - 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.

AB - 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.

U2 - 10.1073/pnas.1804764115

DO - 10.1073/pnas.1804764115

M3 - Journal article

C2 - 30076230

SN - 0027-8424

VL - 115

SP - E8077-E8085

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 34

ER -