Institute of Biomedical Studies, Baylor University, Waco, TX, 76798, USA.
Department of Psychology and Neuroscience, Baylor University, Waco, TX, 76798, USA.
Behav Brain Res. 2021 Jul 23;410:113317. doi: 10.1016/j.bbr.2021.113317. Epub 2021 Apr 25.
Epilepsy is one of the most common neurological disorders, with individuals having an increased susceptibility of seizures in the first few years of life, making children at risk of developing a multitude of cognitive and behavioral comorbidities throughout development. The present study examined the role of PI3K/Akt/mTOR pathway activity and neuroinflammatory signaling in the development of autistic-like behavior following seizures in the neonatal period. Male and female C57BL/6J mice were administered 3 flurothyl seizures on postnatal (PD) 10, followed by administration of minocycline, the mTOR inhibitor rapamycin, or a combined treatment of both therapeutics. On PD12, isolation-induced ultrasonic vocalizations (USVs) of mice were examined to determine the impact of seizures and treatment on communicative behaviors, a component of the autistic-like phenotype. Seizures on PD10 increased the quantity of USVs in female mice and reduced the amount of complex call types emitted in males compared to controls. Inhibition of mTOR with rapamycin significantly reduced the quantity and duration of USVs in both sexes. Changes in USVs were associated with increases in mTOR and astrocyte levels in male mice, however, three PD10 seizures did not result in enhanced proinflammatory cytokine expression in either sex. Beyond inhibition of mTOR activity by rapamycin, both therapeutics did not demonstrate beneficial effects. These findings emphasize the importance of differences that may exist across preclinical seizure models, as three flurothyl seizures did not induce as drastic of changes in mTOR activity or inflammation as observed in other rodent models.
癫痫是最常见的神经障碍之一，个体在生命的头几年中癫痫发作的易感性增加，使儿童在整个发育过程中面临多种认知和行为共病的风险。本研究探讨了 PI3K/Akt/mTOR 通路活性和神经炎症信号在新生期癫痫后发展自闭症样行为中的作用。雄性和雌性 C57BL/6J 小鼠在出生后 (PD) 10 天给予 3 氟噻吨癫痫发作，然后给予米诺环素、mTOR 抑制剂雷帕霉素或两种治疗方法的联合治疗。在 PD12 时，检查小鼠的隔离诱导超声发声 (USVs)，以确定癫痫发作和治疗对交流行为的影响，这是自闭症样表型的一个组成部分。PD10 的癫痫发作增加了雌性小鼠的 USVs 数量，并减少了雄性小鼠与对照组相比发出的复杂叫声类型的数量。mTOR 抑制剂雷帕霉素显著减少了两性 USVs 的数量和持续时间。USVs 的变化与雄性小鼠中 mTOR 和星形胶质细胞水平的增加有关，然而，三次 PD10 癫痫发作并没有导致两性促炎细胞因子表达的增强。除了雷帕霉素抑制 mTOR 活性外，两种治疗方法都没有显示出有益的效果。这些发现强调了临床前癫痫模型之间可能存在差异的重要性，因为三次氟噻吨癫痫发作并没有像在其他啮齿动物模型中观察到的那样导致 mTOR 活性或炎症发生如此剧烈的变化。
