NEUROTROPHIN REGULATION OF GLUTAMATE RECEPTORS

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DESCRIPTION (from applicant's abstract): Neurotrophins play critical roles in the development of the nervous system by promoting neuronal survival and differentiation. These factors have also been implicated in the pathophysiologic mechanisms underlying Alzheimer's and other neurodegenerative diseases. At the cellular level, neurotrophins play a dynamic role in modulating synaptic transmission in the hippocampus, a brain structure of particular interest because of its proposed role in learning and memory processes as well as its selective vulnerability to injury. This research project uses electrophysiological approaches to characterize the molecular targets and signaling cascades underlying neurotrophin-induced synaptic plasticity. Recent evidence has demonstrated specific biochemical effects of neurotrophins on glutamate receptors, mediated by activation of trkB tyrosine kinase receptors in postsynaptic membranes. The proposed studies will examine the physiological context of these novel neurotrophin effects. The proposed studies will examine the physiological context of these novel neurotrophin effects, focusing specifically on functional modulation of glutamate receptor activity. Initial experiments use neuronal cultures and patch-clamp recordings to characterize the regulation of channel kinetics and elucidate underlying protein kinase signaling cascades. Later studies will explore neurotrophin modulation within the more complex cellular environment of hippocampal slices, investigating the roles of neurotrophins in synaptic plasticity and neuronal-glial interactions. These studies will contribute to a broader understanding of neurotrophin action in the brain, with potential therapeutic applications in neurogenerative disease.