Project description
NMDAR-autoantibody effect on psychiatric and neurological symptoms
NMDA glutamate receptors (NMDAR) play a crucial role in synaptic plasticity through calcium permeability. Recent studies have highlighted the significance of NMDAR membrane trafficking and organisation. Autoantibodies targeting NMDARs compromise surface trafficking, impacting membrane dynamics while leaving ionotropic function intact, leading to psychiatric and neurological symptoms. The EU-funded DynamiK project aims to investigate the effect of NMDAR-Abs on the surface interactome of NMDARs. Employing an unbiased proximity labelling approach and quantitative proteomics, DynamiK will identify the NMDAR surface interactome in hippocampal neurons and assess how NMDAR-Abs alter it in patients. The project will specifically target potassium K+ channels, offering valuable insights into a severe neurological and psychiatric autoimmune paradigm.
Objective
NMDA glutamate receptors (NMDAR) are undisputed key players in synaptic plasticity, a role that has been attributed to their calcium permeability. It emerged over the past decade that the membrane trafficking and nanoscale organization of NMDARs also plays a major role in synaptic adaptation. This was further substantiated by the discovery that patients’ autoantibodies targeting NMDARs (NMDAR-Abs) induce major psychiatric and neurological symptoms through compromised NMDAR surface trafficking but intact ionotropic function. NMDAR-Abs rapidly alter NMDAR membrane dynamics by disrupting their interaction with specific interactors whose membrane organization and function are also possibly corrupted.
Herein, I hypothesize that the whole surface interactome of NMDARs, which is still poorly defined, is altered by NMDAR-Abs, explaining the complex neuropsychiatric presentation observed in NMDAR-Ab-positive patients. To tackle this, I will perform an unbiased proximity labelling approach coupled to quantitative proteomics to provide the first identification of the NMDAR surface interactome in hippocampal neurons, and determine how it is altered by patients’ NMDAR-Abs. Among the targets, the potassium K+ channels, which tightly control neuronal excitability, are of prime interest since they functionally interact with NMDARs, and preliminary evidence from the host laboratory show that NMDAR-Abs alter hippocampal neuron excitability. Using super-resolution microscopy and electrophysiology, I will test whether NMDAR-Abs modulate the membrane trafficking and nanoscale topography of K+ channels, impairing K+ channel currents. Genetic or pharmacological modulation will be used to question the membrane interplay between NMDARs and K+ channels in a pathological, as well as basal, context.
This original proposal will thus shed new light on the NMDAR membrane interactome, its dynamics at the nanoscale, and implication in a severe neurological and psychiatric autoimmune paradigm.
Fields of science
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsproteomics
- natural scienceschemical sciencesinorganic chemistryalkali metals
- natural sciencesphysical sciencesastronomyplanetary sciencesplanetary geology
- natural scienceschemical sciencesinorganic chemistryalkaline earth metals
- natural sciencesphysical sciencesopticsmicroscopysuper resolution microscopy
Keywords
Programme(s)
- HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA) Main Programme
Funding Scheme
HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European FellowshipsCoordinator
75794 Paris
France