This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The process of cell damage following excessive glutamate receptor activation has been termed 'excitotoxicity', and may be involved in a range of disorders including ischemia, seizure activity, Parkinson?s Disease and ALS. Strategies that maintain appropriate metabolic function may be a critical consideration for the design of future therapeutic interventions for excitotoxic injuries. The success of such interventions relies on understanding metabolic demands involved in different types of glutamate excitoxicity. This subproject evaluates mitochondrial function in acute hippocampal slices, to evaluate the mechanisms involved in mitochondrial function changes in situ, following glutamate receptor stimulation. The major emphasis is to evaluate multiple imaging approaches. Fluorescence imaging of intrinsic metabolic signals (NADH and flavoprotein) is an approach which has been validated in many previous biochemical and some imaging studies, but which has received a resurgence of interest because of the application of high resolution imaging to intact preparations. Single- and multi-photon imaging will be used to identify cellular sources of mitochondrial signals, and to study mechanisms underlying signals generated by synaptic stimulation, and by exogenous application of glutamate receptor agonists. The overall goal of this work is to develop approaches that can provide high resolution monitoring of mitochondrial function in complex brain tissue, during the progression of excitotoxic injury.
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