An efficient neural network of cooperating serotonergic and noradrenergic neurons in modulating sudden unexpected death in epilepsy.

Sudden unexpected death in epilepsy (SUDEP) is a critical concern, with seizure-induced respiratory arrest (S-IRA) being a major contributing factor. The serotonergic (5-HT) and noradrenergic (NE) neurons have emerged as key modulators of SUDEP, yet the network-level interactions and specific mechanisms underlying their protective roles remain poorly defined. This study is the first to demonstrate a synergistic effect of 5-HT and NE in mitigating S-IRA and SUDEP using DBA/1 mice. Through a combination of pharmacological interventions, calcium signal recordings, and optogenetics, results show that elevating 5-HT and NE levels via 5-hydroxytryptophan and the norepinephrine reuptake inhibitor atomoxetine significantly reduced SUDEP incidence, with evidence of a robust synergistic interaction. Furthermore, venlafaxine, a selective serotonin-norepinephrine reuptake inhibitor, enhances the cooperative regulation of 5-HT and NE, further supporting their combined protective role. Crucially, the dorsal raphe-locus coeruleus-pre-Bötzinger complex (DR-LC-PBC) neural network is demonstrated as a critical pathway underlying this modulation. Targeted administration of the 5-HT2A/NE α-1 receptor antagonist and agonist into the PBC reveal their pivotal roles in mediating the protective effects of 5-HT and NE. Our study reveals that serotonergic and noradrenergic systems synergistically regulate SUDEP, and further identifies that the DR-LC-PBC neural circuit exerts a protective effect through activation of 5-HT2A and NE-α1 receptors within the PBC.