One of the most significant consequences of developmental epilepsy is the long-term effect on behavior. Children who have epilepsy have a higher rate of learning disabilities and share a high comorbidity with autism. Mutations in the mammalian target of rapamycin (mTOR) signaling pathway and fragile x mental retardation protein (FMRP) are associated with higher rate of epilepsy, autism, and cognitive impairments. Therefore, abnormal activation of mTOR and FMRP may be an important mechanism underlying the behavioral outcomes of developmental epilepsy and autism. The long-term goal is to identify the molecular correlates for the social behavior and other behavioral abnormalities that occur after early-life seizures in a monogenic model of autism and to develop therapeutic targets to treat these 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 monogenic mouse model of epilepsy. These mice demonstrate deficits in learning and memory and have upregulation of mTOR signaling in the hippocampus. Guided by the pilot data presented in this proposal and the hypothesis that seizures during early development in mice with deletion of FMR1 will have autistic-like behavioral outcomes and correlated changes in the mTOR signaling pathway and synaptodendritic alterations, this proposal will involve the following two aims.1) Identify the autism-like behavioral deficits and deficits in learning and memory in FMR1 wildtype, hemizygous, and knockout mice that had status epilepticus (SE) or multiple seizures during early-life. 2) Identify the mTOR signaling proteins and synaptic proteins that are altered in FMR1 wildtype, hemizygous, and knockout mice that had a single event of SE or multiple seizures during early-life. We will examine these changes in male (wildtype and knockout) and female mice (wildtype, hemizygous, and homozygous). The approach is innovative because will be the first step in a continuum of research that will systematically examine whether superimposing seizures on a monogenic condition leads to aberrant alterations in synaptodendritic changes. 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 we will compare the effect of seizures induced in early development in a monogenic model of ASD and to examine cognitive deficits and autism behavioral features: social, repetitive, and communication. The ultimate goal of this proposal is 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-like behavioral outcomes and the molecular mechanisms underlying this effect in a mouse model of Fragile X syndrome. 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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