Synaptic transmission and its use-dependent plasticity are critical processes for nervous system function, including learning and memory, and abnormal plasticity is present in many neurological disorders. During sustained neuronal activity, calcium level increases in the postsynaptic neuron can result in synaptic strengthening, referred to as long-term potentiation (LTP). One of the mechanisms for LTP induction is exocytosis of AMPA receptors onto the membrane, a process triggered by the increased calcium levels. In the presynaptic terminal, synaptotagmins 1 and 7 are the calcium sensors that trigger synaptic vesicle exocytosis. I hypothesize that synaptotagmins act as calcium sensors during LTP induction. In the mentored phase of this award, I will test this hypothesis by shRNA-mediated knockdown of these two synaptotagmins in the CA1 region of the hippocampus followed by assaying for LTP by electrophysiology or for behavioral phenotypes in learning tasks. Having established the importance of these molecules in synaptic plasticity, during the independent phase I will generate synaptotagmin-based tools to specifically abolish LTP, and I will try to tune synaptic plasticity efficacy by altering synaptotagmin calcium affinity. These toos will allow us to ask if modulation of these basic parameters of synaptic plasticity can affect behavioral performance. These studies will uncover new molecular mechanisms of the substrates of learning and memory, and how these pathways might be affected in neurological conditions.
Long-term synaptic plasticity is believed to be one of the key mechanisms mediating learning and memory. The proposed research will identify the molecules that sense neuronal calcium changes which can trigger long- term plasticity. Thus, this work will extend our understanding of basic neuronal processes and help define pathways that in the future could be used to ameliorate neurological dysfunctions.
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|Brewer, Kyle D; Bacaj, Taulant; Cavalli, Andrea et al. (2015) Dynamic binding mode of a Synaptotagmin-1-SNARE complex in solution. Nat Struct Mol Biol 22:555-64|