Coordinated structural plasticity across synapses in the adult hippocampus

Neural circuitry is determined primarily by trillions of synaptic junctions that link cells in the nervous system. Understanding how the structure of the synapse influences its function has been a central goal of cellular neuroscience since synapses were first recognized more than a century ago. Long-term potentiation (LTP), a long lasting enhancement of synaptic efficacy, is a well-characterized cellular correlate of learning and memory that results in dramatic structural remodeling of the synapse. Research has focused heavily on the postsynaptic structural remodeling that occurs to support LTP, but concomitant presynaptic and subcellular remodeling during LTP has been left largely unexplored. To address these questions, three-dimensional reconstructions from serial section electron microscopy of presynaptic boutons, vesicle pools, and dendritic smooth endoplasmic reticulum (SER) in hippocampal area CA1 were created and quantified. The data presented in this dissertation demonstrate that coordinated structural plasticity occurs at both pre- and postsynaptic sides of adult hippocampal synapses by 2 hours during LTP induced with theta burst stimulation. Presynaptically, the number of presynaptic boutons correlated perfectly with fewer dendritic spines during LTP that were previously reported, suggesting that synaptic units act as cohesive structures. Vesicle pools were mobilized and vesicle transport packets were moved into boutons or were released in transit. Dendritic SER is a ubiquitous intracellular membranous network involved in calcium signaling and protein modification. The complexity of SER influences the movement of diffusible membrane cargo. SER was dramatically remodeled during LTP, redistributing from the shaft of the dendrite into spines and becoming highly complex near synapses that were largest during LTP. As a preliminary investigation into how normal mechanisms of structural plasticity described in this dissertation might go awry under conditions of synaptic pathology, three-dimensional reconstructions of CA1 synaptic ultrastructure in a mouse model of Fragile X, which is known to express exaggerated mGluR-dependent long-term depression (LTD), were created and quantified. Synaptic ultrastructure was similar with that of the wild-type mouse, suggesting that structural malformation in FX might be confined to development or to other brain regions.