The impact of seizures on REM sleep and the cholinergic pedunculopontine nucleus in a mouse model of Dravet Syndrome

Sleep disruption is a common and burdensome feature in epilepsy, with rapid eye movement (REM) sleep particularly affected. While sleep disturbances in epilepsy patients are multifactorial, clinical evidence suggests that recent seizures acutely impair REM sleep architecture. To investigate this relationship, we used a haploinsufficient mouse model of Dravet Syndrome, which allows experimental control of seizure timing and burden. We found that hyperthermia-induced seizures profoundly decreased subsequent sleep, specifically impairing REM entry. In vivo fiber photometry revealed acute, seizure-induced activation of cholinergic neurons in the pedunculopontine nucleus (PPN), a brainstem structure critical for REM entry. We additionally found that repeated seizures triggered anatomical changes in the PPN, including reduced cholinergic neuron number and significant hypertrophy of remaining cholinergic neurons. These results suggest seizures are a driver of both acute and chronic disruption of PPN cholinergic networks, which in turn impair REM sleep in epilepsy. Our findings identify the PPN as a potential therapeutic target for interventions to address sleep-related sequelae of seizures.