Hyperactive mTOR signals in the proopiomelanocortin-expressing hippocampal neurons cause age-dependent epilepsy and premature death in mice.
Hyperactive mTOR signals in the proopiomelanocortin-expressing hippocampal neurons cause age-dependent epilepsy and premature death in mice.
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DOI：
10.1038/srep22991
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发表时间：
2016-03-10
影响因子：
4.6
通讯作者：
Hara T
中科院分区：
文献类型：
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作者：
Matsushita Y;Sakai Y;Shimmura M;Shigeto H;Nishio M;Akamine S;Sanefuji M;Ishizaki Y;Torisu H;Nakabeppu Y;Suzuki A;Takada H;Hara T
癫痫是局灶性皮质发育不良（FCD）患者常见的共患病。近期利用大量测序数据的研究确定了与癫痫和FCD相关的基因子集。AKT和mTOR相关信号最近被牵涉到癫痫和FCD的致病过程中。为了阐明AKT - mTOR通路在海马神经元中的功能作用，我们构建了在表达阿黑皮素原的神经元中缺失Pten的条件性敲除小鼠（Pten - cKO）。Pten - cKO小鼠在8周龄前发育正常，然后在8 - 10周龄时出现全身性癫痫发作。视频监测脑电图检测到大脑皮质和海马出现阵发性放电。这些小鼠显示齿状回（DG）进行性肥大，兴奋性突触标记物（Psd95、Shank3和Homer）表达增加。相反，抑制性神经元（Gad67）的表达在6 - 8周龄时降低。免疫荧光研究显示，在癫痫发作前，Pten - cKO小鼠的DG中苔藓纤维异常出芽。用mTOR抑制剂雷帕霉素治疗这些小鼠成功地阻止了癫痫发作的发展，并逆转了这些分子表型。这些数据表明，mTOR通路调节出生后大脑中的海马兴奋性。
Epilepsy is a frequent comorbidity in patients with focal cortical dysplasia (FCD). Recent studies utilizing massive sequencing data identified subsets of genes that are associated with epilepsy and FCD. AKT and mTOR-related signals have been recently implicated in the pathogenic processes of epilepsy and FCD. To clarify the functional roles of the AKT-mTOR pathway in the hippocampal neurons, we generated conditional knockout mice harboring the deletion of Pten (Pten-cKO) in Proopiomelanocortin-expressing neurons. The Pten-cKO mice developed normally until 8 weeks of age, then presented generalized seizures at 8–10 weeks of age. Video-monitored electroencephalograms detected paroxysmal discharges emerging from the cerebral cortex and hippocampus. These mice showed progressive hypertrophy of the dentate gyrus (DG) with increased expressions of excitatory synaptic markers (Psd95, Shank3 and Homer). In contrast, the expression of inhibitory neurons (Gad67) was decreased at 6–8 weeks of age. Immunofluorescence studies revealed the abnormal sprouting of mossy fibers in the DG of the Pten-cKO mice prior to the onset of seizures. The treatment of these mice with an mTOR inhibitor rapamycin successfully prevented the development of seizures and reversed these molecular phenotypes. These data indicate that the mTOR pathway regulates hippocampal excitability in the postnatal brain.