RT Journal Article
SR Electronic
T1 Seizure Phenotype and Underlying Cellular Defects in <em>Drosophila</em> Knock-In Models of DS (R1648C) and GEFS+ (R1648H) <em>SCN1A</em> Epilepsy
JF eneuro
JO eNeuro
FD Society for Neuroscience
SP ENEURO.0002-21.2021
DO 10.1523/ENEURO.0002-21.2021
VO 8
IS 5
A1 Alexa Joanna Roemmich
A1 Thy Vu
A1 Tamas Lukacsovich
A1 Charlesice Hawkins
A1 Soleil S. Schutte
A1 Diane K. O’Dowd
YR 2021
UL http://www.eneuro.org/content/8/5/ENEURO.0002-21.2021.abstract
AB Mutations in the voltage-gated sodium channel gene SCN1A are associated with human epilepsy disorders, but how most of these mutations alter channel properties and result in seizures is unknown. This study focuses on two different mutations occurring at one position within SCN1A. R1648C (R-C) is associated with the severe disorder Dravet syndrome, and R1648H (R-H), with the milder disorder GEFS+. To explore how these different mutations contribute to distinct seizure disorders, Drosophila lines with the R-C or R-H mutation, or R1648R (R-R) control substitution in the fly sodium channel gene para were generated by CRISPR-Cas9 gene editing. The R-C and R-H mutations are homozygous lethal. Animals heterozygous for R-C or R-H mutations displayed reduced life spans and spontaneous and temperature-induced seizures not observed in R-R controls. Electrophysiological recordings from adult GABAergic neurons in R-C and R-H mutants revealed the appearance of sustained neuronal depolarizations and altered firing frequency that were exacerbated at elevated temperature. The only significant change observed in underlying sodium currents in both R-C and R-H mutants was a hyperpolarized deactivation threshold at room and elevated temperature compared with R-R controls. Since this change is constitutive, it is likely to interact with heat-induced changes in other cellular properties to result in the heat-induced increase in sustained depolarizations and seizure activity. Further, the similarity of the behavioral and cellular phenotypes in the R-C and R-H fly lines, suggests that disease symptoms of different severity associated with these mutations in humans could be due in large part to differences in genetic background.