Clock neurons modulate seizure timing through a diurnal switch

People with epilepsy experience daily oscillations in seizure risk. Using a video-tracking model to automate detection, we explored mechanisms underlying spontaneous seizures in Drosophila and find that flies, like people, exhibit daily oscillations in seizure risk. These rhythms are absent in flies lacking a molecular circadian clock and are independent of sleep. Thermogenetic screening and cell-specific clock perturbations reveal that the ventrolateral neurons, including "morning cells", and dorsolateral neurons, comprising the "evening cells", modulate diurnal oscillations in seizure risk. Pigment-dispersing factor and short neuropeptide F from morning cells increase seizure risk during the day. During this time, morning cell activity increases whole-brain activity. At night, morning cells switch to glycine signaling likely acting on evening cells to decrease seizure risk. Optogenetic inhibition of clock neurons suppresses seizure risk. Our findings reveal an unexpected role for brain clock neurons in modulating daily seizure risk.