Mutations in DEP domain containing 5 (DEPDC5) are increasingly appreciated as one of the most common causes of inherited focal epilepsy. Epilepsies due to DEPDC5 mutations are often associated with brain malformations, tend to be drug-resistant, and have been linked to an increased risk of sudden unexplained death in epilepsy (SUDEP). Generation of epilepsy models to define mechanisms of epileptogenesis remains vital for future therapies. Here, we describe a novel mouse model of Depdc5 deficiency with a severe epilepsy phenotype, generated by conditional deletion of Depdc5 in dorsal telencephalic neuroprogenitor cells. In contrast to control and heterozygous mice, Depdc5-Emx1-Cre conditional knockout (CKO) mice demonstrated macrocephaly, spontaneous seizures and premature death. Consistent with increased mTORC1 activation, targeted neurons were enlarged and both neurons and astrocytes demonstrated increased S6 phosphorylation. Electrophysiologic characterization of miniature inhibitory post-synaptic currents in excitatory neurons was consistent with impaired post-synaptic response to GABAergic input, suggesting a potential mechanism for neuronal hyperexcitability. mTORC1 inhibition with rapamycin significantly improved survival of CKO animals and prevented observed seizures, including for up to 40 days following rapamycin withdrawal. These data not only support a primary role for mTORC1 hyperactivation in epilepsy following homozygous loss of Depdc5, but also suggest a developmental window for treatment which may have a durable benefit for some time even after withdrawal.

中文翻译：

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通过抑制 mTORC1 在 Depdc5 小鼠癫痫模型中预防过早死亡和癫痫发作。

包含 5 ( DEPDC5) 的DEP 域中的突变越来越被认为是遗传性局灶性癫痫的最常见原因之一。DEPDC5突变引起的癫痫通常与脑畸形有关，往往具有耐药性，并且与癫痫中不明原因猝死 (SUDEP) 的风险增加有关。用于定义癫痫发生机制的癫痫模型的生成对于未来的治疗仍然至关重要。在这里，我们描述了一种新的具有严重癫痫表型的 Depdc5 缺陷小鼠模型，该模型由背侧端脑神经祖细胞中的Depdc5条件性缺失产生。与对照和杂合小鼠相比，Depdc5-Emx1-Cre 条件性敲除 (CKO) 小鼠表现出巨头畸形、自发性癫痫发作和过早死亡。与增加的 mTORC1 激活一致，目标神经元扩大，神经元和星形胶质细胞都表现出增加的 S6 磷酸化。兴奋性神经元中微型抑制性突触后电流的电生理特征与对 GABA 能输入的突触后反应受损一致，表明神经元过度兴奋的潜在机制。用雷帕霉素抑制 mTORC1 可显着提高 CKO 动物的存活率并防止观察到的癫痫发作，包括雷帕霉素停用后长达 40 天。这些数据不仅支持 mTORC1 过度激活在Depdc5纯合缺失后癫痫中的主要作用， 但也提出了一个治疗的发育窗口，即使在停药后的一段时间内，它也可能具有持久的益处。