Modulation Of SUDEP By Central Serotonergic Cooperating with Noradrenergic Circuits: A Synergistic-Dependent Manner

Abstract

Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in refractory epilepsy patients. Despite previous accumulating evidence has shown that seizure-induced respiratory arrest (S-IRA) may play the main contributor to SUDEP as an initiating event preeminent cause of mortality, the specific underlying mechanism of action remains unclear. Based on our previous work, serotonin (5-HT) signaling in the dorsal raphe nucleus (DRN) is strongly implicated in S-IRA in animal models, including the DBA/1 mice, on the meanwhile, norepinephrine (NE) neurons of the locus coeruleus (LC) also plays a vital role in regulating respiratory function on its own. Superficially, monoaminergic neuron, as important neurotransmitters in the central nervous system, have similar modes of action in the maintenance of nervous system balance, and each of them has a regulatory effect on SUDEP. However, it remains to be investigated whether monoaminergic neuron family (NE and 5-HT) are related in the mechanism of regulating SUDEP, what is even more curious is whether the two are intrinsically linked. Thus, we hypothesize neural mechanism of central noradrenergic and serotonergic circuits in modulating SUDEP in a synergistic-dependent manner, this endeavor will culminate in a significant breakthrough in elucidating the precise mechanism of action underlying SUDEP. In our study, we will use chemogenetics, optogenetics, calcium signal recording, and bidirectional tracing to explore the internal mechanism of DR-LC regulating the occurrence of SUDEP, and by specifically injecting 5-HT2AR antagonist Ketanserin (KET) and/or NE-1R antagonist Prazosin into the pre-Botzinger complex (PBC), it was finally elucidate that the DR-LC-PBC network can effectively reduce the incidence of SIRA. We firstly proposed a powerful target for exploring the reduction of the incidence of SUDEP, which has great clinical translation potential.