Glutamatergic transmission in normal and pathological conditions

Glutamate plays a central role in protein metabolism and biosynthesis. Moreover glutamate is the major excitatory neurotransmitter in the CNS.

Glutamate plays a central role in protein metabolism and biosynthesis. Moreover glutamate is the major excitatory neurotransmitter in the CNS. Before its exoctytotic release, glutamate is accumulated in synaptic vesicles by 3 proton-dependent transporters named VGLUT1-3. These 3 transporters are structurally and functionally closely related conserved. In contrast, their distributions are almost complementary.

As can be seen on this figure (parasagital section of a rat brain), VGLUT1 expressing neurons (in blue) are essentially cortical (form the cerebral, hippocampus and cerebellum cortices). VGLUT2-positive neurons (in red) are essentially subcortical (in neurons forming a continuum from the thalamus to the spinal cord. Surprisingly, VGLUT3 is localized in a small population of neurons using another major neurotransmitter than glutamate. VGLUT3 is observed (in yellow) in cholinergic interneurons in the striatum/accumbens, subpopulations of GABAergic interneurons in the cortex as well as the hippocampus, and finally in serotoninergic neurons.

Therefore, VGLUT1-3 define three glutamatergic neuronal systems. Our team is interested in understanding the role of the three glutamatergic systems in normal and pathological brain. Using VGLUTs as biomarkers, we study rodent models as well as Human brain.

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New thematic: Véronique Bernard

During the last fifteen years, we brought new and original data documenting the intraneuronal trafficking of several G-protein coupled receptors (GPCRs) in vivo, including that of m2R and m4R. We have proposed a model of the trafficking of GPCRs in vivo in the somato-dendritic compartment. By using different specific tools to analyze GPCRs trafficking, including high resolution immunolabeling at confocal and electron microscopic levels, we have shown that the trafficking differs according to the characteristics of the neurochemical environment: endocytosis after acute stimulation, blockade on their way out to the membrane after chronic stimulation (Bernard et al., 2006).

These works were mostly devoted to the somato-dendritic receptor trafficking. We now study the trafficking of GPCRs at axonal level. To address this question, we develop, in vitro and ex vivo, different approaches of molecular and cell biology coupled to morphological analyses at dynamic confocal and electron microscopic levels.

Highlights

El Mestikawy et al.2011. From glutamate co-release to vesicular synergy: vesicular glutamate transporters. Nat Rev Neurosci.; 12(4): 204-16

Herzog et al. 2011. In Vivo Imaging of Intersynaptic Vesicle Exchange Using VGLUT1Venus Knock-In Mice. J Neurosci.; 31(43): 15544-59


Gras, Amilhon, et al. 2008. The vesicular glutamate transporter VGLUT3 synergizes striatal acetylcholine tone. Nat Neurosci.; 11(3): 292-300

Future directions

Our work is organized around two major axes:

1) Animal studies

In order to better understand the functional diversity of the glutamatergic systems, we are using genetically modified animals (loss or gain of function) for each VGLUT.

The study of these animals is, and will be held by using various methods such as: anatomy, biochemistry, cellular biology (dynamic fluorescent imaging), in vivo imaging (MRI, PET), electrophysiology and behavior

2) Human studies

The 3 VGluTs by are investigated by quantitative neuroanatomical methods (western blot, and immunoautoradiography). These experiments are made on Human post-mortem brain tissue samples from controls or subject suffering from neurodegenerative (AD or PD) or psychiatric (autism, suicide, anxiety) diseases.

All together these approaches will allow us to

1) Increase our knowledge on the role of the 3 glutamatergic systems in normal and pathological condition

2) Develop therapeutic or diagnostic tools

Collaborations

One original feature of our team is to be an international team, since one part of us is working in France, at the University Pierre and Marie Curie (Paris) whereas the other part is settled in Canada, at the Douglas Mental Health University Institute (McGill, Montreal).

  • Louis Eric Trudeau (Université de Montréal)
  • Bruno Giros (Douglas, McGill University)
  • Sylvain William (Douglas, McGill University)
  • Naguib Mechawar (Suicide Brain Bank, Douglas, McGill University)
  • Marco and Vania Prado (Western Ontario University, London, Canada)
  • Rafael Maldonado (Universitat Pompeu Fabra, Barcelona)
  • Asa Mackenzie (Uspala University)
  • Christian Rosenmund (Charite Universitaetsmedizin Berlin)
  • Francine Acher, Nicolas Pietrancosta (Université René Descartes, Paris)
  • Bruno Gasnier (CNRS UPR1929, IBPC, Paris)
  • Laurence Lanfumey, Raymond Mongeau (INSERM U677, Faculté de la Pitié, Paris 6)
  • Stéphane Jamain (INSERM U955, Hôpital Henri Mondor, Créteil)
  • Frank Bellivier, Florence Vorspan (Hôpital Fernand Widal, Paris)
  • Emanuel Valjent (Inserm U661, UMR 5203 CNRS, University Montpellier I & II)
  • Manuel Mameli (Institut du Fer à Moulin, Paris)
  • Jean-Luc Puel (INSERM U583, INM, Montpellier)
  • Jorge Gallego (INSERM U676, Hôpital Robert Debré, Paris)
  • Martin Oheim (INSERM U603 - CNRS UMR 8154, Faculté des Saint-Pères, Paris)
  • Serge Marty (INSERM U789, ENS Paris)
  • Valentin Näegerl (CNRS UMR 5091, Bordeaux)
  • Eric Krejci (CNRS UMR 8257, Paris Descartes)
  • Pascal Dournaud (INSERM, UMR U676, Université Denis Diderot, Paris)
  • Jürgen Wess (NIDDK, Bethesda, USA)
  • Jacques Epelbeaum, Patrick Dutar (INSERM UMR 894, Paris Descartes)