The goal of our research is to better understand the cellular and molecular mechanisms involved in neuronal and synaptic dysfunctions characterizing neuropsychiatric diseases. Our purpose is to focus on the pathophysiology of autoimmune encephalitis (AE) and paraneoplastic neurological syndromes (PNS). These neuropsychiatric diseases are associated with autoantibodies present in patients’ sera and CSF and directed to neuronal proteins involved in synaptic transmission and excitability (i.e., NMDAr, AMPAr, GABAr), synaptic organization (LGI1, CASPR2), or in somatodendritic signaling modulation (DPPX, CRMP). Interestingly, each of these autoantibodies defines a syndrome that resembles models of pharmacological or genetic disruption of the corresponding antigen. Indeed, patients’ autoantibodies have structural and functional effects on the target antigens by a mechanism of antibody-mediated internalization of the antigen. By integrating basic and clinical researches, we propose to study at the cellular and molecular levels how autoantibodies and associated euro-inflammatory processes impact on synaptic and neuronal functions. Synaptic functions will be investigated in physiological and pathological context, using patient’s autoantibodies as research tools, by focusing on NMDA receptor and key partners, VEGFR2, EphB2, CRMP2 and CRMP5. To determine the role of inflammatory response in the pathophysiology of these diseases, glial cell morphology and essential functions, such as glutamate transport, ion recapture and modulation of neurotransmission will be evaluated following infusion of autoantibodies in the hippocampus. To address these different topics we are developing relevant animal models that will be used in combination with primary neuronal cultures, rodent brain slices, and brain tissues. Furthermore, using our biological collection of serum and CSF of patients with PNS and AE, we already identified samples with autoantibodies targeting unknown neuronal protein or receptors. Translational approaches will be used to identify the targeted proteins. Importantly, newly identified proteins will serve as disease biomarkers and will contribute to the development of novel therapeutic strategies. This work should lead to a better understanding of not only neuropsychiatric diseases associated with autoantibodies but also of more common neurological or psychiatric diseases in which similar protein dysfunction are reported.
- Disrupted surface cross-talk between NMDA and Ephrin-B2 receptors in anti-NMDA encephalitis
Mikasova L, De Rossi P, Bouchet D, Georges F, Rogemond V, Didelot A, Meissirel C, Honnorat J, Groc L Brain (2012) May 1. Pages 1606–1621.
- Clinical specificities of adult male patients with NMDA receptor antibodies encephalitis
Viaccoz A, Desestret V, Ducray F, Picard G, Cavillon G, Rogemond V, Antoine JC, Delattre JY, Honnorat J Neurology (2014) 82:556-563.
- Surface dynamics of GluN2B-NMDA receptors controls plasticity of maturing glutamate synapses
Dupuis JP, Ladepeche L, Seth H, Bard L, Varela J, Mikasova L, Bouchet D, Rogemond V, Honnorat J, Hanse E, Groc L EMBO J (2014) 33:842-861.
- Clinical Spectrum of Encephalitis Associated With Antibodies Against the alpha-Amino-3-Hydroxy-5-Methyl-4-Isoxazolepropionic Acid Receptor: Case Series and Review of the Literature
Joubert B, Kerschen P, Zekeridou A, Desestret V, Rogemond V, Chaffois MO, Ducray F, Larrue V, Daubail B, Idbaih A, Psimaras D, Antoine JC, Delattre JY, Honnorat J JAMA Neurol (2015) 72:1163-1169.
- Motor cortex and hippocampus are the two main cortical targets in LGI1-antibody encephalitis
Navarro V, Kas A, Apartis E, Chami L, Rogemond V, Levy P, Psimaras D, Habert MO, Baulac M, Delattre JY, Honnorat J Brain (2016) 139:1079-93.
- Characterization of a Subtype of Autoimmune Encephalitis With Anti-Contactin-Associated Protein-like 2 Antibodies in the Cerebrospinal Fluid, Prominent Limbic Symptoms, and Seizures
Joubert B, Saint-Martin M, Noraz N, Picard G, Rogemond V, Ducray F, Desestret V, Psimaras D, Delattre JY, Antoine JC, Honnorat J JAMA Neurol (2016) ;73:1115-24.
- A critical role for VEGF and VEGFR2 in NMDA receptor synaptic function and fear-related behavior
De Rossi P, Harde E, Dupuis JP, Martin L, Chounlamountri N, Bardin M, Watrin C, Benetollo C, Pernet-Gallay K, Luhmann HJ, Honnorat J, Malleret G, Groc L, Acker-Palmer A, Salin PA, Meissirel C Mol Psychiatry (2016) 21:1768-1780..
- Characteristics in limbic encephalitis with anti-adenylate kinase 5 autoantibodies
Do LD, Chanson E, Desestret V, Joubert B, Ducray F, Brugière S, Couté Y, Formaglio M, Rogemond V, Thomas-Antérion C, Borrega L, Laurens B, Tison F, Curot J, De Brouker T, Lebrun-Frenay C, Delattre JY, Antoine JC, Honnorat J Neurology (2017) 88:514-524.
- Dynamic disorganization of synaptic NMDA receptors triggered by autoantibodies from psychotic patients
Jézéquel J, Johansson EM, Dupuis JP, Rogemond V, Gréa H, Kellermayer B, Hamdani N, Le Guen E, Rabu C, Lepleux M, Spatola M, Mathias E, Bouchet D, Ramsey AJ, Yolken RH, Tamouza R, Dalmau J, Honnorat J, Leboyer M, Groc L Nat Commun (2017) 8:1791.
- Genetic alterations and tumor immune attack in Yo paraneoplastic cerebellar degeneration
Small M, Treilleux I, Couillault C, Pissaloux D, Picard G, Paindavoine S, Attignon V, Wang Q, Rogemond V, Lay S, Ray-Coquard I, Pfisterer J, Joly F, Du Bois A, Psimaras D, Bendriss-Vermare N, Caux C, Dubois B, Honnorat J, Desestret V Acta Neuropathol (2018) .
- Ministry of Health: Reference center on rare diseases. Autoimmune encephalitis and paraneoplastic neurological syndromes.
- Inca: Protéines de guidage axonal et tumeurs neuroendocrines gastro-entero-pancréatiques: rôle dans la progression tumorale
- ANR: Identification de biomarqueurs diagnostiques, physiopathologiques, pronostiques et de progression des troubles
- ANR-PRTS: MECANO : Mechanisms of autoimmune encephalitis
- FRC: Mechanisms of autoimmune abnormal behaviour