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

Honghai Zhang; Haiting Zhao; Chang Zeng; Christa Van Dort; Carl L Faingold; Norman E Taylor; Ken Solt; Hua-Jun Feng

doi:10.1016/j.nbd.2017.11.003

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

Neurobiol Dis. 2018 Feb:110:47-58. doi: 10.1016/j.nbd.2017.11.003. Epub 2017 Nov 13.

Authors

Honghai Zhang¹, Haiting Zhao², Chang Zeng³, Christa Van Dort⁴, Carl L Faingold⁵, Norman E Taylor⁶, Ken Solt⁶, Hua-Jun Feng⁷

Affiliations

¹ Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Department of Anesthesia, Harvard Medical School, Boston, MA 02114, USA; Department of Anesthesia, Hangzhou First People's Hospital, Nanjing Medical University, Hangzhou 310006, China.
² Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Department of Anesthesia, Harvard Medical School, Boston, MA 02114, USA; Department of Neurology, Xiangya Hospital, Central South University, Changsha 410008, China.
³ Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Department of Anesthesia, Harvard Medical School, Boston, MA 02114, USA; Health Management Center, Xiangya Hospital, Central South University, Changsha 410008, China.
⁴ Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Department of Anesthesia, Harvard Medical School, Boston, MA 02114, USA; Department of Brain and Cognitive Sciences, MIT, Cambridge, MA 02139, USA; Picower Institute for Learning and Memory, MIT, Cambridge, MA 02139, USA.
⁵ Department of Pharmacology and Neurology, Division of Neurosurgery, Southern Illinois University School of Medicine, Springfield, IL 62794, USA.
⁶ Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Department of Anesthesia, Harvard Medical School, Boston, MA 02114, USA.
⁷ Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Department of Anesthesia, Harvard Medical School, Boston, MA 02114, USA. Electronic address: feng.huajun@mgh.harvard.edu.

Abstract

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-hydroxytryptophan, 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.

Keywords: 5-Hydroxytryptophan; Generalized seizures; Ondansetron; Pentylenetetrazole; Photostimulation; Serotonin.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Death, Sudden / etiology*
Disease Models, Animal
Dorsal Raphe Nucleus / metabolism*
Dorsal Raphe Nucleus / physiopathology
Mice
Mice, Inbred C57BL
Mice, Inbred DBA
Mice, Transgenic
Optogenetics
Photic Stimulation* / methods
Respiratory Insufficiency / etiology*
Respiratory Insufficiency / physiopathology
Seizures / complications*
Seizures / physiopathology
Serotonergic Neurons / metabolism*
Serotonergic Neurons / pathology
Serotonin / metabolism

Substances

Serotonin

Abstract

Publication types

MeSH terms

Substances

Grants and funding