Malleability of neuronal connections (synapses) participates in learning and memory. Less appreciated is that some forms of malleability, especially homeostatic or adaptive plasticity, may underlie the neural response to clinical brain stimulation treatments such as electroconvulsive therapy and deep-brain stimulation. These same mechanisms may serve as endogenous neuroprotective mechanisms against excitotoxic insult. To understand and exploit such mechanisms, we need to understand the triggers of adaptive synaptic change. This proposal probes the physiological and pathophysiological triggers of a peculiar form of adaptive synaptic plasticity in which glutamate-using synapses are functionally silenced by activity. Our laboratory has made significant advances in understanding downstream expression mechanisms of this form of plasticity, but our understanding of the upstream triggers remains rudimentary. Here we hypothesize that presynaptic silencing of glutamate synapses is triggered non-autonomously by prolonged adenosine A1 receptor activation. We further hypothesize that presynaptic silencing serves as an endogenous protective mechanism against otherwise excitotoxic insult.
Our first aim i s to test the ability of single-neuron depolarization versus widespread network depolarization to trigger silencing. This will implicate whether induction of silencing requires diffusible signals or whether a single, depolarized neuron contains all the machinery necessary to induce silencing. Second, we will test the hypothesis that A1 adenosine receptor activation is sufficient and necessary to trigger depolarization-induced silencing of glutamate axon terminals. Finally, we will test the hypothesis that synaptic silencing is triggered by anoxic insult thereby protecting against an otherwise excitotoxic anoxic insult. We also evaluate the long-term implications of anoxia-induced silencing on subsequent network activity. Upon completion of our studies, we expect to have a clearer fundamental understanding of the triggers of an important but underappreciated form of long-term presynaptic plasticity and the role of this adaptive plasticity in neuroprotection. We anticipate that our results may spur new ideas for triggering this adaptive form of plasticity as treatment strategy for nervous system dysfunction.
Malleability of neuronal connections (synapses) participates in learning and memory. Some forms of malleability may underlie the neural response to clinical brain stimulation treatments and may serve as endogenous neuroprotective mechanisms. To understand and exploit such mechanisms, we need to understand the triggers of synaptic change. This proposal probes the physiological and pathophysiological triggers of a peculiar form of synaptic plasticity in which glutamate-using synapses are inactivated by over- stimulation.
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