Effectors of presynaptic cAMP dependent potentiation at mossy fiber synapses_Diversity Supplement

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Abstract: Short term synaptic plasticity is a dynamic process that provides moment to moment fluctuations in synaptic strength, but connecting these dynamic changes to complex cognitive processes has been difficult. The mossy fiber (MF) to CA3 synapse in the hippocampus provides a unique opportunity to assess a highly dynamic synapse in a microcircuit important for pattern separation tasks. This microcircuit is formed by the MF axons of dentate gyrus (DG) granule cells (GC) forming en passant synapses with excitatory CA3 pyramidal cells (PYRs), and local circuit inhibitory Stratum lucidum interneurons (SLINs). Critically, these two synaptic connections are central to the role of the MF as a high pass filter of information from the DG to CA3. The low release probability connections onto PYRs show significant facilitation when activated at modest frequencies. In contrast, the high release probability synapses at SLINs depress during elevated bouts of activity, reducing feedforward inhibition. These compartmentalized presynaptic properties of the MF allow the synapses to function as conditional detonators, filtering information from the DG to CA3 and allowing GC bursting activity to produce suprathreshold post synaptic summation on the CA3 network. Yet the mechanisms that control this fundamental property of this important hippocampal microcircuit are not fully known. Presynaptic Ca2+ sensors are known to mediate a major component of synaptic facilitation. Specifically, the high affinity Ca2+ sensor Synaptotagmin 7 (Syt7) is critical for facilitation at synapses in multiple brain regions, including the MF to CA3 PYR synapse. Yet there remain many outstanding questions about how this specialized sensor controls release. Crucially, it remains unknown what roles Syt7 plays in facilitation and other steps in the synaptic vesicle (SV) cycle. Here, I will address whether the subcellular localization and activity of Syt7 is compartmentalized in MF synaptic terminals, and how this affects the CA3 microcircuit. I will determine whether Syt7 is primarily associated with MF SVs, like other synaptotagmins that control release, or whether it is localized to non-vesicular membranes, where it plays a specialized role in other aspects of the SV cycle such as pool replenishment. Finally, I will examine the unique properties of Syt7 that are bestowed by the C2A Ca2+ binding domains of the protein. Together these experiments will establish how the molecular identity and functional characteristics of Ca2+ sensors define the network properties of the CA3 microcircuit.