Increased glycine contributes to synaptic dysfunction and early mortality in Nprl2 seizure model.
Increased glycine contributes to synaptic dysfunction and early mortality in Nprl2 seizure model.
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DOI：
10.1016/j.isci.2022.104334
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发表时间：
2022-05-20
期刊：
影响因子：
5.8
通讯作者：
Tsai, Peter T.
中科院分区：
文献类型：
--
作者：
Dentel, Brianne;Angeles-Perez, Lidiette;Ren, Chongyu;Jakkamsetti, Vikram;Holley, Andrew J.;Caballero, Daniel;Oh, Emily;Gibson, Jay;Pascual, Juan M.;Huber, Kimberly M.;Tu, Benjamin P.;Tsai, Peter T.
目前尚缺乏与 mTORC1 信号负调节因子 GATOR1 相关的癫痫靶向治疗。 NPRL2 是 GATOR1 复合体的一个亚基，GATOR1 亚基（包括 NPRL2）的突变与癫痫相关。为了描述 NPRL2 相关癫痫的潜在机制，我们创建了 Nprl2 新皮质缺失的小鼠（小家鼠）模型。突变小鼠的 mTORC1 信号传导增强并表现出自发性癫痫发作。它们还表现出异常的突触功能，其特征分别是诱发和自发 EPSC 频率增加以及诱发和自发 IPSC 频率降低。 Nprl2 突变体的蛋白质组学和代谢组学研究揭示了已知的癫痫相关蛋白质和代谢途径的改变，包括神经递质甘氨酸的增加。此外，甘氨酸对 NMDA 受体的作用有助于这些小鼠的电生理和生存表型。总而言之，在这个神经元 Nprl2 模型中，我们描绘了导致 mTORC1 相关癫痫的潜在分子、代谢和电生理机制，为癫痫提供了潜在的治疗靶点。 Nprl2 新皮质缺失导致 mTORC1 依赖性癫痫发作和生存率下降 条件性 Nprl2 突变体显示突触兴奋增加和抑制减少 Nprl2 突变体新皮层中神经递质甘氨酸增加 甘氨酸对 NMDA 受体的作用有助于突触和生存表型分子神经科学；组学；代谢组学
Targeted therapies for epilepsies associated with the mTORC1 signaling negative regulator GATOR1 are lacking. NPRL2 is a subunit of the GATOR1 complex and mutations in GATOR1 subunits, including NPRL2, are associated with epilepsy. To delineate the mechanisms underlying NPRL2-related epilepsies, we created a mouse (Mus musculus) model with neocortical loss of Nprl2. Mutant mice have increased mTORC1 signaling and exhibit spontaneous seizures. They also display abnormal synaptic function characterized by increased evoked and spontaneous EPSC and decreased evoked and spontaneous IPSC frequencies, respectively. Proteomic and metabolomics studies of Nprl2 mutants revealed alterations in known epilepsy-implicated proteins and metabolic pathways, including increases in the neurotransmitter, glycine. Furthermore, glycine actions on the NMDA receptor contribute to the electrophysiological and survival phenotypes of these mice. Taken together, in this neuronal Nprl2 model, we delineate underlying molecular, metabolic, and electrophysiological mechanisms contributing to mTORC1-related epilepsy, providing potential therapeutic targets for epilepsy. Neocortical loss of Nprl2 leads to mTORC1-dependent seizures and decreased survival Conditional Nprl2 mutants show increased synaptic excitation and decreased inhibition Neurotransmitter glycine is increased in Nprl2 mutant neocortex Glycine actions at NMDA receptor contribute to synaptic and survival phenotypes Neuroscience; Molecular neuroscience; Omics; Metabolomics
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影响因子：
8.8
作者：
Dutchak PA;Laxman S;Estill SJ;Wang C;Wang Y;Wang Y;Bulut GB;Gao J;Huang LJ;Tu BP
通讯作者：
Tu BP
影响因子：
14.8
作者：
Chen J;Sutter BM;Shi L;Tu BP
通讯作者：
Tu BP
DOI：
10.1038/s41436-018-0060-2
发表时间：
2019-03
期刊：
Genetics in medicine : official journal of the American College of Medical Genetics
影响因子：
--
作者：
Baldassari S;Picard F;Verbeek NE;van Kempen M;Brilstra EH;Lesca G;Conti V;Guerrini R;Bisulli F;Licchetta L;Pippucci T;Tinuper P;Hirsch E;de Saint Martin A;Chelly J;Rudolf G;Chipaux M;Ferrand-Sorbets S;Dorfmüller G;Sisodiya S;Balestrini S;Schoeler N;Hernandez-Hernandez L;Krithika S;Oegema R;Hagebeuk E;Gunning B;Deckers C;Berghuis B;Wegner I;Niks E;Jansen FE;Braun K;de Jong D;Rubboli G;Talvik I;Sander V;Uldall P;Jacquemont ML;Nava C;Leguern E;Julia S;Gambardella A;d'Orsi G;Crichiutti G;Faivre L;Darmency V;Benova B;Krsek P;Biraben A;Lebre AS;Jennesson M;Sattar S;Marchal C;Nordli DR Jr;Lindstrom K;Striano P;Lomax LB;Kiss C;Bartolomei F;Lepine AF;Schoonjans AS;Stouffs K;Jansen A;Panagiotakaki E;Ricard-Mousnier B;Thevenon J;de Bellescize J;Catenoix H;Dorn T;Zenker M;Müller-Schlüter K;Brandt C;Krey I;Polster T;Wolff M;Balci M;Rostasy K;Achaz G;Zacher P;Becher T;Cloppenborg T;Yuskaitis CJ;Weckhuysen S;Poduri A;Lemke JR;Møller RS;Baulac S
通讯作者：
Baulac S
影响因子：
5.3
作者：
de Calbiac H;Dabacan A;Marsan E;Tostivint H;Devienne G;Ishida S;Leguern E;Baulac S;Muresan RC;Kabashi E;Ciura S
通讯作者：
Ciura S
影响因子：
6.1
作者：
De Fusco, Antonio;Cerullo, Maria Sabina;Benfenati, Fabio
通讯作者：
Benfenati, Fabio