The role of DRN circuitry in post-ictal generalized EEG suppression, arousal, and seizure induced mortality

Epilepsy is a neurological disease characterized by recurrent, spontaneous seizures. Over one-third of epilepsy patients will not achieve seizure control with medical treatment. These patients are at greatest risk for sudden unexpected death in epilepsy (SUDEP). The exact cause of SUDEP is unclear, but impairments in breathing and brain activity are implicated. Currently, there are no treatments to prevent SUDEP. Thus, identification of brain circuitry involved in SUDEP or SUDEP risk factors is crucial to further SUDEP research.

One proposed risk factor for SUDEP is the duration of post-ictal generalized EEG suppression (PGES), a period of reduced brain activity and impaired awareness that occurs following some seizures. The mechanisms underlying PGES are likewise unknown. However, the signaling molecule serotonin (5-HT) may be pertinent to PGES and SUDEP because it modulates breathing and awareness. Seizures may disrupt the activity cells that send 5-HT signals. The relevance of these brain regions to PGES and SUDEP is unknown.

We hypothesized that seizure-induced disruption of 5-HT cell activity contributes to PGES and SUDEP and that activating these 5-HT neurons before a seizure would decrease PGES or reduce mortality. Pre-seizure activation of 5-HT neurons reduced PGES duration following seizures in a mouse seizure model with low mortality. In a seizure model with a high mortality rate, we observed a decrease in mortality by activating 5-HT cells before and during the seizure. These results suggest 5-HT signaling can influence PGES and seizure-induced mortality. It is our hope that these results and future experiments defining connections between 5-HT cells and other brain regions could ultimately inform treatments for SUDEP.