Cycle 5 project 6

High-resolution imaging of the functional interplay between surface NMDA receptor and proteasome

 

P06-KellermayerPhD student: Blanka Kellermayer, Hungary
Home Institute: Center for Neuroscience and Cell Biology Coimbra; Principle Investigator: Ana Louisa Carvalho
Host Institute: Bordeaux Neuroscampus; Principle Investigator: Laurent Groc

Executive Summary

The majority of synaptic contacts in the central nervous system use glutamate for neurotransmission, which binds to several types of receptors, including N-methyl-D- aspartate receptors (NMDAR) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole receptors (AMPAR). NMDAR regulate the synaptic content of AMPAR during synaptic plasticity, the process thought to underlie learning and memory formation. Synaptic maturation and long-term changes in the synaptic strength require a tight balance between protein synthesis and protein degradation, the last being regulated by the ubiquitin-proteasome system. Our recent data support the hypothesis that NMDAR play a role in anchoring proteasomes to synapses. The purpose of this project is to test the original hypothesis that NMDAR surface dynamics controls proteasome location and consequently glutamate synapse transmission.

To tackle this question, we will use a variety of imaging (bulk and single molecule- based approaches) and cell biology methods. First, we will establish the cellular distribution of both surface NMDAR and proteasome elements using high-resolution imaging approaches, i.e. single nanoparticle tracking, PALM and d-STORM. This will provide a unique opportunity to establish potential co-variation of these elements in various neuronal compartments (spine heads, neck, dendritic shaft). Second, we will investigate the role of NMDAR in regulating the synaptic localization of the proteasome. We will test whether the mobility and the activity of the synaptic proteasome are altered upon genetic deletion of GluN2B-NMDAR, or in synapses in which GluN2B-NMDAR are displaced to extrasynaptic locations using biomimetic ligands (Bard et al., PNAS, 2010). Third, we will study the relationship between the surface dynamics of GluN2A-/GluN2B-NMDAR and the localization of the proteasome in the synaptic area, since we recently uncovered that surface dynamics of GluN2B-NMDAR is required for glutamate synapse plasticity. Finally, we will identify the specific molecular determinants in GluN2B which are required to regulate the synaptic anchorage of the proteasome and test the hypothesis that CaMKII translocation to the synapse, by binding to GluN2B, is required for synaptic localization of the proteasome, and for synaptic signaling mediating plasticity. All together, this project will use conventional and cutting-edge single molecule imaging approaches to unveil a novel role for NMDAR in regulating the synaptic levels of the proteasome, and will allow us to infer about the mechanisms through which NMDAR act to regulate synaptic glutamate receptor content at developing neurons.

This project is a collaborative effort between the laboratories of Ana Luisa Carvalho (Coimbra, Portugal) and Laurent Groc (Bordeaux, France). We expect to unravel how the synaptic proteasome is involved in spine signaling mediated by the surface dynamics of NMDA receptors.

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