Via zoom : https://u-bordeaux-fr.zoom.us/j/82043365426
Defense in english
Title: Molecular impact of the antagonist ketamine in Auto-immune encephalitis with NMDAR-Ab
Abstract
Among autoimmune encephalitis, the discovery of autoantibodies directed against the glutamatergic NMDA receptor (NMDAR-Ab), in the so-called anti-NMDAR encephalitis, has shed new lights on how neurological and psychiatric features can be directly related to NMDAR dysfunction. In particular, it emerged that NMDAR-Ab profoundly alter the receptor membrane dynamics and content without affecting per se its ionotropic transmission (no antagonistic action). Because the therapeutic removal of NMDAR-Ab in anti-NMDAR encephalitis patients takes time and some neuropsychiatric features remains well after treatment, the search for complementary drugs that would prevent the deleterious effect of NMDAR-Ab is of great interest. Using a unique combination of single molecule, FRAP, and FRET imaging, immunocytochemical, and behavioural approaches, we here demonstrate that the non-competitive NMDAR antagonist ketamine is also potent regulator of the receptor surface dynamics, stabilizing synaptic NMDARs. Ketamine prevents synaptic and behavioural deficits induced by NMDAR-Ab from anti-NMDAR encephalitis patients. This action was not due to the blockade of the ionotropic transmission since a competitive antagonist was fully ineffective. Instead, ketamine alters NMDAR conformation, favoring its synaptic anchoring and preventing receptor dispersal by autoantibodies. Thus, we unveil a non-canonical action of the clinically-relevant ketamine on the NMDAR trafficking, opening new avenues of research and therapeutical use.
Keywords: NMDAR-Encephalitis, NMDAR, auto-antibodies, Ketamine
Jury
Patrick Blanco, President
Pierre Gressens, Judge
Josep Dalmau, Judge
Ana Luísa Carvalho, Referee
Jérome Honnorat, Referee
Frédéric Villéga
Team Groc
IINS
Thesis surpervisor: Laurent Groc