The applicant has shown that ampakines (positive modulators of AMPA-class glutamate receptors) stimulate BDNF expression and reduce neuronal vulnerability to ischemic insult. With prolonged ampakine exposure AMPA receptor (AMPAr) subunit expression is reduced and BDNF expression becomes refractory to ampakine effects, whereas with intermittent (on/off) ampakine treatments BDNF can be reinduced and elevated BDNF protein levels sustained. These results suggest that ampakines might be used to increase BDNF availability and thereby support neuronal viability and function but the development of treatment strategies will depend on understanding mechanisms and temporal parameters of ampakine effects on BDNF and AMPAr expression and BDNF signaling. The proposed research will address these issues in 5 specific aims.
Aim 1 is to determine the rate at which BDNF and AMPAr subunit expression decreases with prolonged ampakine exposure and the latency to the return of BDNF inducibility with ampakine removal.
Aim 2 will test if spaced ampakine treatments can relnduce BDNF mRNA and sustain elevated BDNF protein levels without down regulating AMPAr subunit expression.
Aim 3 will test the hypothesis that ampakine-induced increases in BDNF signaling increase neuronal survival of an ischemic/hypoglycemic insult.
Aim 4 will test the hypothesis that ampakine-induced increases in BDNF protein, also increase TrkB signaling. Measures of TrkB protein, phosphorylation, and proportionate surface expression will test for changes in the TrkB system that could augment or limit ampakine-induced trophic support.
Aim 5 will identify channels and signaling intermediaries that support ampakine-induced increases in BDNF expression (calcium channels; MAPK vs CaMK pathways) and test for differences between hippocampal and cortical neurons. Together these studies (a) will evolve treatment regimens for increasing BDNF expression and (b) test if increasing BDNF levels is neuroprotective. Much of the work is designed to complement studies in other Program Project laboratories: Strategies for increasing BDNF expression devised here will be used in Project 3 to test endogenous BDNF effects on synaptic plasticity and in Project 4 to test BDNF effects on axonal growth and neuronal viability; studies of AMPAr subunit gene expression will complement analyses of GIuR protein and AMPAr function in Project 2. This integrated program will identify fundamental mechanisms through which activity regulates neurotrophin signaling in adult brain, the functional consequences of changes in endogenous neurotrophin content and the utility of manipulating neurotrophin expression for therapeutic purposes.
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