The ketogenic diet increases Neuregulin 1 expression via elevating histone acetylation and its anti-seizure effect requires ErbB4 kinase activity.
The ketogenic diet increases Neuregulin 1 expression via elevating histone acetylation and its anti-seizure effect requires ErbB4 kinase activity.
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生酮饮食通过提高组蛋白乙酰化来增加神经调节蛋白 1 的表达，其抗癫痫作用需要 ErbB4 激酶活性
DOI：
10.1186/s13578-021-00611-7
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发表时间：
2021-05-21
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;Yao S;Wu JH;Li HB;Gao F;Wang Y;Huang GB;You QL;Li J;Chen X;Sun XD
生酮饮食（ketogenic diet，KD）被认为是治疗癫痫的有效方法，但其机制尚不清楚。我们以前曾报道，KD喂养增加神经调节蛋白1（NRG 1）在海马的表达;通过基因删除其受体ErbB 4破坏NRG 1信号传导，消除KD的抑制性突触活动和癫痫发作的影响。然而，它仍然是不清楚的KD对NRG 1表达的影响的机制，以及KD的影响是否需要ErbB 4激酶activity.MethodsThe KD对NRG 1表达的影响进行了评估，通过蛋白质印迹和实时PCR。用染色质免疫沉淀技术检测Nrg 1启动子位点的乙酰化水平。采用海人酸（KA）致小鼠急性癫痫模型，观察KD和组蛋白去乙酰化酶载体TSA对癫痫发作的影响。采用电生理技术记录海马突触活动。通过使用ErbB激酶拮抗剂和转基因小鼠T796G.ResultsKD的癫痫发作和抑制性突触活动的影响中的ErbB 4激酶活性的强制性作用进行了评估，我们报告说，KD特异性增加I型NRG 1在海马的表达。使用染色质免疫沉淀技术，我们观察到增加的乙酰化组蛋白占用在kd喂养小鼠的nrg 1启动子位点。TSA的治疗显著提高了NRG 1的表达，并减少了对照饮食（CD）和KD之间的差异。这些数据表明KD通过上调组蛋白乙酰化增加NRG 1表达。此外，药理学和遗传抑制的ErbB 4激酶活性显着阻止KD的抑制性突触活动和癫痫发作的影响，这表明一个必不可少的作用ErbB 4激酶activity.ConclusionThese结果加强了我们的理解NRG 1/ErbB 4信号转导在KD的作用，并揭示了新的治疗癫痫的干预措施。
BackgroundThe ketogenic diet (KD)has been considered an effective treatment for epilepsy, whereas its underlying mechanisms remain obscure. We have previously reported that the KD feeding increased Neuregulin 1 (NRG1) expression in the hippocampus; disruption of NRG1 signaling by genetically deleting its receptor-ErbB4 abolished KD’s effects on inhibitory synaptic activity and seizures. However, it is still unclear about the mechanisms underlying the effect of KD on NRG1 expression and whether the effects of KD require ErbB4 kinase activity.MethodsThe effects of the KD on NRG1 expression were assessed via western blotting and real-time PCR. Acetylation level at theNrg1promoter locus was examined using the chromatin immunoprecipitation technique. Kainic acid (KA)-induced acute seizure model was utilized to examine the effects of KD and histone deacetylase inhibitor-TSA on seizures. Synaptic activities in the hippocampus were recorded with the technique of electrophysiology. The obligatory role of ErbB4 kinase activity in KD’s effects on seizures and inhibitory synaptic activity was evaluated by using ErbB kinase antagonist and transgenic mouse-T796G.ResultsWe report that KD specifically increases Type I NRG1 expression in the hippocampus. Using the chromatin immunoprecipitation technique, we observe increased acetylated-histone occupancy at theNrg1promoter locus of KD-fed mice. Treatment of TSA dramatically elevates NRG1 expression and diminishes the difference between the effects of the control diet (CD) and KD. These data indicate that KD increases NRG1 expression via up-regulating histone acetylation. Moreover, both pharmacological and genetic inhibitions of ErbB4 kinase activity significantly block the KD’s effects on inhibitory synaptic activity and seizure, suggesting an essential role of ErbB4 kinase activity.ConclusionThese results strengthen our understanding of the role of NRG1/ErbB4 signaling in KD and shed light on novel therapeutic interventions for epilepsy.
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影响因子：
9.3
作者：
Fleiss B;Nilsson MK;Blomgren K;Mallard C
通讯作者：
Mallard C
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