Encephalitis with synaptic receptors’ autoantibodies: a new model of psychotic disorders – AutoMobil

Psychotic disorders, encompassing schizophrenia and bipolar disorders, are major health problems worldwide. Decades of research have shown that they result from a synaptic imbalance between neurotransmitter systems. However, due to their complexity and the restrained number of pertinent molecular tools, our understanding of psychotic disorders remains limited. Recently, description of encephalitis with specific autoantibodies directed against synaptic receptors has provided a new way to better explore the molecular mechanisms of psychotic disorders. The most frequent one is the synaptic autoimmune encephalitis associated with autoantibodies (Ab) against extracellular domains of the glutamatergic NMDA receptor (NMDAR). Patients initially present psychiatric symptoms with delusional ideas and manic symptoms before developing few days’ later neurological symptoms such as seizures and dyskinesia. Despite the severity of symptoms, approximately 80% of patients fully recover after immunomodulatory treatments, suggesting a direct role of NMDAR-Ab. Encephalitis with NMDAR-Ab offer thus a unique human models of brain-immune interactions in which the target antigens have critical roles in synaptic transmission and psychotic disorders. The presence and role of such autoantibodies in population of patients with psychotic disorders remain however unknown, although it likely constitutes a major conceptual breakthrough.
The aim of our project is to combine multidisciplinary approaches (clinical, immunological, neuroscience and cutting-edge imaging) to explore the emerging hypothesis that sub-groups of psychotic disorders may be the consequences of abnormal immune-brain interplay. We will i) identify and purify auto-antibodies directed against synaptic receptors in populations of well characterized psychotic patients (with or without neurological associated symptoms), ii) characterize the clinical and immunological presentation of patients with autoantibodies targeting synaptic proteins (NMDAR and others), and iii) use autoantibodies as scientific tools to understand their functional consequences on receptor mobility and neuronal dysfunctions. On top of exploring new etio-pathogenic mechanisms underlying psychotic disorders, this project should lead to the identification of innovative biomarkers for early-diagnosis and prognosis and should unravel new therapeutic strategies. This multidisciplinary and innovative project will be performed by 3 partners that have internationally-recognized expertise in the field of clinical and fundamental aspect of autoimmune encephalitis disorders (Honnorat’s lab, French Reference Center for paraneoplastic neurological syndrome and head of INSERM unit, Lyon), clinical research in psychiatry (Fondamental Foundation, director Leboyer, Créteil), and cutting-edge imaging in neuroscience (Groc’s team, CNRS Interdisciplinary Institute for NeuroScience, Bordeaux). The expertise of Honnorat’s lab to purify NMDAR-Ab from encephalitis patients is, and will, be central in the identification of new autoantibodies and other biomarkers. The network of expert centers established by the FondaMental Foundation will allow systematic clinical (psychiatric and cognitive) and biological (immuno-inflammation) assessment of patients with NMDAR-Ab encephalitis and/or first psychotic episode patients. In order to gain molecular insights into the mechanism activated by these markers, Groc ‘s lab will use the cutting-edge single nanoparticle imaging to follow over time the impact of autoantibodies on their neuronal targets. In a promising series of preliminary investigations, the partners unraveled that NMDAR-Ab severely affect NMDAR surface mobility through altered protein interactions. Together, we are thus confident that this multidisciplinary project will favor our basic and clinical understanding of the synaptic dysfunctions implicated in psychotic disorders, opening avenues of research to improve diagnosis and treatment.