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

KL Richards; CJ Milligan; RJ Richardson; N Jancovski; M Grunnet; LH Jacobson; EAB Undheim; M Mobli; CY Chow; V Herzig; A Csoti; G Panyi; CA Reid; GF King; S Petrou

Journal article

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

KL Richards, CJ Milligan, RJ Richardson, N Jancovski, M Grunnet, LH Jacobson, EAB Undheim, M Mobli, CY Chow, V Herzig, A Csoti, G Panyi, CA Reid, GF King, S Petrou

Proceedings of the National Academy of Sciences of the United States of America | NATL ACAD SCIENCES | Published : 2018

DOI: 10.1073/pnas.1804764115

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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 r..

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University of Melbourne Researchers

Laura Jacobson Author

Christopher Reid Author

Grants

Awarded by Citizens United for Research in Epilepsy

Funding Acknowledgements

We thank Prof. Kazuhiro Yamakawa (RIKEN Brain Science Institute) for donating Dravet syndrome mice and Prof. Gilles Guillemin (St Vincent's Centre for Applied Medical Research) for human CSF. This work was supported by Citizen's United for Research in Epilepsy Pediatrics Award 353711, Australian National Health and Medical Research Council Program Grant 10915693 (to S.P. and C.A.R.), Principal Research Fellowships (to S.P. and G.F.K.), an Australian Research Council Discovery Early Career Researcher Award Fellowship (to E.A.B.U.), a Dowd Foundation Research Fellowship (to C.A.R.), and by the GINOP-2.3.2-15-2016-00044 Project cofinanced by the European Union and the European Regional Development Fund (G.P.). The Florey Institute of Neuroscience and Mental Health is supported by infrastructure funds from the Department of Health, State Government of Victoria.