Optogenetic activation of 5-HT neurons in the dorsal raphe suppresses seizure-induced respiratory arrest and produces anticonvulsant effect in the DBA/1 mouse SUDEP model

NEUROBIOLOGY OF DISEASE

卷:110

Article

Zhang, Honghai^1,2  Zhao, Haiting^1,3  Zeng, Chang^1,4  Van Dort, Christa^1,5,6  Faingold, Carl L.⁷  Taylor, Norman E.¹  Solt, Ken¹  Feng, Hua-Jun¹ 

[1] Harvard Med Sch, Massachusetts Gen Hosp, Dept Anesthesia, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA

[2] Nanjing Med Univ, Hangzhou Peoples Hosp 1, Dept Anesthesia, Hangzhou 310006, Zhejiang, Peoples R China

[3] Cent S Univ, Xiangya Hosp, Dept Neurol, Changsha 410008, Hunan, Peoples R China

[4] Cent S Univ, Xiangya Hosp, Hlth Management Ctr, Changsha 410008, Hunan, Peoples R China

[5] MIT, Dept Brain & Cognit Sci, E25-618, Cambridge, MA 02139 USA

[6] MIT, Picower Inst Learning & Memory, 77 Massachusetts Ave, Cambridge, MA 02139 USA

[7] Southern Illinois Univ, Sch Med, Dept Pharmacol & Neurol, Div Neurosurg, Springfield, IL 62794 USA

关键词: Photostimulation;    Serotonin;    5-Hydroxytryptophan;    Ondansetron;    Generalized seizures;    Pentylenetetrazole;   

DOI  :  10.1016/j.nbd.2017.11.003

来源: Elsevier

【 摘 要 】

Sudden unexpected death in epilepsy (SUDEP) is a devastating epilepsy complication. Seizure-induced respiratory arrest (S-IRA) occurs in many witnessed SUDEP patients and animal models as an initiating event leading to death. Thus, understanding the mechanisms underlying S-IRA will advance the development of preventive strategies against SUDEP. Serotonin (5-HT) is an important modulator for many vital functions, including respiration and arousal, and a deficiency of 5-HT signaling is strongly implicated in S-IRA in animal models, including the DBA/1 mouse. However, the brain structures that contribute to S-IRA remain elusive. We hypothesized that the dorsal raphe (DR), which sends 5-HT projections to the forebrain, is implicated in S-IRA. The present study used optogenetics in the DBA/1 mouse model of SUDEP to selectively activate 5-HT neurons in the DR. Photostimulation of DR 5-HT neurons significantly and reversibly reduced the incidence of S-IRA evoked by acoustic stimulation. Activation of 5-HT neurons in the DR suppressed tonic seizures in most DBA/1 mice without altering the seizure latency and duration of wild running and clonic seizures evoked by acoustic stimulation. This suppressant effect of photostimulation on S-IRA is independent of seizure models, as optogenetic stimulation of DR also reduced S-IRA induced by pentylenetetrazole, a proconvulsant widely used to model human generalized seizures. The S-IRA-suppressing effect of photostimulation was increased by 5-hydro-xytryptophan, a chemical precursor for 5-HT synthesis, and was reversed by ondansetron, a specific 5-HT3 receptor antagonist, indicating that reduction of S-IRA by photostimulation of the DR is specifically mediated by enhanced 5-HT neurotransmission. Our findings suggest that deficits in 5-HT neurotransmission in the DR are implicated in S-IRA in DBA/1 mice, and that targeted intervention in the DR is potentially useful for prevention of SUDEP.

【 授权许可】

Free