Brain Derived Neurotrophic Factor (BDNF) causes a modest increase in transmitter release and a marked facilitation of long-term potentiation (LTP) at glutamatergic synapses in hippocampal slices. Work by the applicants indicates that it also has a profound effect on rhythms triggered by the cholinergic septo-hippocampal projections. The proposed studies will determine if up-regulation of BDNF reproduces the effects obtained with exogenous BDNF. A second goal is to test the hypothesis that BDNF's effects on LTP depend on activation of adhesion receptors belonging to the integrin family. Positive modulators of AMPA-type glutamate receptors (ampakines) will be used to increase BDNF production in cultured hippocampal slices. Physiological tests will be carried out after AMPA receptor drugs have been washed out and BDNF protein levels are greatly elevated above control.
Specific Aim #1 tests the prediction that increased BDNF will be accompanied by reduced paired pulse facilitation and greater resistance to 'synaptic fatigue' during high frequency stimulation. Inhibitors of BDNF's trkB receptor will be used in this and subsequent experiments to confirm that the consequences of ampakine treatments depend on the neurotrophin.
Specific Aim #2 examines post-synaptic functioning and plasticity including the NMDA components of synaptic responses and the induction / expression of LTP. This experiment is closely related to a component of Project Two.
Specific Aim #3 compares cholinergically induced beta-rhythms in BDNF elevated slices with those in yoked controls (collaboration with Project 4). Recently discovered spontaneous rhythms will be used to determine if BDNF's effects are selective to cholinergic modulation.
Specific Aim #4 will test if (a) the enhanced LTP caused by BDNF is blocked by integrin antagonists and (b) BDNF activates integrins.
Specific Aim #5 tests the prediction that acute (6 hrs) and chronic (5 days) increases in BDNF protein content will be associated with different changes in synaptic physiology. Chronic increases in BDNF protein in Aim #5 will be induced with spaced applications of ampakines (see Project One). Together these studies will 1) provide a first description of the physiological changes that accompany pharmacologically-elevated endogenous BDNF levels, 2) explore a novel route whereby the neurotrophin could regulate plasticity, and 3) address issues that are critical to the clinical use of AMPA receptor modulators.
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