![]() ![]() In adult zebrafish, scn1laa and scn1lab are both expressed in the brain, eye and spinal cord. At 3 days post-fertilization (dpf) scn1laa and scn1lab are both expressed in the brain, with faint expression of scn1lab in the heart at 5 and 7 dpf, resembling SCN1A, although expression in the heart was not confirmed in a later study. After fertilization and until 48 h, scn1lab is expressed in ventral regions of the nervous system such as the hindbrain and spinal cord, while scn1laa is expressed in sensory neurons of the peripheral nervous system. This model shows a comparable phenotype to the models based on scn1lab.Ĭuriously, the spatial localization of scn1laa and scn1lab transcripts does not overlap during early development. One DS zebrafish model, scn1laa sa1674 is based on the paralog gene and was generated via ENU mutagenesis. The drug response of scn1lab zebrafish models mimic that of the majority of DS patients, showing no effect, or increased epileptiform and burst movement activity after treatment with Carbamazepine or Phenytoin, and a reduction when Valproate, Stiripentol or Fenfluramine are applied. Six DS zebrafish models are based on disruption of scn1lab, which leads to locomotor hyperactivity, burst movements and epileptiform activity recorded from the brain. Therefore, under this assumption, homozygous KO of either scn1lab or scn1laa would mimic the haploinsufficiency of Nav1.1 observed in human DS patients. Homozygous scn1lab knockout (KO) zebrafish are considered to be haploinsufficient for the Nav1.1 sodium ion channel, due to the expression of the paralog gene scn1laa. References for each model from top to bottom scn1laa −/−, scn1laa sa1674, scn1lab MO, scn1lab s552, scn1lab sa16474, scn1lab −/−, scn1lab ∆44, scn1lab mut/mut. ![]() Disruption is achieved via gene knockdown, missense mutations, or gene knockout introduced by different technologies. SCN1A haploinsufficiency in DS patients is modeled by homozygous disruption of one of the two zebrafish paralogs. Current DS zebrafish models are based on this assumption ( Figure 1).Ĭurrent zebrafish models for Dravet Syndrome. Zebrafish carry two genes for human SCN1A named scn1laa and scn1lab, which are duplicated paralog genes that were initially assumed to have similar, or even identical function. These have fast-forwarded our understanding of epileptogenesis and behavioral comorbidities, enabled rapid drug repurposing for Fenfluramine and Clemizole, yielded the efficacy of novel VGSC subtype-selective compounds, and were used to test in-vivo functionality of CRISPR activation. ![]() The past ten years, a total of seven different zebrafish models have been generated to model DS, using morpholino antisense oligomers, random mutagenesis using N-ethyl- N-nitrosourea (ENU), or CRISPR/Cas9, including the heterozygous and homozygous scn1lab knockout strains by our lab. DS has an age of onset within the first year of life and a severe disease prognosis. Dravet Syndrome (DS) is a developmental epileptic encephalopathy caused by heterozygous loss-of-function mutations in the voltage-gated sodium channel (VGSC) gene SCN1A. ![]()
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