Cycle 3 project 5

Regulation of receptor recycling by synaptotagmins in neuronal dendrites

 

PhD student: Julia Krapivkina, Russia
Home Institute: Bordeaux Neurocampus; Principle Investigator: David Perrais
Host Institute: European Neuroscience Institute Göttingen; Principle Investigator: Camin Dean

Executive Summary

A central problem in neurobiology is to understand how cells of the nervous system are organized in a functional network. Neurons must be able to connect each other through synapses and process the information they receive. To achieve this goal, neuronal dendrites possess an elaborate endosomal system, through which receptors are recycled to and from the post-synaptic membrane. These intracellular organelles act as a reservoir to quickly provide receptors to potentiate synaptic transmission. However, despite substantial evidence for post-synaptic receptor recycling, virtually nothing is known about the mechanisms by which this recycling is regulated.

Recently, Partner-1 (Perrais) has examined the dynamics of receptor membrane trafficking in cultured hippocampal neurons transfected with the transferrin receptor (TfR) a model receptor widely used to study endocytosis and recycling, present in recycling endosomes (REs) containing glutamate receptors. This reporter construct consists of a receptor fused to superecliptic phluorin (SEP), which enables detection of single exocytotic events in live cells, characterized by a sudden increase in fluorescence. They found a number of features of TfR-SEP events (Jullié et al. submitted) and hypothesized that some aspects of RE exocytosis could be regulated at a late stage.

Among the proteins engaged in exocytosis, synaptotagmins (syts) have emerged as potential players in regulating exo-endocytotic events in neuronal dendrites: Partner-2 (Dean) has analyzed the recycling site and kinetics of the 17 syt isoforms in cultured hippocampal neurons and found clear dendritic recycling for 6 of them. These syts are thus potential candidates for regulating exocytosis in neuronal dendrites. Interestingly, different syts exhibit distinct kinetics of recycling in response to depolarization, and thus may regulate specific aspects of post-synaptic function and plasticity.

For this project, we will test the involvement of syts in RE exocytosis using live fluorescence imaging, electrophysiology and immunocytochemistry with STED microscopy. The expertise in RE exo- and endocytosis imaging using dedicated protocols of Partner-1 will be nicely complemented by the expertise of Partner-2 in molecular studies of synaptotagmins. Close collaboration is further guaranteed by a common interest in how the regulation of endosomal recycling affects synaptic physiology and plasticity.

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