Tuberous sclerosis complex (TSC), a multi-system genetic disorder often associated with autism spectrum disorder (ASD), is caused by mutations of TSC1 or TSC2, which lead to constitutive overactivation of mammalian target of rapamycin (mTOR). In several Tsc1+/- and Tsc2+/- animal models, cognitive and social behavior deficits were reversed by mTOR inhibitors. However, phase II studies have not shown amelioration of ASD and cognitive deficits in individuals with TSC during mTOR inhibitor therapy. We asked here if developmental epilepsy, common in the majority of individuals with TSC but absent in most animal models, could explain the discrepancy. At postnatal day P12, developmental status epilepticus (DSE) was induced in male Tsc2+/- (Eker) and wild-type rats, establishing four experimental groups including controls. In adult animals (n = 36), the behavior was assessed in the paradigms of social interaction test, elevated plus-maze, light-dark test, Y-maze, and novel object recognition. The testing was carried out before medication (T1), during a 2-week treatment with the mTOR inhibitor everolimus (T2) and after an 8-week washing-out (T3). Electroencephalographic (EEG) activity was recorded in a separate set of animals (n = 18). Both Tsc2+/- mutation and DSE caused social behavior deficits and epileptiform EEG abnormalities (T1). Everolimus led to a persistent improvement of the social deficit induced by Tsc2+/-, while deficits related to DSE did not respond to everolimus (T2, T3). These findings may contribute to an explanation why ASD symptoms in individuals with TSC, where comorbid early-onset epilepsy is common, were not reliably ameliorated by mTOR inhibitors in clinical studies.

中文翻译：

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mTOR 抑制剂可改善与 Tsc2 单倍体不足相关的自闭症样行为，但不遵循发育性癫痫持续状态

结节性硬化症 (TSC) 是一种多系统遗传性疾病，通常与自闭症谱系障碍 (ASD) 相关，由 TSC1 或 TSC2 突变引起，导致哺乳动物雷帕霉素靶标 (mTOR) 的组成型过度激活。在几个 Tsc1+/- 和 Tsc2+/- 动物模型中，mTOR 抑制剂逆转了认知和社会行为缺陷。然而，II 期研究并未显示在 mTOR 抑制剂治疗期间 TSC 患者的 ASD 和认知缺陷有所改善。我们在这里询问发育性癫痫（在大多数 TSC 患者中常见但在大多数动物模型中不存在）是否可以解释这种差异。在出生后第 12 天，在雄性 Tsc2+/- (Eker) 和野生型大鼠中诱导发育性癫痫持续状态 (DSE)，建立包括对照在内的四个实验组。在成年动物 (n = 36) 中，在社交互动测试、高架十字迷宫、明暗测试、Y 型迷宫和新物体识别等范式中对行为进行了评估。该测试在用药前 (T1)、mTOR 抑制剂依维莫司治疗 2 周期间 (T2) 和 8 周清洗后 (T3) 进行。在一组单独的动物 (n = 18) 中记录脑电图 (EEG) 活动。Tsc2+/- 突变和 DSE 均导致社会行为缺陷和癫痫样脑电图异常 (T1)。依维莫司导致 Tsc2+/- 诱导的社会缺陷持续改善，而与 DSE 相关的缺陷对依维莫司没有反应（T2、T3）。这些发现可能有助于解释为什么在临床研究中 mTOR 抑制剂不能可靠地改善 TSC 患者的 ASD 症状，其中早发性癫痫共病很常见。