Rationale: Dravet Syndrome (DS) is a form of drug-resistant epilepsy in both children and adults, caused by variants in the
SCN1A gene encoding the voltage-gated sodium channel α subunit Nav1.1. DS patients experience cognitive, behavioral, and social impairments which significantly impair quality of life and persist despite improvement of seizures. Recent clinical trials led to FDA approval of the serotonin (5-HT)-boosting agent fenfluramine (FFA) for treatment of seizures in DS patients. Preliminary studies suggest that FFA might also improve non-seizure comorbidities; however, the specific effects of FFA on cognitive-behavioral deficits in DS remains underexplored.
Methods: We assessed the effect of FFA on temperature-induced seizures as well as behavioral testing in an animal model of DS. Experiments were performed in a validated DS mouse model (
Scn1a+/- mice harboring an exon 1 deletion leading to a null allele) and wild type (WT) controls at ~1-2.5 months of age. FFA 15 mg/kg or saline vehicle was injected intraperitoneally in both genotypes 30 minutes prior to testing. All experiments were performed in an age-, sex-, and littermate-matched manner, using equivalent numbers of male and female mice. Each test (open field, three-chamber sociability, thermally induced seizures) was separated by 1 week starting at ~P35.
Results: FFA 15 mg/kg significantly increased the temperature threshold for thermally-induced seizures in DS mice and had no significant effect on WT controls. FFA did not change basal temperature and had no significant effect on survival following seizures. FFA also increased the amount of time spent in the center of the open field testing in both WT and DS mice, consistent with a potential anxiolytic effect. FFA had no significant effect on velocity or total distance traveled in open field testing in either genotype. FFA also significantly improved both sociability and social memory in both WT and DS mice in the three-chamber sociability testing, consistent with a pro-social effect.
Conclusions: We found that FFA exerted anti-seizure, anxiolytic, and pro-social effects in the DS mouse model. These findings reinforce preliminary clinical results that FFA exerts beneficial effects on the behavioral comorbidities of DS, in addition to its seizure-reducing effects. Future studies will further examine the region- and cell-type specific mechanism by which FFA mediates its effects on seizures and behavior in DS.
Funding:
This work is supported by NIH NINDS R01 NS110869 (EMG), R25 NS065745 (ECR), the Institute for Translational Medicine and Therapeutics of the Perelman School of Medicine at the University of Pennsylvania (ECR, EMG), the Louis H Castor, M.D., Undergraduate Research Grant, and Frances Velay Fellowship from Penn CURF (CW). Research reported in this publication was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number UL1TR001878.