Circadian Rhythms Time Seizure Severity in Drosophila

It is established that epilepsy patients can exhibit 24-h rhythms in seizure severity and occurrence. While the pathways underlying seizure rhythmicity remain poorly understood, it seems likely that a contribution from the biological clock is involved. A better understanding of any such contribution may translate to better treatments. Here, the influence of the 24-h circadian rhythm on seizure activity in Drosophila melanogaster is investigated. Seizure-susceptible bang-sensitive mutants (julius seizure and paralytic^{bangsenseless1}) were subjected to mechanically induced seizure at 6 different zeitgeber points. A clear sex-dependent phenotype was observed, with seizure severity showing a greater time-of-day effect in females than males. The temporal pattern of seizure recovery time was bimodal, exhibiting both a morning and an evening peak. Rearing flies in constant light (LL), which renders the molecular clock dysfunctional, abolished the seizure rhythm. Conversely, female seizure mutants reared in constant darkness (DD), allowing free running of the circadian clock, continued to exhibit a bimodal rhythm of seizure severity. Moreover, seizure mutant females lacking a functional clock (period⁰) did not show rhythmicity of seizure severity. These findings support a role for the biological clock in seizure activity, at least in female Drosophila. Finally, seizure mutant females showed normal PERIOD clock protein intensity oscillations in clock neurons, supporting the hypothesis that seizure rhythmicity requires a functional circadian clock. Thus, this study validates Drosophila as a potential model for the identifying the mechanisms modulating seizure rhythmicity, with the potential to aid future treatment of epilepsy.