Elevated susceptibility to exogenous seizure triggers and impaired interneuron excitability in a mouse model of Leigh syndrome epilepsy.
Elevated susceptibility to exogenous seizure triggers and impaired interneuron excitability in a mouse model of Leigh syndrome epilepsy.
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DOI：
10.1016/j.nbd.2023.106288
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发表时间：
2023-10-15
影响因子：
6.1
通讯作者：
Kalume, Franck
中科院分区：
文献类型：
--
作者：
Manning, Arena;Han, Victor;Stephens, Alexa;Wang, Rose;Bush, Nicholas;Bard, Michelle;Ramirez, Jan M.;Kalume, Franck
NADH 脱氢酶（泛醌还原酶）铁硫蛋白 4 (NDUFS4) 基因（编码 OXFOS 复合物 I (CI) 的关键结构亚基）的突变会导致儿童最常见的线粒体疾病，即 Leigh 综合征 (LS)。与其他线粒体疾病一样，癫痫发作是 LS 最重要的临床特征之一。这些癫痫发作通常很难治疗，并且是疾病预后不良的征兆。全身 Ndufs4 KO 的小鼠是经过充分验证的 LS 模型；他们表现出癫痫和 LS 的其他一些临床特征。我们之前已经证明，仅在 GABA 能中间神经元中敲除 Ndufs4 的小鼠 (Gad2-Ndufs4-KO) 会重现在整体敲除小鼠中观察到的严重癫痫表型。这一观察结果表明，这些小鼠代表了与该疾病的其他临床表现分离的优秀 LS 癫痫模型。为了进一步表征这种癫痫表型，我们研究了 Gad2-Ndufs4-KO 小鼠对选定的外源性癫痫发作触发因素的癫痫发作易感性。然后，我们利用电生理学、成像和免疫组织化学研究了 Ndufs4 KO 在 GABA 能中间神经元中的细胞、生理和神经解剖学后果。 GABA能中间神经元中Ndufs4的纯合子敲除导致对外源性癫痫发作的显着易感性、中间神经元兴奋性受损和中间神经元丢失。最后，我们发现海马和皮质参与了 Gad2-Ndufs4-KO 小鼠癫痫发作活动的产生。这些发现进一步定义了 LS 癫痫表型，并为 LS 和其他线粒体疾病中癫痫的细胞机制提供了重要的见解。
Mutations in the NADH dehydrogenase (ubiquinone reductase) iron-sulfur protein 4 (NDUFS4) gene, which encodes for a key structural subunit of the OXFOS complex I (CI), lead to the most common form of mitochondrial disease in children known as Leigh syndrome (LS). As in other mitochondrial diseases, epileptic seizures constitute one of the most significant clinical features of LS. These seizures are often very difficult to treat and are a sign of poor disease prognosis. Mice with whole-body Ndufs4 KO are a well-validated model of LS; they exhibit epilepsy and several other clinical features of LS. We have previously shown that mice with Ndufs4 KO in only GABAergic interneurons (Gad2-Ndufs4-KO) reproduce the severe epilepsy phenotype observed in the global KO mice. This observation indicated that these mice represent an excellent model of LS epilepsy isolated from other clinical manifestations of the disease. To further characterize this epilepsy phenotype, we investigated seizure susceptibility to selected exogenous seizure triggers in Gad2-Ndufs4-KO mice. Then, using electrophysiology, imaging, and immunohistochemistry, we studied the cellular, physiological, and neuroanatomical consequences of Ndufs4 KO in GABAergic interneurons. Homozygous KO of Ndufs4 in GABAergic interneurons leads to a prominent susceptibility to exogenous seizure triggers, impaired interneuron excitability and interneuron loss. Finally, we found that the hippocampus and cortex participate in the generation of seizure activity in Gad2-Ndufs4-KO mice. These findings further define the LS epilepsy phenotype and provide important insights into the cellular mechanisms underlying epilepsy in LS and other mitochondrial diseases.
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影响因子：
9.9
作者：
Lacuey, Nuria;Hampson, Johnson P.;Lhatoo, Samden
通讯作者：
Lhatoo, Samden
影响因子：
5.8
作者：
Joseph DJ;Von Deimling M;Hasegawa Y;Cristancho AG;Ahrens-Nicklas RC;Rogers SL;Risbud R;McCoy AJ;Marsh ED
通讯作者：
Marsh ED
影响因子：
5.3
作者：
Barros VN;Mundim M;Galindo LT;Bittencourt S;Porcionatto M;Mello LE
通讯作者：
Mello LE
影响因子：
4.7
作者：
Eloqayli, H;Dahl, CB;Sonnewald, U
通讯作者：
Sonnewald, U
影响因子：
5.3
作者：
Dlouhy, Brian J.;Gehlbach, Brian K.;Richerson, George B.
通讯作者：
Richerson, George B.