Jean-Antoine Girault

Introduction

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 are regulated by their activity and by multiple neuromodulators. Intracellular signaling pathways essential for these adaptations include the regulation of protein phosphorylation. Durable changes also involve morphological modifications and variations in protein translation and gene transcription. Jean-Antoine Girault leads a team whose goal is to identify the intracellular signaling mechanisms underlying long-term behavioral 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 striatal projection neurons (SPNs) a.k.a. 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.

 Results

The team’s work has contributed to the identification of signaling 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 signaling pathways, particularly in the nucleus, and highlighted the multiple signaling differences between the two main populations of SPNs, striatonigral (expressing the D1 receptor) and striatopallidal (D2 receptor). These signaling pathways contribute to the long-lasting effects of addictive drugs, the onset of L-DOPA-induced abnormal movements (dyskinesia), and the effects of antipsychotic drugs. Using confocal and multiphoton imaging of biosensors analyzed the dynamics of intracellular signaling from synapses to nuclei and revealed the importance of dendrite geometry.

The lab is also studying the two related non-receptor tyrosine kinases FAK (focal adhesion kinase) and Pyk2. It has recently clarified the molecular mechanisms of activation of these kinases and showed Pyk2 nuclear translocation. Recent work identified the role of Pyk2 in hippocampal synaptic functions and learning and memory as well as their alterations in Alzheimer’s and Huntington’s disease.

Projects 

The group of JA Girault investigates transcriptional and epigenetic regulations in identified striatal cell populations. Ongoing work reveals the importance of gene expression and DNA modifications (methylation, hydroxymethylation) differences between SPN populations. This allows to study by psychostimulant drugs and operant learning. The lab also investigates molecular mechanisms of L-DOPA-induced dyskinesia and primary dystonia caused by deficits in Golf (GNAL gene mutations). Other projects are related to the regulation and role of Pyk2 including its nuclear function and implication in Alzheimer’s disease.

To carry out these projects Jean-Antoine Girault’s group combines multiple approaches from biochemistry and molecular genetics to behavioral studies and functional anatomy.

Implications

The research pursued by Jean-Antoine Girault’s team provides understanding of the pathophysiological mechanisms of diseases affecting the basal ganglia, particularly Parkinson’s disease, primary dystonia and drug addiction. It is makes it possible to propose new therapeutic approaches in these diseases and provides information about the actions of currently used drugs. Work on Pyk2 is also relevant for the pathophysiology of neurodegenerative diseases such as Alzheimer’s and Huntington’s diseases.