Signaling Mechanisms Underlying Epilepsy and Autism Cormorbidity

 描述(由申请人提供)：发育性癫痫最严重的后果之一是对儿童行为的长期影响。早期患有癫痫的儿童有较高的智力低下、学习障碍和 自闭症的高共病。哺乳动物雷帕霉素靶标(MTOR)信号通路的突变与癫痫、自闭症和认知障碍的发生率较高有关。因此，mTOR信号通路的异常激活可能是导致发育性癫痫行为结局的重要机制。长期目标是确定早期癫痫发作后社会行为和其他行为异常的分子相关性，并开发治疗这些行为异常的治疗靶点。这一假设是根据试点数据提出的，这些数据显示了癫痫早期发作与癫痫小鼠模型中社会行为缺陷的发展之间的联系。这些小鼠表现出学习和记忆方面的缺陷，并在海马区上调了mTOR通路信号。在这项建议中提出的先导数据和假设的指导下，在不同发育期诱导的癫痫发作会导致孤独症样行为结果和mTOR信号通路的相关变化，该建议将涉及以下两个目标：1)识别早期或成年期癫痫持续状态或多次发作的小鼠的孤独症样行为缺陷和学习记忆缺陷。2)确定早期或成年期癫痫持续状态或多次发作的小鼠的mTOR信号蛋白和突触蛋白的变化。 这种方法是创新的，因为它试图使用两种癫痫发作模型来研究癫痫发作造成的行为后果的更广泛的行为光谱。这项拟议的研究还将研究一种在减少/消除癫痫发作方面表现出巨大希望，但在癫痫发作后的行为后果方面受到较少关注的途径。我们还将研究mTOR异常激活时突触前和突触后的变化。这项拟议的研究意义重大，因为这将是一系列研究的第一步，该研究将系统地确定癫痫发作后发生的自闭症样行为变化和mTOR信号通路的变化。这项提案的最终目标是为自闭症和癫痫患者的行为和分子改变提供可能的药物治疗。此外，这项提案中概述的工作将为本科生提供从事实践生物医学研究的机会，这些研究将为癫痫和自闭症之间的关系提供洞察力。

 DESCRIPTION (provided by applicant): One of the most significant consequences of developmental epilepsy is the long-term effect on behavior in children. Children who have epilepsy early in life have a higher rate of mental retardation, learning disabilities, and share a high comorbidity with autism. Mutations in the mammalian target of rapamycin (mTOR) signaling pathway are associated with higher rate of epilepsy, autism, and cognitive impairments. Therefore, abnormal activation of the mTOR signaling pathway may be an important mechanism underlying the behavioral outcomes of developmental epilepsy. The long-term goal is to identify the molecular correlates for the social behavior and other behavioral abnormalities that occur after early-life seizures and to develop therapeutic targets to treat thes behavioral abnormalities. This hypothesis has been formulated on pilot data that show a link between early-life seizures and the development of social behavior deficits in a mouse model of epilepsy. These mice demonstrate deficits in learning and memory and have upregulation of mTOR pathway signaling in the hippocampus. Guided by the pilot data presented in this proposal and the hypothesis that seizures induced at different developmental periods induce autistic-like behavioral outcomes and correlated changes in the mTOR signaling pathway, this proposal will involve the following two aims: 1) Identify the autism-like behavioral deficits and deficits in learning and memory in mice that had status epilepticus or multiple seizures during early-life or in adulthood. 2) Identify the mTOR signaling proteins and synaptic proteins that are altered in mice that had status epilepticus or multiple seizures during early-life or in adulthood. The approach is innovative because it seeks to examine the wider behavioral spectrum of the behavioral consequences due to seizures using two seizure models. The research proposed will also examine a pathway that has shown great promise to reduce/eliminate seizures but has received less attention in terms of behavioral consequences after seizures. We will also examine the pre-and postsynaptic changes that occur with aberrant mTOR activation. The proposed research is significant because it will be the first step in a continuum of research that will systematically identify the autistic- like behavioral changes and alterations in the mTOR signaling pathway that occur after seizures. It is the ultimate goal of this proposal to provide possible pharmacological treatments for the behavioral and molecular alterations in individuals with autism and epilepsy. Furthermore, the work outlined in this proposal will provide research opportunities for undergraduates to engage in hands-on biomedical research that will provide insights into the relationship between epilepsy and autism.