Neuropharmacology of VGLUTs

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.

Highlights

Sakae DY, Ramet L, et al. 2019. Differential expression of VGLUT3 in laboratory mouse strains: impact on drug-induced hyperlocomotion and anxiety-related behaviors. Genes Brain Behav. 2018 Oct 15:e12528. doi: 10.1111/gbb.12528.

Poirel O, Mella S, et al. 2018. Moderate decline in select synaptic markers in the prefrontal cortex (BA9) of patients with Alzheimer's disease at various cognitive stages. Sci Reports. 2018 Jan 17;8(1):938.

Henderson F,et al. 2017. Effects of Social Defeat Stress on Sleep in Mice. Front Behav Neurosci. 2017 Nov 28;11:227.

Ramet L., Bersot T., et al. 2017. Characterization Of A Human Point Mutation Of Vglut3 (P.A211v) In The Rodent Brain Unravels Synaptic Vesicles Heterogeneity. J. Neuroscience 37(15): 4181-4199

Sakae DY, Marti F, Lecca S, et al. 2015. The Absence Of The Vesicular Glutamate Transporter Vglut3 Predisposes To Cocaine Abuse By Increasing Dopamine And Glutamate Signaling In The Nucleus Accumbens. Molecular Psychiatry. Nov;20(11):1448-59.

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

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

Future directions

Glutamate plays a central role in protein metabolism and biosynthesis. In addition, glutamate is the main excitatory neurotransmitter in the central nervous system.

In order to better understand the diversity of function of glutamategic systems, we use genetically modified mice (loss or gain of function) for each of the three VGLUTs. The study of these animal models is or will be addressed by methods of anatomy, biochemistry, cell biology (dynamic fluorescence imaging), in vivo imaging (MRI, PET), electrophysiology and behaviour.

We quantify the 3 VGLUTs using quantitative neuroanatomical methods (western blot and immunoautoradiography). These experiments are carried out on post-mortem samples of human brains from subjects with neurological (Parkinson's, Alzheimer's) or psychiatric (autistic disorders, suicide, anxiety) pathologies or controls.

All these approaches should enable us to: 1) increase our knowledge of the role of each of the three glutamatergic systems in the normal or pathological brain, 2) generate 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 Sorbonne University (Campus Pierre and Marie Curie) 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)
  • Christian Rosenmund (Charite Universitaetsmedizin Berlin)
  • Stéphane Jamain (INSERM U955, Hôpital Henri Mondor, Créteil)
  • Frank Bellivier, Florence Vorspan (Hôpital Fernand Widal, Paris)
  • Jean-Luc Puel (INSERM U583, INM, Montpellier)