Neuropharmacology of VGLUTs

The specificity of our team is to be at the interface between the Neurosciences Paris Seine laboratory (Dr. S.Daumas-INSB) and the Biomolecules laboratory (Dr. N.Pietrancosta-INC) thanks to the support of the CNRS 80/PRIME campaign.

Thus, we address the question of the role of glutamatergic co-transmission through a combined biological and chemical approach.

Before being released into the synaptic cleft, glutamate is accumulated in synaptic vesicles by 3 transporters called VGLUT1-3. However, some neurons initially described as non-glutamatergic express the vesicular glutamate transporter type 3 (VGLUT3) and are thus capable of glutamatergic co-transmission.

Surprisingly, VGLUT3 is expressed by populations of neurons involved in other classical neurotransmitter systems. It is found in striatal cholinergic interneurons, some cortical GABAergic interneurons and in 5HT neurons of the raphe nuclei.

Our team seeks to understand the role of this co-transmission in normal and pathological brain function in mammals.

Using behavioural biology, molecular biology, anatomy, microscopy and chemistry approaches, we are studying:

  • The role of glutamatergic co-transmission in the establishment and maintenance of memories in mice
  • The functional and behavioural consequences of variants identified in humans and their links with susceptibility to stress and the development of psychiatric pathologies 
  • Characterisation of the networks expressing VGLUT3 and their role in the regulation of anxiety and vigilance states
  • Differential expression of vesicular transporters in these bilingual neurons by developing high resolution microscopy approaches (STED, STORM)
  • We are developing new ligands to control the expression and function of VGLUTs


Our team is attached to the Memory Research Group, which brings together French teams working on memory from the point of view of biological sciences as well as human and social sciences


Pietrancosta N, Djibo M, Daumas S, El Mestikawy S, Erickson JD. 2020. Molecular, Structural, Functional, and Pharmacological Sites for Vesicular Glutamate Transporter Regulation. Mol Neurobiol. 2020 May 30. REVIEW.

Poirel O, Mamer LE, Herman MA, Arnulf-Kempcke M, Kervern M, Potier B, Miot S, Wang J, Favre-Besse FC, Brabet I, Laras Y, Bertrand HO, Acher F, Pin JP, Puel JL, Giros B, Epelbaum J, Rosenmund C, Dutar P, Daumas S, El Mestikawy S, Pietrancosta N. 2020. LSP5-2157 a new inhibitor of vesicular glutamate transporters. Neuropharmacology. 2019 Dec 4;164:107902.

Mansouri-Guilani N, Bernard V, Vigneault E, Vialou V, Daumas S,#, El Mestikawy S#, Gangarossa G#. 2019. VGLUT3 gates psychomotor effects induced by amphetamine. J. Neurochem. 2018 Dec 17.

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.


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)
  • Michaël Rera (CRI, Paris)