Autoimmune Encephalitis Clinical Trial
Official title:
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, inhibitory and modulatory systems in key brain
structures. Although the network and neurotransmitter systems involved have been delineated,
the mechanisms leading to 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.
The amino-acid glutamate mediates the vast majority of excitatory neurotransmission in the
mammalian brain. 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. This synaptic plasticity underlies higher
cognitive functions such as learning and memory and is likely compromised in several disease
states. Regulating glutamate receptor number and function is thus of primary importance. New
subcellular imaging technique rendered possible the study of receptor trafficking and
receptor regulation in various conditions including pathological models opening new
fundamental questions. Moreover, recent breakthroughs on glutamate receptor structure offer
unprecedented clues on the molecular and 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) opens new lights in the
pathophysiological 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. The investigators recently demonstrated 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; Dupuis et al, EMBOJ 2014). These data suggest that NMDAR-Abs could directly participate
in the neuropsychiatric disorders observed in patients and that NMDAR dysfunctions could be
directly responsible for 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 NMDAR-Abs.
The aim of MECANO is to combine multidisciplinary approaches (clinical, immunological, and
neurobiological ones) to identify new NSA-Abs, to characterize their specific pathological
roles and to decipher acute and chronic NMDAR-Abs effects on biophysical and structural
properties of the NMDA receptor, synaptic plasticity, neuronal morphology, and cognitive
performance. This project should provide key insights onto the effects of patients' NSA-Abs
on the cellular dynamic and regulation of synaptic proteins or receptors and on the molecular
cascades activated during synapse dysfunction. The investigators will investigate how NSA-Abs
binding alter receptor activity, modify surface receptor mobility and dynamically regulate
the maturation of synapses and circuitries. For that purpose, The investigators will use a
unique combination of high-resolution imaging (single nanoparticle tracking), receptor
engineering, cellular electrophysiology, computational (structural modeling) and cellular and
molecular biology approaches and finally behaviour assays. Based on both cutting-edge
neurobiology and clinical expertise of autoimmune disorders, and strengthened by promising
preliminary experiments, the MECANO project will likely open new avenues of fundamental
research in the understanding of synaptic dysfunction and clinical research for the treatment
of neuropsychiatric disorders.
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