Mechanisms of cAMP dependent potentiation of mossy fiber synapses

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Synaptic plasticity in the hippocampus is critical to the formation, storage and retrieval of episodic memories. The separate regions of the hippocampus have evolved to play distinct roles in spatial navigation, contextual memories, social memories, and our ability to separate patterns or complete patterns to reconstruct partial memories. In particular the dentate and CA3 regions of the hippocampus are involved in our pattern separation that is vital to the integrity of episodic memories. At the center of this region are the mossy fiber afferents that make conditional detonator synapses onto CA3 pyramidal neurons, which have a distinct form of presynaptic cAMP dependent plasticity. Despite the importance of cAMP plasticity to memory formation and retrieval in the CA3 the exact molecular mechanisms underlying MF LTP have not been uncovered. The premise of this research builds upon our finding that there are at least two downstream cAMP effectors, PKA (protein kinase A) and Epac2 (exchange protein directly activated by cAMP 2), that contribute to cAMP dependent MF LTP. Despite these findings it is still not known how signaling by each of these effectors results in elevated release from MF synapses and, what are the important targets and substrates that are involved in MF LTP. Here we will use a comprehensive approach with leading edge proteomic, biochemical and electrophysiological approaches to determine the signaling partners of the cAMP effectors, and uncover the physiological mechanism of their actions. Thus, in Aim 1 we will take orthogonal approaches to find the interactors and substrates of PKA and Epac2 and validate and verify these by performing high resolution labeling in situ. In Aim 2 we will determine the exact physiological mechanism that underlie increases in release of neurotransmitter at MF synapses using a combined optogenetic-knockout/pharmacological strategy. In the final Aim we will answer the question of how these different but convergent mechanisms are engaged during naturalistic activity patterns, and whether selective disruption of these effectors impairs the ability of mice to separate similar patterns that underlie the formation and retrieval of episodic memories.