Modeling Developmental and Epileptic Encephalopathies in Drosophila melanogaster as a Rapid In Vivo Assay System for Antiseizure Medication Response and Neurodevelopment

Background/Purpose: Dravet syndrome (DS) is the model disorder for developmental and epileptic encephalopathies (DEE). Currently, there are no therapeutic approaches that target the developmental issues. Some studies have suggested that a presymptomatic ASM treatment may be beneficial. Here, we propose the use of the fruit fly, Drosophila melanogaster, as a rapid in vivo model for preclinical antiseizure medication (ASM) efficacy testing and for the evaluation of early-life ASM treatment on development and survival.

Methods: The sodium channel-associated epilepsies were modeled in Drosophila using two established models: generalized epilepsy with febrile seizures plus (GEFS+) and DS. Heat shock assays were conducted on flies treated with and without ASM to induce seizures. Further, survival rates were compared. The developmental phenotype was analyzed using movement tracking assays and immunohistochemical staining of the neuromuscular junctions.

Results: ASM effective in humans with DS (valproate, clobazam, stiripentol, fenfluramine) effectively reduced seizures. The application of unspecific sodium channel blocking ASM phenytoin was deleterious. DS flies exhibited aberrant larval crawling behavior that resembles the developmental phenotype of DS patients, associated with synaptic abnormalities revealed by immunohistochemical analysis of neuromuscular junctions. The survival of DS flies was reduced. Both the developmental phenotype and the reduced survival were rescued by an early-onset treatment of larvae with fenfluramine. Furthermore, early fenfluramine treatment could partially rescue the synaptic abnormalities.

Conclusion: Our study demonstrates the value of the fruit fly as a rapid in vivo preclinical model for ASM testing and the investigation of DEEs. This approach has the potential to facilitate the development of tailored treatments for patients with various rare genetic epilepsies. The data presented suggest that presymptomatic treatment may influence neurodevelopment.

Publication History

Article published online:
08 October 2024