NaV1.1 and NaV1.6 selective compounds reduce the behavior phenotype and epileptiform activity in a novel zebrafish model for Dravet Syndrome.

PloS One
W. J. WeuringBobby P.C. Koeleman

Abstract

Dravet syndrome is caused by dominant loss-of-function mutations in SCN1A which cause reduced activity of Nav1.1 leading to lack of neuronal inhibition. On the other hand, gain-of-function mutations in SCN8A can lead to a severe epileptic encephalopathy subtype by over activating NaV1.6 channels. These observations suggest that Nav1.1 and Nav1.6 represent two opposing sides of the neuronal balance between inhibition and activation. Here, we hypothesize that Dravet syndrome may be treated by either enhancing Nav1.1 or reducing Nav1.6 activity. To test this hypothesis we generated and characterized a novel DS zebrafish model and tested new compounds that selectively activate or inhibit the human NaV1.1 or NaV1.6 channel respectively. We used CRISPR/Cas9 to generate two separate Scn1Lab knockout lines as an alternative to previous zebrafish models generated by random mutagenesis or morpholino oligomers. Using an optimized locomotor assay, spontaneous burst movements were detected that were unique to Scn1Lab knockouts and disappear when introducing human SCN1A mRNA. Besides the behavioral phenotype, Scn1Lab knockouts show sudden, electrical discharges in the brain that indicate epileptic seizures in zebrafish. Scn1Lab knockouts sho...Continue Reading

References

Apr 15, 2006·Developmental Dynamics : an Official Publication of the American Association of Anatomists·Alicia E NovakAngeles B Ribera
May 25, 2007·American Journal of Physiology. Cell Physiology·Christian RoskerWolfgang Schreibmayer
Sep 21, 2007·Human Molecular Genetics·Melinda S MartinAndrew Escayg
Oct 22, 2008·Journal of Medical Genetics·C DepienneE LeGuern
Jan 2, 2009·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Andrea Lorincz, Zoltan Nusser
Apr 21, 2009·Methods in Molecular Biology·Ewart de BruijnHarma Feitsma
Sep 14, 2010·Epilepsia·Andrew Escayg, Alan L Goldin
Aug 26, 2011·The European Journal of Neuroscience·Linda VolkersMartin B Rook
Jan 10, 2012·Proceedings of the National Academy of Sciences of the United States of America·Sung HanHoracio O de la Iglesia
Jul 26, 2013·Journal of Human Genetics·Rashmi Parihar, Subramaniam Ganesh
Sep 5, 2013·Nature Communications·Scott C BarabanGabriela A Hortopan
Aug 9, 2015·Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics·Ragna S BoermaBobby P C Koeleman
Nov 11, 2015·Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics·Rikke S Møller, Katrine M Johannesen
Nov 26, 2015·Therapeutic Advances in Neurological Disorders·An-Sofie SchoonjansBerten Ceulemans
Jan 8, 2016·Trends in Cell Biology·Nathan D Lawson
May 18, 2016·Nucleic Acids Research·Kornel LabunEivind Valen
Jun 7, 2016·The Canadian Journal of Neurological Sciences. Le Journal Canadien Des Sciences Neurologiques·Elaine C Wirrell
Jan 12, 2017·Brain : a Journal of Neurology·Aliesha GriffinScott C Baraban
Apr 13, 2017·Brain : a Journal of Neurology·Peter de Witte, Lieven Lagae
May 12, 2017·Annals of Clinical and Translational Neurology·Nicole A HawkinsJennifer A Kearney
Jul 14, 2017·PLoS Genetics·Mohamed A El-Brolosy, Didier Y R Stainier
Aug 5, 2018·Proceedings of the National Academy of Sciences of the United States of America·Kay L RichardsSteven Petrou

❮ Previous
Next ❯

Citations

Oct 6, 2020·Frontiers in Pharmacology·Luis Felipe Santos MenezesElisabeth Ferroni Schwartz
Jun 5, 2021·Communications Biology·Aliesha GriffinScott C Baraban
Jul 8, 2021·Disease Models & Mechanisms·Scott C Baraban

❮ Previous
Next ❯

Methods Mentioned

BETA
in vitro transcription
PCR
genotyping

Software Mentioned

CHOPCHOP
ZebraLab
Screenworks
WinEDR
Viewpoint
CCtop

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.