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.
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.
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DBA/1 小鼠 SUDEP 模型中中缝背侧 5-HT 神经元的光遗传学激活可抑制癫痫引起的呼吸骤停并产生抗惊厥作用
DOI：
10.1016/j.nbd.2017.11.003
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发表时间：
2018-03
影响因子：
6.1
通讯作者：
Feng HJ
中科院分区：
文献类型：
--
作者：
Zhang H;Zhao H;Zeng C;Van Dort C;Faingold CL;Taylor NE;Solt K;Feng HJ
癫痫猝死（SUDEP）是一种毁灭性的癫痫并发症。癫痫发作引起的呼吸骤停（S-IRA）发生在许多目击的 SUDEP 患者和动物模型中，是导致死亡的始发事件。因此，了解 S-IRA 的潜在机制将促进针对 SUDEP 预防策略的制定。血清素 (5-HT) 是许多生命功能的重要调节剂，包括呼吸和唤醒，5-HT 信号传导的缺乏与动物模型（包括 DBA/1 小鼠）的 S-IRA 密切相关。然而，导致 S-IRA 的大脑结构仍然难以捉摸。我们假设中缝背侧 (DR) 向前脑发送 5-HT 投射，与 S-IRA 有关。本研究在 SUDEP 的 DBA/1 小鼠模型中使用光遗传学选择性激活 DR 中的 5-HT 神经元。 DR 5-HT 神经元的光刺激显着且可逆地降低了声刺激诱发的 S-IRA 的发生率。 DR 中 5-HT 神经元的激活抑制了大多数 DBA/1 小鼠的强直性癫痫发作，而不改变由声刺激引起的狂奔和阵挛性癫痫发作的癫痫潜伏期和持续时间。光刺激对 S-IRA 的这种抑制作用与癫痫模型无关，因为 DR 的光遗传学刺激也减少了戊四唑（一种广泛用于模拟人类全身性癫痫发作的促惊厥药物）诱导的 S-IRA。光刺激的 S-IRA 抑制作用可被 5-羟色氨酸（5-HT 合成的化学前体）增强，并被昂丹司琼（一种特定的 5-HT3 受体拮抗剂）逆转，表明 DR 光刺激减少 S-IRA 是由增强的 5-HT 神经传递特异性介导的。我们的研究结果表明，DR 中 5-HT 神经传递的缺陷与 DBA/1 小鼠的 S-IRA 有关，并且对 DR 进行针对性干预可能有助于预防 SUDEP。
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.
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DOI：
10.1016/j.yebeh.2016.09.034
发表时间：
2016-11
期刊：
Epilepsy & behavior : E&B
影响因子：
--
作者：
Faingold CL;Randall M;Zeng C;Peng S;Long X;Feng HJ
通讯作者：
Feng HJ
影响因子：
5.6
作者：
Klassen TL;Bomben VC;Patel A;Drabek J;Chen TT;Gu W;Zhang F;Chapman K;Lupski JR;Noebels JL;Goldman AM
通讯作者：
Goldman AM
影响因子：
2.2
作者：
Faingold, Carl L.;Randall, Marc;Kommajosyula, Srinivasa P.
通讯作者：
Kommajosyula, Srinivasa P.
影响因子：
30.8
作者：
Brennan, TJ;Seeley, WW;Tecott, LH
通讯作者：
Tecott, LH
羟色胺神经元具有抗惊厥作用，可降低癫痫发作引起的死亡率
影响因子：
5.5
作者：
Buchanan, Gordon F.;Murray, Nicholas M.;Richerson, George B.
通讯作者：
Richerson, George B.