Neuregulin 1/ErbB4 signaling contributes to the anti-epileptic effects of the ketogenic diet.
Neuregulin 1/ErbB4 signaling contributes to the anti-epileptic effects of the ketogenic diet.
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Neuregulin 1/ErbB4 信号传导有助于生酮饮食的抗癫痫作用
DOI：
10.1186/s13578-021-00536-1
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发表时间：
2021-02-03
影响因子：
7.5
通讯作者：
Sun XD
中科院分区：
文献类型：
--
作者：
Wang J;Huang J;Li YQ;Yao S;Wu CH;Wang Y;Gao F;Xu MD;Huang GB;Zhao CQ;Wu JH;Zhang YL;Jiao R;Deng ZH;Jie W;Li HB;Xuan A;Sun XD
生酮饮食（KD）已被认为是治疗神经精神疾病（包括癫痫）的潜在有效疗法。先前的研究表明，KD治疗提高了人和小鼠大脑中的γ-氨基丁酸（GABA）水平，这可能有助于KD的抗癫痫作用。然而，这尚未在突触水平进行系统研究，其潜在的分子机制仍有待阐明。采用海人酸（KA）诱导的急性和慢性癫痫模型，观察KD治疗对癫痫发作阈值和癫痫发生的影响。采用电生理技术记录海马突触活动。通过RNA测序、实时PCR和Western印迹评估KD对神经调节蛋白1（Nrg 1）表达的影响。Nrg 1在KD对癫痫发作的影响中的强制性作用通过在小鼠中通过基因删除其受体ErbB 4来破坏Nrg 1信号来评估。我们发现KD治疗抑制了急性和慢性癫痫发作模型中的癫痫发作，并增强了海马中突触前GABA释放的概率。通过转录组分析筛选与GABA能活性相关的分子靶点，我们发现KD治疗显著增加了海马中Nrg 1基因的表达。通过基因删除其受体ErbB 4来破坏Nrg 1信号传导，消除了KD对GABA能活性和癫痫发作的影响。我们的研究结果表明，Nrg 1/ErbB 4信号在介导KD对GABA能活性和癫痫发作的影响中起着关键作用，为开发新的治疗干预措施以控制癫痫发作提供了线索。
The ketogenic diet (KD) has been recognized as a potentially effective therapy to treat neuropsychiatric diseases, including epilepsy. Previous studies have indicated that KD treatment elevates γ-Amino butyric acid (GABA) levels in both human and murine brains, which presumably contributes to the KD’s anti-seizure effects. However, this has not been systematically investigated at the synaptic level, and the underlying molecular mechanisms remain to be elucidated. Kainic acid (KA)-induced acute and chronic seizure models were utilized to examine the effects of KD treatment on seizure threshold and epileptogenesis. Synaptic activities in the hippocampus were recorded with the technique of electrophysiology. The effects of the KD on Neuregulin 1 (Nrg1) expression were assessed via RNA sequencing, real-time PCR and Western blotting. The obligatory role of Nrg1 in KD’s effects on seizures was evaluated through disruption of Nrg1 signaling in mice by genetically deleting its receptor-ErbB4. We found that KD treatment suppressed seizures in both acute and chronic seizure models and enhanced presynaptic GABA release probability in the hippocampus. By screening molecular targets linked to GABAergic activity with transcriptome analysis, we identified that KD treatment dramatically increased the Nrg1 gene expression in the hippocampus. Disruption of Nrg1 signaling by genetically deleting its receptor-ErbB4 abolished KD’s effects on GABAergic activity and seizures. Our findings suggest a critical role of Nrg1/ErbB4 signaling in mediating KD’s effects on GABAergic activity and seizures, shedding light on developing new therapeutic interventions to seizure control.
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DOI：
10.1126/science.1227166
发表时间：
2013-01-11
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Shimazu T;Hirschey MD;Newman J;He W;Shirakawa K;Le Moan N;Grueter CA;Lim H;Saunders LR;Stevens RD;Newgard CB;Farese RV Jr;de Cabo R;Ulrich S;Akassoglou K;Verdin E
通讯作者：
Verdin E
影响因子：
5.3
作者：
Bean, Jonathan C.;Lin, Thiri W.;Mei, Lin
通讯作者：
Mei, Lin
DOI：
10.1073/pnas.1010669107
发表时间：
2010-12-14
影响因子：
11.1
作者：
Chen, Yong-Jun;Zhang, Meng;Gao, Tian-Ming
通讯作者：
Gao, Tian-Ming
影响因子：
21.1
作者：
Brodie MJ;Besag F;Ettinger AB;Mula M;Gobbi G;Comai S;Aldenkamp AP;Steinhoff BJ
通讯作者：
Steinhoff BJ
影响因子：
16.2
作者：
Juge, Narinobu;Gray, John A.;Omote, Hiroshi;Miyaji, Takaaki;Inoue, Tsuyoshi;Hara, Chiaki;Uneyama, Hisayuki;Edwards, Robert H.;Nicoll, Roger A.;Moriyama, Yoshinori
通讯作者：
Moriyama, Yoshinori