Examination of Synaptic and Intrinsic Plasticity in Hippocampal CA1 Neurons

Within the brain, memories are generated during experience; learning activates a subpopulation of neurons – a neural ensemble, or engram – in the hippocampus that then encodes episodic, spatial, or contextual memories. It is thought that experience-dependent synaptic and intrinsic changes work in conjunction to form engrams; synaptic plasticity establishes neural ensembles via maintenance of connections between neurons with coincident activity, while intrinsic plasticity is responsible for the actual activation of engram. In the CA1 region of the hippocampus, functional and structural synaptic changes are typically dependent on the NMDA receptor, which have a unique requirement for concurrent glutamate and co-agonist (glycine or D-serine) binding. Despite the extensive characterization of the NMDAR’s role in synaptic plasticity, it is still unclear what fundamental role co-agonism serves. Our current best guess, based on evidence of structural and functional plasticity in the absence of NMDAR-mediated ion-flux, is that the co-agonist site serves as a modulator of non-ionotropic NMDAR-mediated LTD (niLTD). Therefore, my first project investigated the role of the GluN1 co-agonist site in niLTD. In this study, we tested the effects of varying extracellular co-agonist availability on non-ionotropic plasticity. In-depth examination of this cellular phenomenon may reveal a novel role for non-ionotropic NMDAR plasticity in learning and memory. Indeed, under physiological conditions, synaptic activity drives changes in intrinsic plasticity, in an activity-dependent manner. My second project explored the relationship between learning-induced changes in CA1 pyramidal neurons and behavior following contextual fear conditioning. Future studies are needed to specifically pinpoint the interaction of these two phenomena and how exactly they work in combination to underlie learning and memory. By moving towards a more neurocentric view of learning mechanisms, we can appreciate the wide range of cellular tools employed for memory formation and storage. It should come as no surprise that the complexity of cellular processes underlying memory, mirrors the complexity of our own human experience