Drosophila melanogaster as a versatile model organism to study genetic epilepsies: An overview

Abstract

Epilepsy is one of the most prevalent neurological disorders, affecting more than 45 million people worldwide. Recent advances in genetic techniques, such as next-generation sequencing, have driven genetic discovery and increased our understanding of the molecular and cellular mechanisms behind many epilepsy syndromes. These insights prompt the development of personalized therapies tailored to the genetic characteristics of an individual patient. However, the surging number of novel genetic variants renders the interpretation of pathogenetic consequences and of potential therapeutic implications ever more challenging. Model organisms can help explore these aspects in vivo. In the last decades, rodent models have significantly contributed to our understanding of genetic epilepsies but their establishment is laborious, expensive, and time-consuming. Additional model organisms to investigate disease variants on a large scale would be desirable. The fruit fly Drosophila melanogaster has been used as a model organism in epilepsy research since the discovery of “bang-sensitive” mutants more than half a century ago. These flies respond to mechanical stimulation, such as a brief vortex, with stereotypic seizures and paralysis. Furthermore, the identification of seizure-suppressor mutations allows to pinpoint novel therapeutic targets. Gene editing techniques, such as CRISPR/Cas9, are a convenient way to generate flies carrying disease-associated variants. These flies can be screened for phenotypic and behavioral abnormalities, shifting of seizure thresholds, and response to anti-seizure medications and other substances. Moreover, modification of neuronal activity and seizure induction can be achieved using optogenetic tools. In combination with calcium and fluorescent imaging, functional alterations caused by mutations in epilepsy genes can be traced. Here, we review Drosophila as a versatile model organism to study genetic epilepsies, especially as 81% of human epilepsy genes have an orthologous gene in Drosophila. Furthermore, we discuss newly established analysis techniques that might be used to further unravel the pathophysiological aspects of genetic epilepsies.

KDM5-mediated transcriptional activation of ribosomal protein genes alters translation efficiency to regulate mitochondrial metabolism in neurons

“…Bang-sensitive Drosophila go through a stereotypic seizure cycle during which the fly may turn onto its side or back and exhibit behaviors such as shaking and paralysis. ( 33 ) Similar numbers of males and females were used for each variant tested. Statistical analysis was done using a Chi-Square Test in GraphPad PRISM 8.4 (GraphPad Software, Inc., CA, USA) followed by a Marascuilo procedure to adjust for multiple comparisons, which was done in R.…”

Toward the use of novel alternative methods in epilepsy modeling and drug discovery

“…Among them, organotypic brain slice cultures (OSCs), Induced pluripotent Stem Cells (iPSC) and organoids appear as relevant models for new antiseizure drug candidates screening. On another hand, several models not classified as animals larval stage of Danio rerio ( 70 ) or non-vertebrates C. elegans ( 71 , 72 ) and Drosophila melanogaster ( 73 ), traditionally used in basic research on embryonic development, have proven valuable in epilepsy research. This is because these models allow for high-throughput pharmacological screening, enabling the simultaneous evaluation of a large number of samples, the automated analysis of different phenotypes in short times, and the generation of avatars of human patients for the testing of new therapies.…”