Jean-Antoine Girault aims to identify the intracellular signalization mechanisms which underlie long term behavioral changes. The ability of the nervous system to adapt to a variable environment indeed depends on the modulation and plasticity of synapses between these neurons, which is regulated by their activity and by multiple neuromodulators.
Long term changes also involve morphological modifications and variations in the translation of proteins and transcription of genes.
Current research in the lab includes genome-wide studies of cell type-specific transcription and epigenetic modifications in basal ganglia, as well as exploration of the role of tyrosine kinase Pyk2 in neuronal properties and neurodegenerative diseases.
The ability of the nervous system to adapt to a variable environment depends on the modulation and plasticity of the synapses between these neurons, which is regulated by their activity and by multiple neuromodulators. Durable changes also involve morphological modifications and variations in protein translation and gene transcription. Intracellular signalling pathways essential for these adaptations include the regulation of protein phosphorylation. Jean-Antoine Girault leads a team with Denis Hervé whose goal is to identify the intracellular signalling mechanisms underlying long-term behavioural changes.
Their main model of study is the striatum, which plays an essential role in movement control, motivation, habit formation and procedural memory. The striatum is the entry structure of the basal ganglia, a complex set of neural loops with a proposed function of action selection. The main neurons of the striatum are the medium-size GABAergic neurons (medium-size spiny neurons) which integrate the sensorimotor information of the glutamatergic fibers coming from the cerebral cortex and the thalamus, with the reward prediction error provided by dopaminergic afferents.
Dopamine controls the function of striatal neurons and their long-term plasticity, thus contributing to reinforcement learning. Addictive drugs hijack these normal processes by directly increasing extracellular dopamine. Dopamine is also necessary for the initiation and execution of movement. Its absence is responsible for Parkinson’s disease.
The team’s work has contributed to the identification of signalling pathways activated by dopamine receptors and other neurotransmitters. These pathways involve the G(alpha)olf protein, the protein kinases PKA (activated by cAMP) and ERK (extracellular signal-regulated kinase), and the regulation of protein phosphatase 1 by DARPP-32 (dopamine- and cAMP-regulated phosphoprotein, 32 kDa). The team identified some functionally important targets of these signalling pathways, particularly in the nucleus, and highlighted the multiple signalling differences between the two main populations of striatum exit neurons, striatonigraux (expressing the D1 receptor) and striatopallidals (D2 receptor). These signalling pathways contribute to the long-lasting effects of addictive drugs, the onset of L-DOPA-induced abnormal movements (dyskinesias), and the effects of antipsychotic drugs.
The team is also studying the role and regulation of non-receptor tyrosine kinases FAK (focal adhesion kinase) and Pyk2. It has recently clarified the molecular mechanisms of AKF activation and Pyk2 nuclear translocation.
Current work is focused on signaling from the synapses to the nucleus using the mouse as a model. The team is studying the dynamics of these responses in living neurons using confocal and multiphoton biosensor imaging. It characterizes nuclear responses, in particular transcriptional and epigenetic regulations in identified striatum cell populations. The team is also studying the molecular mechanisms underlying L-DOPA-induced dyskinesias and primary Gulf deficiency dystonia.
The main goal of Jean-Antoine Girault’s team is to further identify signaling pathways normally active in the striatum through reinforcement learning and leading to lasting behavioral changes. They are attempting to characterize the deregulation of these pathways in response to addictive drugs and L-DOPA in models of Parkinson’s disease.
They are also studying the molecular properties of certain signalling enzymes and the mechanisms of information transfer between the cytoplasm and the nucleus.
Jean-Antoine Girault’s team uses a combination of experimental approaches ranging from biochemistry and molecular genetics to the study of behaviour and functional anatomy.
The research pursued by Jean-Antoine Girault’s team is providing a better understanding of the pathophysiological mechanisms of diseases affecting the basal ganglia, particularly Parkinson’s disease and drug addiction. It is making it possible to propose new therapeutic approaches in these diseases and to better understand the mechanisms of action of neuroleptics or L-DOPA. This research also has more general applications, particularly in the field of cancer, due to the involvement of the same signalling pathways in the control of numerous cellular properties.
• 1984 MD., University Paris 6, France
• 1986 Ph.D. in Health and Life sciences, Molecular and Cellular Pharmacology, University Paris 6, France, Marie-Jo Besson’s lab
• 1987 Postdoctoral fellow, Rockfeller University, New-York, USA, Paul Greengard’s lab
• 1990 Appointed Group Leader at the Collège de France and Research Scientist (CR1) at Inserm, Paris, France
• Brixham Foundation Price, attributed by the Foundation for Medical Research, 2016
• Lamonica Award for Neurobiology, French Academy of Sciences, 2013
• European Research Council (ERC) Advanced Grant 2010
• Coup d’élan Grant, Foundation Bettencourt-Schueller, 2002
• Antoine Lacassagne Award, French Academy of Sciences, 1997
• Stanley Award, National Alliance for the Mentally Ill, 1990
Interview in Le Figaro Où se trouve le siège de la mémoire ?
Brain’s week 2017
Semaine du cerveau 2016
Semaine du cerveau 2016
Interview in Santé Magasine A quoi sert la dopamine ?
Brain’s week 2016
Feb 2015, Nat Commun.
June 2013, Proc. Natl. Acad. Sci. USA