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Modulation of synaptic plasticity and circuit function by regulation of neurotrophin exocytosis

Final Report Summary - SYT ACTIVITY (Modulation of synaptic plasticity and circuit function by regulation of neurotrophin exocytosis)

One of the most prominent features of the brain is that it must constantly sense and adapt to changes in the environment. This is especially important for learning and remembering. This adaptation occurs at synapses - the connections between neurons in the brain. Modification of these connections can occur via the regulation of exo- and endocytotic events on both sides of the synapse, including release of presynaptic neurotransmitter from synaptic vesicles, recycling of post-synaptic neurotransmitter receptors to or from the cell surface, and the release of neuropeptides and neurotrophins from dense core vesicles from both sides of the synapse, which in turn modulate neurotransmitter release and receptor recycling to affect synaptic strength. We found that the synaptotagmin family of molecules regulates these events to modulate synaptic plasticity – the ability of synapses to change their strength in response to environmental perturbations. While synaptotagmin 1 is essential for fast neurotransmitter release from synaptic vesicles, we found that synaptotagmin 4 is localized to neurotrophin-containing dense core vesicles and promotes their targeting and capture at active synapses to modulate synaptic function. We found that synaptotagmin 3 is localized to the post-synaptic side of the synapse where it is essential for removal of receptors from the post-synaptic membrane during plasticity to promote “forgetting“ of transient information during working memory tasks. Other synaptotagmin isoforms have distinct localizations and recycling kinetics in neurons (and in astrocytes) where they regulate distinct events during changes in neuronal activity. Together, our research has uncovered the mechanism by which a family of proteins differentially regulates multiple aspects of synaptic plasticity to ensure reliable adaptation of synapse and circuit function underlying behavior.