The long-term goal of this research is to specify changes in synapse structure in the brain that subserve learning and memory. Changes in synapse number or size have long been thought to underpin memory, but this hypothesis has not been proven because structural changes are difficult to measure, the altered synapses are difficult to identify, and the relevant circuits are not easily specified in mammals. To simplify this task the model system hippocampal long-term potentiation (LTP) is used to investigate these synaptic mechanisms. LTP is a protein synthesis-dependent enhancement in synaptic efficacy that can persist for months and there is abundant evidence that it plays an important role in learning and memory. Polyribosomes (PR) are structures where new proteins are synthesized. A discrete population of dendritic spines acquires PR and their synapses enlarge during LTP in hippocampal slices from immature rats. Missing from the slice experiments is information about whether the synaptic changes are sustained beyond several hours, whether the changes are strictly developmental, and whether similar changes occur in whole animals. The present experiments are designed to investigate synapses in the hippocampal dentate gyrus from mature rats that have undergone LTP after high-frequency stimulation in the medial perforant path. Quantitative serial electron microscopy and immunogold labeling will be used to distinguish changes in synapse structure and composition during different phases of LTP from 30 minutes to 3 months after its induction. Comparisons will be made between the potentiated medial perforant path synapses, the contralateral control medial perforant path synapses and the neighboring lateral perforant path and proximal associational synapses that become heterosynaptically depressed.
Specific aims i nclude: 1) Test for synapse enlargement at spines undergoing protein synthesis during LTP. 2) Investigate roles for synapse perforation, spinule formation, and cell adhesions in synapse enlargement and molecular components of synaptic remodeling during LTP. 3) Determine whether new dendritic protrusions give rise to enhanced connectivity during LTP. 4) Test NMDA receptor-dependence of structural and molecular changes to ensure they are related to synaptic plasticity, and not simply driven by neural activity. Understanding structural plasticity during LTP will elucidate mechanisms underlying normal changes as a basis for understanding brain pathology.
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