The French National Research Agency Projects for science

Voir cette page en français

ANR funded project

Innovation biomédicale (DS0404) 2014
Projet MECANO

Mechanisms of auto-immune encephalitis

Neurological and psychiatric diseases are one of the major health problems worldwide. Decades of fundamental and clinical research have led to the model that these disorders results from synaptic imbalance between excitatory and modulatory systems in key brain structures. Although the network and neurotransmitter systems involved have been delineated, the mechanisms leading to an improper neurotransmissions remain poorly understood. One major limitation lays in the difficulty to transpose the identified dysregulation in humans to relevant animal models in which molecular and cellular targets can be manipulated.
We know that the glutamatergic synapses can change their strength by regulating surface expression and dynamics of their postsynaptic receptors, through changes in receptor recycling and/or lateral diffusion. New imagery technique with subcellular resolution rendered possible the study of receptor trafficking and receptor regulation in various pathological models opening new fundamental questions. Moreover, recent breakthroughs on glutamate receptor structure offer unprecedented clues on the structural mechanisms underpinning receptor dysfunction at the atomic level.
Recently, description of encephalitis associated with specific autoantibodies (Abs) directed against neuronal synaptic receptors or proteins (NSA-Abs) open new lights in the molecular mechanisms of some human brain disorders. The best example and the most frequent syndrome is the synaptic autoimmune encephalitis associated with autoantibodies against extracellular domains of the glutamatergic NMDA receptor (NMDAR-Abs). Classically, patients first present psychiatric symptoms with hallucinations and bizarre behavior before development of neurological symptoms such as seizures, dyskinesia, and autonomic instability. Despite the severity of neuropsychiatric symptoms, more than 80% of patients fully recover after immunomodulatory treatments and many arguments suggest a direct role of NMDAR-Abs in the symptoms. We recently demonstrated and published that NMDAR-Abs directly modify, at the synaptic level, NMDAR lateral diffusion by disruption of the interaction between NMDAR and EphrinB2 receptor, a synaptic protein anchoring NMDAR at the synapse (Mikasova et al, Brain 2012). These data suggest that NMDAR-Abs could directly explain neuropsychiatric disorders observed in patients and that NMDA receptors are responsible of the observed symptoms. Furthermore, these data suggest that other NSA-Abs directed against other synaptic proteins could explain specific neurological symptoms in patients with encephalitis that are not associated with NMDA-Abs.
The aim of MECANO is to combine multidisciplinary approaches (clinical, immunological, and high-tech neurobiology) to identify new NSA-Abs, to characterize NSA-Abs specific pathological roles and to decipher NMDAR-Abs effects on biophysical and structural properties of the NMDA receptor, synaptic plasticity and morphology.
This project will provide the first insights onto the effects of patients’ NSA-Abs on the dynamic and regulation of surface glutamatergic receptors and on the molecular cascades activated during dysfunction of synapses. We specifically plan to unravel the molecular and cellular processes involved in the disease mechanisms. We will investigate, how NSA-Abs binding alter glutamate receptor activity, modify surface receptor mobility and dynamically regulate the maturation of synapses and circuitries using a unique combination of high-resolution imaging (single nanoparticle tracking), cellular electrophysiology, computational (structural modeling) and molecular biology approaches. Based on both cutting-edge neurobiology and clinical expertise of autoimmune disorders, the MECANO project strengthen by our preliminary experiments will likely open new avenues of fundamental research in the understanding of synaptic dysfunction and clinical research for the treatment of neuropsychiatric disorders.

Partners

HCL Centre de référence des syndromes neurologiques paranéoplasiques, Hospices Civils de Lyon

IBENS Institut de Biologie de l'Ecole Normale Supérieure

Inserm 1028 / CNRS 5292 Centre de recherche en neurosciences de Lyon, équipe "neuro-oncologie et neuro-inflammation"

UMR CNRS 5297 Interdisciplinary institute for neurosciences Bordeaux. Team Development and Adaptation of Neuronal Circuits

ANR grant: 561 138 euros
Beginning and duration: janvier 2015 - 48 mois

 

ANR Programme: Innovation biomédicale (DS0404) 2014

Project ID: ANR-14-CE15-0001

Project coordinator:
Monsieur Jerome Honnorat (Centre de recherche en neurosciences de Lyon, équipe "neuro-oncologie et neuro-inflammation")

 

Back to the previous page

 

The project coordinator is the author of this abstract and is therefore responsible for the content of the summary. The ANR disclaims all responsibility in connection with its content.