Venue: CGFB
Thesis defense in english
Zoë Jamet
IINS
Team : Development and adaptation of neuronal circuits
Thesis director : Laurent Groc
Title
Molecular impact of anti-NMDA receptor autoantibodies
Abstract
The N-methyl-D-aspartate receptor (NMDAR) plays a pivotal role in both health and disease, serving as a crucial mediator of synaptic plasticity and memory while also being implicated in various neurological and psychiatric disorders when dysregulated. In 2007, the discovery of autoantibodies targeting the NMDAR (NMDAR-Ab) in NMDAR encephalitis has offered valuable insights into the direct role of NMDAR dysfunction in human brain disorders. In this disease, NMDAR-Ab induce a massive loss of surface NMDAR resulting in NMDAR hypofunction. This hypofunction manifests as a spectrum of severe symptoms encompassing behavioral disturbances, changes in consciousness, abnormal movements, and seizures, showing how complex neuropsychiatric symptoms can arise from NMDAR signaling deficits. Although the study of NMDAR-Ab is still in its infancy, a model has emerged to describe the mechanism of action of NMDAR-Ab. This model predominantly focuses on synaptic NMDAR as the principal target of NMDAR-Ab. In the synapse, NMDAR-Ab can disrupt NMDAR-EphB2 receptor (EphB2R) interaction, causing synaptic NMDAR translocation to the extrasynaptic region via lateral diffusion. Subsequently, these newly positioned extrasynaptic NMDAR may become cross-linked by NMDAR-Ab and internalized. However, this view is not fully consistent with existing experimental data on receptor membrane trafficking and lack insight on the acute and fast effect of NMDAR-Ab. Thus, using a combination of live imaging, single particle tracking and super-resolution microscopy, we investigated the molecular impact of NMDAR-Ab on synaptic and extrasynaptic NMDAR, their interactome and the surfaceome. Surprisingly, we found that NMDAR-Ab acutely altered extrasynaptic NMDAR surface trafficking with no effect on synaptic NMDAR surface trafficking. Both extrasynaptic NMDAR interactome and surfaceome were disorganized after acute exposure with NMDAR-Ab whereas no alterations were observed in the synaptic interactome. Furthermore, NMDAR-Ab fail to trigger NMDAR clathrin-mediated internalization, in contrast to a crosslinker antibody. Finally, we demonstrate that NMDAR-EphB2R interaction is not required for NMDAR-Ab pathogenicity whereas selectively targeting of extrasynaptic NMDAR with NMDAR-Ab is sufficient to induce NMDAR synaptic hypofunction. Altogether, these results indicate that NMDAR-Ab do not act as crosslinkers but rather as disorganizers of the extrasynaptic membrane. Thus, we propose a novel mechanism of action that is not focused on synaptic receptors but rather on the extrasynaptic compartment. In parallel, we developed a model of organotypic human brain slices that were structurally characterized using electron microscopy and immunohistochemistry in order to test the effect of NMDAR-Ab in a human cortex. The use of this human brain tissue will be, in the future, of significant interest to reveal more deeply the broad spectrum of action of NMDAR-Ab. Overall, the work of my thesis provide a new, and unsuspected, insight on the mechanism of action of NMDAR-Ab from encephalitis patients, opening new perspective to correct deficit in NMDAR signaling.
Key words
NMDA receptor – autoantibodies – psychosis – interactome – auto-immune encephalitis – super-resolution microscopy
Publications
D.Hunter*, Z.Jamet*, L.Groc. Autoimmunity and NMDA receptor in brain disorders : Where do we stand? Neurobiol Dis. 2021 Jan;147:105161. *co-first author
Jury
Mme. Daniela COTA, Directrice de recherche, Université de Bordeaux, Présidente
Mme. Monica DILUCA, Professeur, Université de Milan, Examinatrice
Harold MACGILLAVRY Directeur de recherche, Université de Utrecht, Rapporteur
Christian GEIS Professeur, Université de Jena, Rapporteur
Laurent GROC Directeur de recherche, Université de Bordeaux, Directeur de thèse