FIGURE SUMMARY
Title

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

Authors
Weuring, W.J., Singh, S., Volkers, L., Rook, M.B., van 't Slot, R.H., Bosma, M., Inserra, M., Vetter, I., Verhoeven-Duif, N.M., Braun, K.P.J., Rivara, M., Koeleman, B.P.C.
Source
Full text @ PLoS One
Fig 1

Morphology of the <italic>Scn1Lab</italic> knockout.

A) 5 dpf Scn1Lab homozygous knockout larvae show hyperpigmentation and the absence of an inflated swim-bladder. These morphological defects are absent in heterozygous (B) or wildtype (C) zebrafish larvae.
Fig 2

A) Spontaneous burst movements quantified in two knockout lines using the locomotor burst movement assay B) Burst movements are unique to <italic>Scn1lab</italic> knockouts, and not caused by the absence of an inflated swimming bladder C) The burst movement phenotype of <italic>Scn1lab</italic> knockouts is partially rescued when human SCN1A, either mRNA or cDNA is introduced D) <italic>Scn1Lab</italic> knockouts show a reduction in free GABA levels E) Both heterozygote and homozygous <italic>Scn1lab</italic> knockouts show sensitivity to exposure of 5mM pentylenetetrazole F) Representative non-invasive local field potential recordings from the brain of wildtype and <italic>Scn1Lab</italic> knockout zebrafish (n = 3).

Only two types of signals can be detected in wildtype embryos: low amplitude waves and very occasional sharp single spikes from an otherwise straight and silent baseline (1 and 2). In Scn1Lab knockouts, at least three types of signal differ from wildtype recordings including trains of biphasic spikes lasting seconds (3) and several short spike events (4 and 5) which resembles epileptiform activity. Error bars = S.D. (-/-) = Scn1Lab knockout, locomotor assay n = 12 per group * <0.05 **<0.005 ***<0.0005.
Fig 3

Pharmacologic validation of <italic>Scn1Lab</italic> knockouts by 60 minutes (light blue) or 18 hours (dark blue) exposure of anti-epileptic drugs A) 50μM Carbamazepine B) 100μM Phenytoin C) 100μM Sodium valproate D) 12.5μM Stiripentol E) 50μM Fenfluramine F) 50μM Clemizole.

Dashed lines indicate a novel experimental plate with a seperate experimental group. Error bars = S.D., (-/-) = Scn1Lab knockout, n = 12 per group * <0.05 **<0.005 ***<0.0005.
Fig 4

Characterization of novel compounds and their effect on Scn1Lab knockout burst movements by 60 minute (light green) or 18 hours (dark green) exposure A) 10μM Veratridine B) 5uM AA43279 C) MV1312 show blocking selectivity for NaV1.6 over the other human ion channel subtypes but not NaV1.8. D) 5μM MV1312 E) MV1369 shows blocking selectivity for NaV1.6 over NaV1.2, NaV1.5 and NaV1.7. F) 50μM MV1369. Dashed lines indicate a novel experimental plate with a seperate experimental group. Error bars = S.D., (-/-) = Scn1Lab knockout, locomotor assays n = 12 per group, selectivity assays n = 3 per group, * <0.05 **<0.005 ***<0.0005.
Fig 5

Epileptiform event scoring of wildtype or <italic>Scn1Lab</italic> knockout embryos exposed to FA, AA43279 or MV1312 for 60 minutes.

Error bars = S.D n = 3 per group * <0.05 **<0.005.
Scheme 1

Reagents and conditions: 1 equiv of 2 and 5 with 4 equiv CH<sub>3</sub>COONH<sub>4</sub> in 3.8 mL CH<sub>3</sub>OH; 1 equiv of 1 and 4 (respectively) in 3.5 mL CH<sub>3</sub>OH.

Overnight rt.
Acknowledgments
This image is the copyrighted work of the attributed author or publisher, and ZFIN has permission only to display this image to its users. Additional permissions should be obtained from the applicable author or publisher of the image. Full text @ PLoS One
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