Aquaporin Water Transport, Extracellular Space, and Epilepsy

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DESCRIPTION (provided by applicant): This project is focused on developing novel diagnostics and treatments for epilepsy based on glial cell regulation of extracellular space volume and components, and novel optical methods for seizure detection. Accumulating evidence supports a functional role for glial cells in epilepsy, at least in part via their effect on neuronal environment. Aquaporin-4 (AQP4) is the main water-selective transporting protein expressed in glial cells, and alterations in AQP4 expression in human epileptic specimens suggest that AQP4 may play a functional role in epilepsy. In recent work, I demonstrated that AQP4-deficient mice have markedly altered seizure threshold and duration. However, the regulation and function of AQP4 in the hippocampus, a structure critical to seizures and epilepsy, have not yet been studied. I propose to explore the regulation of AQP4 in the hippocampus by seizure activity and its functional role in epileptogenesis (Aims 1 and 2). Furthermore, I aim to test the hypothesis that movement of brain water can be used to develop novel optical methods for early detection of seizures (Aim 3). This proposal utilizes available mouse strains, confocal immunofluorescence and in situ hybridization, and in vivo pharmacology, electrophysiology and imaging in well-established epilepsy models. I am a fully-trained clinician-scientist specializing in epilepsy surgery and epilepsy research. I have been given the opportunity and resources for my new laboratory in the Department of Neurological Surgery at the University of California, Irvine, a world-renowned center for neuroscience and a recognized center for epilepsy research. In the training portion of this proposal, I will learn state-of-the-art optics and biophotonics techniques applied to neural tissue. My ultimate goals are to identify novel targets for antiepileptic drugs, and bridge translational and clinical research to develop optical seizure detection for use in patients. RELEVANCE: Epilepsy is a major public health problem as it is common (about 1 % of population) and causes severe neurological, psychiatric, and social disability. Current antiepileptic drugs (AEDs) are ineffective in many patients and even when effective can cause long-term cognitive impairment due to suppression of neuronal activity. Identification of glial cell-specific targets may lead to the development of novel AEDs that are effective and have fewer side effects. Glial water channels (aquaporins) are a promising target for new drug development. In addition, development of novel optical techniques for seizure detection based on changes in the brain that occur just prior to seizure onset will have a direct clinical impact on the many patients whose seizures remain uncontrolled.