Several lines of evidence indicate that fast excitatory transmission mediated by AMPA receptors regulates expression of BDNF. As predicted from this, increasing the size of excitatory postsynaptic currents with positive modulators of AMPA receptors (ampakines) increases BDNF expression both in cultured brain slices and in vivo. These results raise the possibility of using AMPA receptor modulators to produce sustained increases in the brain's concentration of a critical trophic factor. However, preliminary studies using a novel cultured slice technique for 'chronic' recording of synaptic responses led to the discovery that ampakines depress excitatory responses after about 24-36 hours. Follow on experiments showed that the depression is accompanied by a marked reduction in the number of AMPA receptors in membrane fractions. Separate work in the laboratory of Dr. Gall uncovered a parallel effect with regard to BDNF induction: prolonged exposure causes cultured slices to become refractory to ampakines. The proposed work has five objectives relating to these findings.
Specific Aim One will define the time course for the onset of, and recovery from, EPSP depression. This information will be compared to the temporal parameters of the BDNF refractory period (see Project One).
Specific Aim Two will test the hypothesis that down-regulation of AMPA receptors is responsible for EPSP depression. Number and affinity of the membrane receptors will be measured first; subsequent work will assay for changes in levels of receptor subunits and turnover.
Specific Aim Three addresses additional mechanistic questions relating to EPSP depression: What are the triggering events? Are signaling pathways linking AMPA receptor activation to AMPA receptor regulation and BDNF expression disturbed? (Also see Project One).
Specific Aim Four investigates the functional consequences of AMPA receptor down-regulation. Long term potentiation, long term depression, and seizure susceptibility will be tested prior to and after the onset of the effect. Studies on how LTP is affected by ampakine-induced elevation of BDNF in the absence of depression are described in Project Three.
Specific Aim Five will test for the occurrence of AMPA receptor down-regulation and signaling in vivo. In all, the results of the proposed study are expected to yield new and fundamental information concerning AMPA receptor regulation. They are also expected to be critical in the development of an AMPA receptor based strategy for up-regulating a critical trophic factor.
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