The long-range goal of our research is to understand the structural basis of synaptic plasticity, especially in relationship to learning and memory. The current proposal will test whether conditions that do or do not induce long-term potentiation (LTP) result in structural changes in the rat hippocampus. LTP is an activity-dependent enhancement of synaptic transmission which involves activation of glutamatergic synapses on dendritic spines and is considered to be a good model of some forms of learning. Due to its long endurance (hours to weeks), LTP is thought to involve the formation of new synapses and/or the remodeling of existing synapses. This hypothesis is being tested directly by comparing synaptic structure in the in vivo hippocampal neuropil with hippocampal slices that obtain LTP; have LTP blocked by APV, an antagonist to the NMDA class of glutamate receptors; or receive only non-tetanic control stimulation either in normal media or media with APV. So far the slices with LTP show an increase in one type of dendritic spine (stubby), in the number of synapses per presynaptic bouton, and in glial processes surrounding the synapses. In contrast, the only difference between in vivo hippocampus and control slices is a substantial increase in spines having a large head (mushroom) with a parallel decrease in thin spines. Based on these results, the proposed experiments provide a comprehensive strategy to distinguish among activity-dependent structural changes that share or do not share the same mechanisms as LTP.
The specific aims are: 1) determine whether activation of non-NMDA or metabotropic glutamate receptors is required for the structural changes; 2) ascertain when the structural changes first occur post-tetanus and whether they are altered during later stages of LTP; 3) determine when mushroom dendritic spines first increase in vitro and whether low frequency stimulation retains the high ratio of thin to mushroom spines that occur in vivo and in the tetanized slices. Physiological responses and LTP will be measured in hippocampal slices that will then be rapidly fixed by a microwave-enhanced protocol. The unbiased series sampling method and 3-dimensional reconstructions from serial electron microscopy will be used to determine the underlying frequencies and structure of different types of synapses and glial processes. Given the involvement of glutamatergic synapses in numerous neurological disorders, it is increasingly important to understand their role in normal brain function at the most basic levels.
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