Peri-ictal activation of dorsomedial dorsal raphe serotonin neurons reduces mortality associated with maximal electroshock seizures

Abstract

Over one-third of patients with epilepsy will develop refractory epilepsy and continue to experience seizures despite medical treatment. These patients are at the greatest risk for sudden unexpected death in epilepsy. The precise mechanisms underlying sudden unexpected death in epilepsy are unknown, but cardiorespiratory dysfunction and arousal impairment have been implicated. Substantial circumstantial evidence suggests serotonin is relevant to sudden unexpected death in epilepsy as it modulates sleep/wake regulation, breathing and arousal. The dorsal raphe nucleus is a major serotonergic center and a component of the ascending arousal system. Seizures disrupt the firing of dorsal raphe neurons, which may contribute to reduced responsiveness. However, the relevance of the dorsal raphe nucleus and its subnuclei to sudden unexpected death in epilepsy remains unclear. The dorsomedial dorsal raphe may be a salient target due to its role in stress and its connections with structures implicated in sudden unexpected death in epilepsy. We hypothesized that optogenetic activation of dorsomedial dorsal raphe serotonin neurons in TPH2-ChR2-YFP (n = 26) mice and wild-type (n = 27) littermates before induction of a maximal electroshock seizure would reduce mortality. In this study, pre-seizure activation of dorsal raphe nucleus serotonin neurons reduced mortality in TPH2-ChR2-YFP mice with implants aimed at the dorsomedial dorsal raphe. These results implicate the dorsomedial dorsal raphe in this novel circuit influencing seizure-induced mortality. It is our hope that these results and future experiments will define circuit mechanisms that could ultimately reduce sudden unexpected death in epilepsy.

5-HT receptors exert differential effects on seizure-induced respiratory arrest in DBA/1 mice

“…SUDEP mainly occurs in epilepsy patients at younger ages, in which the risk of sudden death is 24-to 28-fold higher than that in the general population [1,2]. Although several pathophysiological mechanisms are proposed to contribute to the SUDEP [3][4][5][6][7][8][9][10], cardiorespiratory and arousal deficits have received large attention [11,12]. Both clinical and animal studies demonstrated that seizure-induced respiratory arrest (S-IRA) contributes importantly to death in most SUDEP cases [13][14][15][16][17][18][19][20][21][22][23][24][25][26].…”