The main goal of our team is to unravel the intracellular events that govern cerebral plasticity and long-term behavioral alterations. We study their roles in gene regulations, neuronal adaptations in physiological (learning and memory) or pathophysiological (exposure to addictive drugs, neurodegenerative diseases) contexts. More specifically, we study these mechanisms within the striatum, the major input structure of the basal ganglia, which plays key roles in action selection and execution of movements as well as in reward-dependent learning and cognition. These diverse functions of the basal ganglia require the processing of glutamate inputs arising from the entire cerebral cortex and thalamus together with dopamine (DA) signals.
Our team pioneered the characterization of the role of ERK (Extracellular-signal Regulated Kinase) signaling in gene expression, long-term neuronal adaptations, as well as in learning and memory. Over the past few years, we studied how integration of DA and glutamate signals by the chief neuronal population of the striatum, the medium-sized spiny neurons (MSNs), orchestrates ERK activation by drugs of abuse. We made the original observation that DA/D1 receptors (D1R) stimulation leads to a cAMP-independent potentiation of calcium influx through glutamate receptor of NMDA subtype (NMDAR), which triggers cocaine-induced ERK activation and behavioral responses. We also characterized the critical role of this kinase cascade in genetic and epigenetic responses to drugs of abuse, more specifically cocaine. We designed and patented new molecular tools, cell-penetrating peptides, which specifically interfere with docking domains of ERK towards their substrates. We demonstrated the potent role of one of these peptides (TDE peptide, Pepsignal patent; WO 2006/0872 242) in pathologic hypermnesia (addiction, PTSD), as well as depressive-like behavior.We are currently using cutting-edge methods to identify molecular and morphological changes engaged by chronic cocaine at glutamatergic synapses in vivo. Preclinical studies will be performed to normalize these changes and overcome chronic cocaine-induced behavior in mice. Through collaborations with groups belonging to our Labex BioPsy, genes coding for proteins involved in addictive-like behavior in mice will be studied in human through gene association/mutation screening, performed from a cohort of cocainne-addicts.
Our group also largely contributed to the identification of major striatal signaling pathways involved in early stages of neurodegenerative processes in Huntington’s Disease (HD). HD is a hereditary neurodegenerative disease, characterized by a poly CAG repeat in the gene encoding Huntingtin. In HD striatal neurons are more vulnerable to dysfunctions, which is associated with the progressive appearance of motor, cognitive and behavioral abnormalities leading to dementia. The transmission is dominant; so several members of a family can be affected. Imaging biomarkers of HD progression indicates that striatal atrophy begin up to 15 years before predicted onset and continues through the period of manifest illness. We studied cellular and molecular events that drive striatal neurodegenerescence in HD and showed a critical role of the RhoA/ROCK signaling downstream from DA D2 receptor (D2R). We also observed a deficiency of Mitogen and Stress-activated Kinase 1 (MSK-1) expression in the striatum of murine HD models and post-mortem striatal extracts of HD patients, which causes transcriptional dysregulation and altered chromatin remodeling at specific genes, including the anti-apoptotic mitochondrial gene PGC-1-alpha. Importantly, our results posit MSK-1 as a potential therapeutic target for HD since we established that MSK-1 overexpression appears to be neuroprotective in both in vitro and in vivo models of HD. We are currently analyzing, using large-scale analyses (miRNA-sequencing), the molecular substrates of MSK1 that could account for its neuroprotective effect. Our current studies also address the role of cholesterol metabolism in striatal signaling and neuroprotection in HD.