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Thèse Julie Jezequel

Impact of psychotomimetic molecules on glutamatergic N-Methyl-D-Aspartate receptors surface trafficking

Le 18 novembre 2016

Soutenance  de Julie Jezequel dans le Nouveau Bâtiment Neurocampus à 14h30 / Institut Interdisciplinaire de Neurosciences / CNRS UMR 5297 - Equipe GROC / Une étudiante soutenue par le LabEx BRAIN




 Glutamatergic N-Methyl-D-Aspartate receptors (NMDAR) play a key role in many physiological processes, and their implication in the pathophysiology of several neuropsychiatric disorders is now well established.
Multiple lines of evidence converge towards a dysregulation of the NMDAR in psychotic disorders such as schizophrenia (SCZ). However, the molecular and cellular deficits underlying NMDAR dysfunction remain misunderstood. By tightly controlling NMDAR synaptic localization, surface trafficking represents a powerful regulator of synaptic transmission. Could an alteration of NMDAR surface trafficking underlie NMDAR dysfunction and contribute to the emergence of psychotic disorders? To tackle this question, my PhD project aimed at investigating the impact of different psychotomimetic molecules on NMDAR surface trafficking. In the first part of my project, I explored the impact of NMDAR autoantibodies (NMDAR-Ab) from SCZ and healthy subjects. My results revealed that NMDAR-Ab from SCZ patients rapidly disturb NMDAR synaptic trafficking and distribution, through a loss of NMDAR-EphrinB2 receptor interaction, eventually preventing the induction of synaptic plasticity. In the second part of my PhD project, I showed that psychotomimetic NMDAR antagonists also alter NMDAR synaptic mobility and localization. Downregulation of PSD proteins expression prevented NMDAR antagonists-induced deficits, suggesting that such alterations ensue from modifications of NMDAR intracellular interactions. Taken together, these results demonstrate that psychotomimetic molecules profoundly impact NMDAR surface trafficking, supporting a pathogenic role of this unsuspected process in the emergence of psychotic symptoms.


Key words: N-Methyl-D-Aspartate receptor, glutamatergic synapse, surface trafficking, nanoparticle tracking, quantum dots, schizophrenia, psychosis, autoantibodies, NMDAR antagonists

Publications

Sarabdjitsingh, R. A., Jezequel, J., Pasricha, N., Mikasova, L., Kerkhofs, A., Karst, H., Groc, L and Joëls, M. (2014). Ultradian corticosterone pulses balance glutamatergic transmission and synaptic plasticity. Proceedings of the National Academy of Sciences of the United States of America, 111(39), 14265–70.

Lesept, F., Chevilley, A*., Jezequel, J*., Ladépêche, L., Macrez, R., Aimable, M., Lenoir, S., Bertrand, T., Rubrecht, L., Galea, P., Lebouvier, L., Pertersen, K.U., Ali, C., Laubert, E., Groc, L and Vivien, D. (2016). Tissue-type plasminogen activator controls neuronal death by raising surface dynamics of extrasynaptic NMDA receptors. Cell Death and Disease

Jezequel, J., Johansson, E., Gréa, H., Rogemond, V., Kellermayer,B., Hamadani, N., Le Guen, E., Rabu, C., Mathias, E., Lepleux, M., Bouchet, D., Yolken, R.H., Tamouza, R., Dalmau, J., Honnorat, J., Leboyer, M., and L. Groc. Heterogeneity of human anti-NMDA receptor antibodies: nanoscale disorganization of synaptic receptors by autoantibodies from schizophrenic patients. In submission

Jezequel, J., Rogemond, V., Pollak, T., Vincent, A., L. Groc and OPTIMISE (Optimisation of Treatment and Management of Schizophrenia in Europe) Consortium. Detection of anti-NMDA receptor autoantibody in first episode psychotic patients. In submission

 

Jury

Stéphane OLIET,
Président, DR Inserm
Neurocentre Magendie
Université de Bordeaux

Belinda LENNOX 
Rapportrice, Professeur associé,
Department of Psychiatry,
Oxford University, UK

Julie PERROY,
Rapportrice, DR,

Institut Génomique Fonctionelle
Université de Montpellier


Pierre PAOLETTI,

Examinateur,
DR IBENS CNRS

Martha CONSTANTINE-PATON,
Examinateur, Professeur,
McGovern Institute for Brain Research
MIT, USA

Laurent GROC,
Directeur de thèse,
DR, IINS
Université de Bordeaux

Directeur de thèse



Laurent Groc
Team leader: Development and Adaptation of Neuronal Circuits . Research Director (DR) and Principal Investigator at the CNRS and Université de Bordeaux. 


http://www.iins.u-bordeaux.fr/research-teams-laurent-groc?lang=en