Cycle 3 project 6

Excitatory Synaptic Vesicle Tracking Using Fluorescent VGLUT1 Tagging in Mice


PhD student: Xiaomin Zhang, China
Home Institute: Bordeaux Neurocampus; Principle Investigator: Etienne Herzog
Host Institute: European Neuroscience Institute Göttingen; Principle Investigator: Nils Brose

Executive Summary

The vesicular glutamate transporter VGLUT1 loads synaptic vesicles (SV) with the neurotransmitter glutamate at many synapses in the mammalian brain. Due to its function and selective localization, VGLUT1 is one of the most specific markers for glutamatergic synaptic vesicles. It has been used widely to identify glutamatergic synapses, and its expression levels are tightly correlated with changes in quantal size (Wojcik et al., PNAS, 2004; Wilson et al., J. Neurosci 2005), modulations of synaptic plasticity, and corresponding behavioral phenotypes (Balschun et al., Cereb. Cortex, 2009; Tordera et al., Eur J Neurosci, 2007). Finally, VGLUT1 plays additional roles in the homeostasis of SV clusters through its interaction with endophilinA1 (Voglmaier et al., Neuron, 2006; Weston et al., Neuron, 2011).

In 2006, Etienne Herzog (exchange PI) generated a fluorescent VGLUT1venus knock-in mouse in the laboratory of Nils Brose (host PI) for the analysis of VGLUT1 and SV trafficking. They established that the mutation does not affect synapse function, and thus the new mouse model represents a universal tool for the analysis of glutamatergic systems in the forebrain. Using the VGLUT1venus knock-in, they showed that SVs are dynamically shared among en passant presynaptic boutons in vivo and described how network homeostasis leads to the dynamic scaling of VGLUT1 and SV levels at boutons in vitro (Herzog et al., J. Neurosci, in press). Over the past three years, a continued fruitful collaboration has been maintained between Paris and Goettingen (Biesemann et al., in preparation). With the recent appointment of Dr Herzog in the team of Yann Humeau (Bordeaux), who is studying presynaptic physiology in different neuronal systems (Humeau et al., Neuron, 2005; Humeau et al., Nature, 2003, Doussau et al., 2010, J. Neurosci.), we wish to reinforce the collaboration with dedicated funding and new projects. Our goals for this joint Ph.D project proposal are to extend the array of VGLUT1 knock in mice available to the community (VGLUT1P554AVENUS, VGLUT1miniSOG, VGLUT1mEOS) and to implement slice physiology and imaging to extend our knowledge on the roles of SV mobility and VGLUT1 scaling in the physiology of glutamatergic systems.

The combined expertise of Etienne Herzog, Yann Humeau and Nils Brose is an absolute prerequisite for the success of the planned project. Through this Ph.D project, the trainee will become an expert in the study of glutamatergic presynapses, in mouse molecular genetics, electrophysiology and imaging. Finally, our project will allow to better characterize the role of VGLUT1 in SV biology at glutamatergic synapses and the role of inter-synaptic sharing of SVs in neurotransmission.

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