Adhesion molecules and developmental epilepsy disorders

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PROJECT SUMMARY This is a renewal application for a grant aimed to understand abnormal brain development and function in neurodevelopmental disorders co-morbid with epilepsy, and to explore preclinical rescue strategies with the potential of to reverse these abnormalities. Neurodevelopmental disorders, such as intellectual disability and autism are often comorbid with seizure disorders, such as epilepsy. Mutations in a number of genes have recently been discovered which cause neurodevelopmental disorders comorbid with epilepsy, suggesting common etiological mechanisms. Among these, genes encoding neuronal adhesion molecules are very highly represented. Here we propose to continue to investigate novel neuronal functions of a prominent representative of this family, CNTNAP2, mutations in which cause monogenic syndromes of intellectual disability, autism, and language disorder, comorbid with epilepsy. Specifically, we will investigate the neurodevelopmental functions of CNTNAP2 ectodomain shedding (cleavage and release of the extracellular domain) in paracrine signaling. Based on our findings from the previous funding period, we hypothesize that specific regions on CNTNAP2's ectodomain can modulate network properties and seizure activity in the intact mouse brain; CNTNAP2-ecto shedding is dysregulated in human subjects with and mouse models of neurodevelopmental seizure disorders. We will test this hypothesis by combining expertise in molecular neurobiology, epilepsy, proteomics, and pharmacology, using animal models and human clinical CSF samples, and by employing several cutting-edge methodologies, in the following Specific Aims: 1) To map the structural determinants of CNTNAP2-ecto function. 2) To characterize the impact of CNTNAP2-ecto on network and seizure activity in mice. 3) To explore the relationship between shed ectodomains detected in the CSF and seizure activity. On a basic level, data generated will provide new insights into the biology of paracrine signaling by neuronal ectodomain shedding and reveal novel mechanisms of regulation neuronal network activity during brain development. In the long run, our studies will provide novel insight into the molecular basis of alterations in both epilepsy and neurodevelopmental disorders and have the potential to provide preclinical proof-of-principle for novel therapeutic strategies for interventions in developmental seizure disorders.