The long term goal of the proposed research is to define better the mechanisms underlying synaptic plasticity in the mammalian hippocampus. Over the last two decades, a great deal has been learned about the mechanisms underlying synaptic enhancement, or long-term potentiation. More recently, an opposing mechanism, which causes a decrease in synaptic strength, called long-term depression (LTD) has been identified. Both heterosynaptic and homosynaptic long-term depression have been identified. Heterosynaptic LTD has been described in the dentate granule cells; however, a detailed understanding of the mechanisms underlying homosynaptic long-term depression is lacking. The main goal of the proposed research is to elucidate the cellular and biochemical mechanisms underlying homosynaptic long-term depression in the medial and lateral perforant path inputs to the dentate granule cells of the hippocampus.
The specific aims and methods are: l. To optimize procedures for the induction of homosynaptic LTD in dentate granule cells using physiologically relevant stimuli. The optimal procedures for inducing LTD in the medial and lateral perforant path inputs to the dentate granule cells will be contrasted. 2. To determine the roles of NMDA receptors, metabotropic glutamate receptors and changes in postsynaptic intracellular calcium in the induction of LTD in the dentate granule cells. Extensive experiments will be performed to determine whether a rise in intracellular calcium alone is sufficient to generate LTD. 3. To test whether activation of protein phosphatases is required for the generation of LTD. Specific inhibitors of a number of different protein phosphatases will be applied to determine whether they block or reduce LTD. The effects of these inhibitors on NMDA receptor-mediated synaptic currents will also be examined to determine whether any observed effect on LTD is due to interference with NMDA channel activity. 4. To determine whether induction of LTD causes a reduction in the probability of neurotransmitter release or alternatively a reduction in the response of postsynaptic glutamate receptors to released neurotransmitter using analysis of spontaneous miniature excitatory postsynaptic currents and an analysis of failures of synaptic transmission.