The overall goal is to understand synaptic mechanisms of learning and memory. Long-term potentiation (LTP) is a model of learning and memory that is well-suited to investigate these processes. Dendritic spines host about ninety percent of excitatory synapses in the brain and are well known to show structural plasticity following induction of LTP. The developmental onset of dendritic spines coincides with an abrupt developmental onset for LTP lasting more than three hours (L-LTP) at postnatal day 12 (P12) in rat hippocampus. At P10 and P15, LTP enhances synaptogenesis and small spine formation. With maturation, the LTP-accelerated synaptogenesis shifts to a process that enlarges specific synapses and retains spine clusters locally but is balanced by reduction in spine numbers elsewhere on the dendrite. The spine clusters are locally delimited by the availability of smooth endoplasmic reticulum (SER), an organelle critical for regulating calcium, and the transport of lipids and proteins, and by the presence of polyribosomes, which mediate local protein synthesis. The LTP-produced synapse enlargement is greatest on spines that contain a spine apparatus, which is a structure derived from SER that provides synthesis and post-translational modification of transmembrane proteins. Structural changes in presynaptic axons are also developmentally regulated following LTP and mirror the spine changes with new boutons forming to accommodate the LTP-accelerated synaptogenesis at P15, and fewer boutons occurring with spine reduction at P60. Thus, LTP in developing hippocampus accelerates synaptogenesis, whereas resource-dependent synapse growth and spine clustering occur on mature dendrites. This homeostatic balance in synaptic plasticity is hypothesized to be disrupted with cognitive decline in the aging brain. A comprehensive analysis of structural synaptic plasticity during maturation and senescence is proposed as a foundation for understanding lifelong changes in cognitive capacity. Specifically, the aims are: 1) To determine whether shifts in synaptic plasticity underlie maturational milestones in learning. 2) Determine generality of resource-dependent synapse growth and spine clustering across circuits. 3) To determine whether LTP-related structural plasticity diminishes in the aging hippocampus as cognitive capacity declines. 4) To test whether removal of the spine apparatus impairs resource-dependent synapse growth and spine clustering following LTP. Outcomes promise essential insight into the synaptic basis of learning and memory across lifespan and will provide basic knowledge that could inform new therapies for developmental and age-related brain disorders.
The overall goal is to understand biological mechanisms of learning and memory. The nanometer resolution of electron microscopy, and long-term potentiation, a model of learning and memory, are combined in a comprehensive analysis of structural synaptic plasticity to elucidate lifelong changes in cognitive capacity.