Petrucci Alexandra N, Joyal Katelyn G, Chou Jonathan W, Li Rui, Vencer Kimberly M, Buchanan Gordon F
Interdisciplinary Graduate Program in Neuroscience, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, United States; Department of Neurology, Carver College of Medicine, Carver College of Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, United States; Iowa Neuroscience Institute, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, United States.
Department of Neurology, Carver College of Medicine, Carver College of Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, United States; Department of Health and Human Physiology, College of Liberal Arts and Sciences, University of Iowa, Iowa City, IA 52242, United States.
Neuroscience. 2021 Jan 15;453:206-221. doi: 10.1016/j.neuroscience.2020.11.029. Epub 2020 Nov 24.
Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in patients with refractory epilepsy. A proposed risk marker for SUDEP is the duration of post-ictal generalized EEG suppression (PGES). The mechanisms underlying PGES are unknown. Serotonin (5-HT) has been implicated in SUDEP pathophysiology. Seizures suppress activity of 5-HT neurons in the dorsal raphe nucleus (DRN). We hypothesized that suppression of DRN 5-HT neuron activity contributes to PGES and increasing 5-HT neurotransmission or stimulating the DRN before a seizure would decrease PGES duration. Adult C57BL/6J and Pet1-Cre mice received EEG/EMG electrodes, a bipolar stimulating/recording electrode in the right basolateral amygdala, and either a microdialysis guide cannula or an injection of adeno-associated virus (AAV) allowing expression of channelrhodopsin2 plus an optic fiber into the DRN. Systemic application of the selective 5-HT reuptake inhibitor citalopram (20 mg/kg) decreased PGES duration from seizures induced during wake (n = 23) and non-rapid eye movement (NREM) sleep (n = 13) whereas fluoxetine (10 mg/kg) pretreatment decreased PGES duration following seizures induced from wake (n = 11), but not NREM sleep (n = 9). Focal chemical (n = 6) or optogenetic (n = 8) stimulation of the DRN reduced PGES duration following seizures in kindled mice induced during wake. During PGES, animals exhibited immobility and suppression of EEG activity that was reduced by citalopram pretreatment. These results suggest 5-HT and the DRN may regulate PGES.
癫痫性猝死（SUDEP）是难治性癫痫患者的主要死因。一个被提出的SUDEP风险标志物是发作后广泛性脑电图抑制（PGES）的持续时间。PGES的潜在机制尚不清楚。血清素（5-HT）与SUDEP的病理生理学有关。癫痫发作会抑制中缝背核（DRN）中5-HT神经元的活动。我们假设，抑制DRN中5-HT神经元的活动会导致PGES，而在癫痫发作前增加5-HT神经传递或刺激DRN会缩短PGES的持续时间。成年C57BL/6J和Pet1-Cre小鼠接受了脑电图/肌电图电极、右侧基底外侧杏仁核中的双极刺激/记录电极，以及一个微透析引导套管或注射腺相关病毒（AAV），使通道视紫红质2加上一根光纤在DRN中表达。全身应用选择性5-HT再摄取抑制剂西酞普兰（20mg/kg）可缩短清醒（n=23）和非快速眼动（NREM）睡眠（n=13）期间诱发癫痫后的PGES持续时间，而氟西汀（10mg/kg）预处理可缩短清醒（n=11）而非NREM睡眠（n=9）期间诱发癫痫后的PGES持续时间。对DRN进行局灶性化学刺激（n=6）或光遗传学刺激（n=8）可缩短清醒期间点燃小鼠癫痫发作后的PGES持续时间。在PGES期间，动物表现出不动和脑电图活动抑制，西酞普兰预处理可减轻这种抑制。这些结果表明5-HT和DRN可能调节PGES。
