Dorsal raphe nucleus to pre-Bötzinger complex serotonergic neural circuit is involved in seizure-induced respiratory arrest

HaiXiang Ma; Qian Yu; Yue Shen; XiTing Lian; LeYuan Gu; YuLing Wang; Qing Xu; Han Lu; HaiTing Zhao; Chang Zeng; Kazuki Nagayasu; HongHai Zhang

doi:10.1016/j.isci.2022.105228

Dorsal raphe nucleus to pre-Bötzinger complex serotonergic neural circuit is involved in seizure-induced respiratory arrest

iScience. 2022 Sep 27;25(10):105228. doi: 10.1016/j.isci.2022.105228. eCollection 2022 Oct 21.

Authors

HaiXiang Ma^{1

2}, Qian Yu^{1

2}, Yue Shen^{1

2

3}, XiTing Lian¹, LeYuan Gu^{1

2}, YuLing Wang², Qing Xu¹, Han Lu⁴, HaiTing Zhao⁵, Chang Zeng⁶, Kazuki Nagayasu⁷, HongHai Zhang^{1

2

3

8}

Affiliations

¹ Department of Anesthesiology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China.
² Department of Anesthesiology, the Fourth Clinical School of Medicine, Zhejiang Chinese Medical University, Hangzhou 310006, China.
³ Department of Anesthesiology, Hangzhou First People's Hospital, Nanjing Medical University, Hangzhou 310006, China.
⁴ Department of Anesthesiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁵ Department of Neurology, Xiangya Hospital, Central South University, Changsha 410008, China.
⁶ Health Management Center, Xiangya Hospital, Central South University, Changsha 410008.
⁷ Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.
⁸ Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310006, China.

Abstract

Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death among patients with epilepsy. However, the underlying mechanism of SUDEP remains elusive. Previous studies showed seizure-induced respiratory arrest (S-IRA) is the main factor in SUDEP, and that enhancement of serotonin (5-HT) function in the dorsal raphe nucleus (DR) can significantly reduce the incidence of S-IRA in the DBA/1 mouse model of SUDEP. The pre-Bötzinger complex (PBC), known for its role in regulating respiratory rhythm, can express the 5-HT2A receptor (5-HT2AR). Here, using the pharmacological and optogenetic methods, respectively, we observed that the serotonergic neural circuit between DR and PBC was involved in S-IRA evoked by either acoustic stimulation or pentylenetetrazole (PTZ) injection in the DBA/1 mice, and found 5-HT2AR located in PBC plays an important role in it. Our findings will further significantly improve our understanding of SUDEP and provide a promising therapeutic target for SUDEP prevention.

Keywords: Molecular physiology; neuroscience.