Our purpose is to better understand synapthopathies in general with a special focus on synaptic dysfunction induced by autoantibodies.
The goal of our research is to better understand the cellular and molecular mechanisms involved in neuronal and synaptic dysfunctions in neuropsychiatric diseases. We are particularly interested in the pathophysiology of autoimmune encephalitis (AE) and paraneoplastic neurological syndromes (PNS). These neuropsychiatric diseases are associated with autoantibodies present in patients’ serum and CSF, which target neuronal proteins involved in synaptic transmission (ie, NMDAR, AMPAR, GABABR), synapse organization (LGI1, CASPR2), or signaling (DPPX, CRMP). Each of these autoantibodies is associated with a clinical syndrome similar to what is observed when these same proteins are disrupted by pharmacological or genetic means. These autoantibodies have an impact on the structure and function of the antigens they target. Our strategy is to integrate basic and clinical research to study the mechanism of action of autoantibodies and their effects on synaptic and neuronal functions and associated neuro-inflammatory processes. We study synaptic functions in a physiological and pathological context, using patient autoantibodies as research tools. We focus in particular on NMDA receptors and some of their partners, such as VEGFR2, and on proteins involved in neuronal excitability, such as LGI1 or CASPR2. We have developed animal models with autoantibody infusion in the hippocampus via osmotic pumps, and in vitro models of neuronal primary cultures and organotypic brain slices. The use of these different models allows us to study the effect of the inflammatory response on neurons and glial cells, the transport of glutamate, and the modulation of neurotransmission.
Our biological collection of serum and CSF from SNP and EA patients allows us to detect autoantibodies targeting unknown proteins or neuronal receptors. A translational approach is then used to identify the targeted proteins and understand their roles. These new targets can also serve as biomarkers of the disease and contribute to the development of new therapeutic strategies.
This work should lead to a better understanding of neuropsychiatric diseases associated with autoantibodies, but also of neurodegenerative pathologies such as Alzheimer’s disease.
The BETPSY project, coordinated by Prof. Honnorat, has received a 7.3 million euro “Future Investment Program (PIA)” funding. It is based on the collaboration of 5 academic research teams (UCBL, HCL, ICM, CLB and INSERM), and an industrial partner (Euroimmun), specialized in the development and marketing of autoantibody detection kits.
The aim of the BETPSY project is to better characterize EA and SNPs in order to improve the care and treatment of patients suffering from these diseases, through the identification of new biomarkers, the understanding of the mechanisms involved in these autoimmune diseases and the development of animal models: https://www.rhu-betpsy.fr/.
UCBL – CNRS UMR 5310 – INSERM U1217
Faculté de Médecine et de Pharmacie – 3ème étage – Couloir AB
8 avenue Rockefeller