In vivo two-photon imaging of glial dysfunction in stroke

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A number of neurological diseases for which current therapies are nonexisting or inadequate involve deficiencies in glial function. Examples are stroke, epilepsy and Alzheimers disease. The recent Nobel-recognized discovery of aquaporins - the channels th at mediate rapid and regulated transport of water - opened up a new field in molecular medicine. The applicant pioneered the research on aquaporins in the CNS and disclosed that aquaporin-4 (AQP4), the predominant brain aquaporin, is concentrated in speci alized glial membranes at the brain-blood interface. Despite a decade of intense research the roles of glial water channels are still an enigma. The project combines in vivo two-photon imaging to unravel novel roles of AQP4 in experimental stroke and bloo d flow dynamics. The new concepts launched are that AQP4 facilitates glial Ca2+ signaling and release of glutamate, thus promoting excitotoxic neuronal damage, cortical spreading depression and vascular dysfunction. We will delineate mechanisms underlying glial dysfunction in stroke, and assess roles of glial water channels in neurovascular coupling. The project is multidisciplinary and draws on the expertise of a national and international competence network including the EMBL Partnership for Molecular M edicine, an US group that is among the leading groups in the world on in vivo two-photon imaging, and Centre for Integrative Genetics (CIGENE) at the Norwegian University of Life Sciences.