Regulation of post-synaptic receptor recycling by synaptotagmin 3

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In the last funding period we proposed to investigate the localization of different synaptotagmin (syt) isoforms to distinct vesicle subtypes in neurons, using a new technique to isolate vesicles from very small amounts of neuronal tissue, developed by a postdoc in the lab (now published: Ahmed et al. Nat. Protocols 2013). Data from the last funding period (now published: Dean et al. Mol. Biol. Cell 2012) suggested that members of the syt family of molecules are differentially localized to distinct vesicle subtypes in neurons. In a further characterization of one isoform, syt4, we found that syt4/ BDNF-harboring vesicles with distinct fusion properties are sorted to axons versus dendrites (now published: Dean et al., J. Neurosci. 2012). While examining the properties of the syt isoforms, we discovered, in preliminary data described below, that syt3 is uniquely localized exclusively to the post-synaptic membrane, where it regulates endocytosis of post-synaptic AMPA receptors. This is a particularly interesting finding because post-synaptic receptor recycling to and from the post-synaptic membrane is essential for long-term potentiation (LTP) and long-term depression (LTD) of synaptic strength - a fundamental property of neurons that is crucial for learning and information storage in the brain. But the molecular machinery mediating the exo- and endocytosis of receptors to and from the post-synaptic membrane is poorly understood. We propose to determine, using a combination of imaging, biochemical, and electrophysiological approaches, if syt3 is the post-synaptic calcium sensor that regulates recycling of receptors during synaptic plasticity. This will not only reveal the location and function of this unique syt isoform in neurons, but will also answer a long-standing question regarding how post-synaptic receptor recycling is regulated to affect synaptic plasticity.