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.
The proposed research is relevant to public health because it will use behavioral, molecular, and imaging studies to examine the relationship between epilepsy and autism. This work will provide insights into the influence of seizures in autistic-lik behavioral outcomes and the molecular mechanisms underlying this effect. The proposed research is relevant to the part of NIH's mission that pertains to expanding knowledge base in medical sciences and to foster innovative research strategies to improve human health.
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