Neuronal signaling and gene regulation

We study intracellular signaling pathways involved in the control of long-term neuronal adaptations induced by drugs of abuse or striatal dysfunctions resulting from the genetic mutation encountered in Huntington’s disease (HD). 

We study the cellular and molecular events that govern neuronal adaptation at the origin of long-term behavioral changes in physiological (learning and memory) or pathophysiological (toxicomany, neurodegenerative diseases) contexts. We analyze these mechanisms within the striatum, a brain structure involved in action selection, execution of movements and reward-dependent learning and cognition.

Using a combination of multidisciplinary approaches ranging from a molecular standpoint to behavioral studies in rodents, our overall goals are:


Addiction can be considered as a form of pathological memory in which neuronal plasticity mechanisms involved in normal learning and memory processes are "highjacked” by exposure to drugs of abuse. These deleterious memories are robust, persistent and require gene regulation in specific neuronal populations. Drugs of abuse increase dopamine in the striatum, where it triggers molecular alterations within striatal projection neurons (SPN), which fall into two subpopulations depending on the dopamine receptor subtype they express (D1R or D2R). SPN receive glutamate inputs from the cortex, thalamus, amygdala and hippocampus that encode contextual and emotional information together DA signals, which modulate the efficacy of glutamate synapses. Over the past years, we have been studying the molecular and cellular basis by which cocaine alters the integration of dopamine/glutamate signals to persistently usurp the neural circuitry of reward.

By contrast, Huntington’s disease (HD), a genetic disease characterized by abnormal, expanded poly CAG repeats in the gene encoding Huntingtin (Exp-HTT) is characterized by a progressive loss of plasticity and neurodegenerescence of SPN. Multiple attempts have been made over the past few years in order to unravel the cellular and molecular mechanisms that underlie this neuronal vulnerability in HD. Among these, altered gene expression, cellular metabolism and DA/glu signaling have been largely incriminated. We participated to these studies by showing a key role of D2R-mediated signaling to Rho/Rock signaling, along with altered histone modifications and cholesterol metabolism. 


We established that the heteromer formation (i.e. direct physical interaction) by D1R and GluN1 subunits of NMDAR control the potentiation of NMDA current by DA, as well as long-term synaptic plasticity and cocaine-induced signaling in the striatum. We drew these original conclusions due to the development of a strategy to disrupt D1R/GluN1 heteromers without altering the signaling downstream individual D1R or NMDAR. Downstream from D1R/GluN1, we found that ERK activation is responsible for the induction of the immediate early gene Arc, which behaves as brake on chromatine remodeling and behavioral sensitization induce by cocaine. We also applied a 3D-automated analysis of neuronal morphology, which was previously set up in the group, to mice expressing the Vesicular GLUtamate Transporter 1 fused to the fluorescent Venus. This allowed us studying cocaine-induced structural plasticity at both pre- and post-synaptic levels to demonstrate that chronic cocaine favors the formation of glutamatergic synapse in the striatum.

We recently showed that expression levels of CYP46A1, the rate-limiting enzyme for the degradation of cholesterol in the brain, are decreased in putamen extracts of post-mortem HD patients and in the striatum of a transgenic mouse model of HD (R6/2 mice). Restoring CYP46A1 expression in striatal neurons in vitro significantly reduced neuronal dysfunctions induced by Expanded Huntingtin (exp-HTT). In vivo, in the transgenic R6/2 HD mouse model, AAV-mediated expression of CYP46A1 into the striatum improved motor behavior performance, decreased neuronal dysfunctions, aggregate formation, and restored a normal lipidomic signature.

Future direction

Based on our previous results our main projects fall into 4 axis:

  • Defining the role of dopamine- glutamate receptor heteromers in addiction (ANR Glad (2016-2019); FRM équipe (2016-2019)) and stress-related disorders.
  • Studying the implication of nuclear calcium signaling in addiction (ANR Glad (2016-2019); FRM équipe (2016-2019)).
  • Unraveling the role of non-coding micro-RNAs in addiction: towards biomarkers of vulnerabilty (FRM équipe (2016-2019) Labex BioPsy (2016-2019)
  • Deciphering the role of Cyp46A1 in neuroprotection in Huntington’s disease: a lipidomic and transcriptomic study (ANR CYPHUNT (2013-2017).


  • Hilmar Bading - Interdisciplinary Center for Neurosciences, University of Heidelberg.
  • Naguib Mechawar - Dept of psychiatry; McGill University; Douglas-Bell Canada Brain bank.
  • Ernest Fraenkel - Dept of Biological Engineering, MIT, Boston, United States.
  • Ferah Yildirim – Dept of experimental Neurobiology, University of Berlin.
  • Alessandro Usiello – Dept of environmental, biological and pharmaceutical science and technology, University of Naples.
  • Pierre Trifilieff - INRA, Nutrineuro, Université Bordeaux 2.
  • Laurent Prézeau – Institut de Génomique Fonctionnelle, Montpellier.
  • Jean-Antoine Girault - Institut du Fer à Moulin, Paris.
  • Franck Belivier - Hopital F. Widal, Dept of Adult Psychiatry, Paris, France.
  • Nathalie Cartier - Faculté des Sciences Pharmaceutiques et Biologiques-Paris 5.
  • Emmanuel Brouillet - CEA, MirCen ; Fontenay aux Roses.
  • Alexis Bemelmans - CEA, MirCen ; Fontenay aux Roses.
  • Frederic Saudou – Grenoble : Institut des Neurosciences ; Université de Grenoble.
  • Marie-Claude Potier - CRICM, Paris.
  • Bruno Giros & Eleni Tzavara – Laboratoire de Neuroscience Paris - Seine, IBPS, Paris.
  • Antonin Lamazière – Laboratory of Mass Spectometry – UPMC, Paris
  • Thomas Boudier - IBPS, Paris.