• Jérôme HONNORAT
  PROFESSOR
• Jean-Christophe ANTOINE
  PROFESSOR
• Roger BESANCON
  ASSISTANT PROFESSOR
• Nadia BOUTAHAR
  ASSISTANT PROFESSOR
• Jean-Philippe CAMDESSANCHE
  PROFESSOR
• Virginie DESESTRET
  ASSISTANT PROFESSOR
• Claire MEISSIREL  CV
  INSERM RESEARCHER
• Nelly NORAZ-BUET
  INSERM RESEARCHER
• Olivier PASCUAL CV
  INSERM RESEARCHER
• Véronique PELLIER-MONNIN
  ASSISTANT PROFESSOR
• Fabrice FAURE
  RESEARCH ASSISTANT
• Céline MALLEVAL
  RESEARCH ASSISTANT
• Marie-Eve MAYEUR
  RESEARCH ASSISTANT
• Véronique ROGEMOND
  RESEARCH ASSISTANT
• Anne-Laurie PINTO
  RESEARCH ASSISTANT
• Naura CHOUNLAMOUNTRI
  RESEARCH ASSISTANT
• Chantal WATRIN
  RESEARCH ASSISTANT
• Sterenn CLOSS
  RESEARCH ASSISTANT
• Sonia GALLEGO
  RESEARCH ASSISTANT
• Le Duy DO
  POST-DOC
• Delphine PINATEL
  POST-DOC
• Laurent MARTIN
  PHD STUDENT
• Margaux SAINT-MARTIN
  PHD STUDENT
• Ines HRISTOVSKA
  PHD STUDENT
• Alanah PIETERS
  PHD STUDENT
• Bastien JOUBERT
  PHD STUDENT
• Elodie FELS
  PHD STUDENT
• Benoit DECHELOTTE
  MASTER
• Pauline BOUVET
  MASTER
• Kassandre COMBET
  MASTER

PROJECTS

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.

SELECTED PUBLICATIONS

• 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 JJAMA 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) .

FUNDING

• 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