Research in my team is focused on neuronal G-protein Coupled Receptors (GPCRs). These sensory proteins are important targets oftherapeutic and abused drugs, and are usually studied by pharmacology or electrophysiology, but we assume that their functioncannot be fully understood without considering their sub-cellular environment. We have indeed found unexpectedly close relationshipbetween neuropharmacology and neuronal cell biology. Specifically, axonal GPCR targeting and signaling is highly constrained by thespecificities of mature axons and that in turn, GPCR activity may rapidly modify neuronal structure. Our model GPCR is the CB1cannabinoid receptor, one of the most abundant brain GPCRs and cerebral target of endocannabinoids and marijuana. Our projects between 2004 and 2012 were focused to decipher the closely intertwined relationship between GPCR activation and sub-neuronaltargeting, by developing quantitative approaches and kinetic modeling. We discovered a novel, activation-dependent protein targeting pathway, leading to the description of previously unanticipated high plasticity in polarized distribution of GPCRs on the neuronalsurface. In 2009, we discovered a surprisingly rapid cannabis-mediated regulation of neuronal structure. This result openedunexpected broad perspectives in the better comprehension of neuronal function. In consequence, our team, called ‘System Biologyof the Neuron’, has recently changed its name to ‘Neuronal Structure and Dynamics' in order better to reflect the shift of our research focus.
Our current research project is based on compelling literature evidence showing that cannabis exposure in adolescence, a criticalperiod of structural maturation in the prefrontal cortex and the limbic system, may result, in predisposed individuals, in long-lastingstructural alterations of neuronal structure of these regions which are critically involved in the aethiology of psychosis.
Notably, ourrecent results suggest that CB1R can rapidly transform the neuronal cytoskeleton through actomyosin contractility, resulting in cellularremodeling events ultimately able to affect brain architecture and wiring (Roland et al., 2014, eLife). Altered neuronal connectivity is acausative element in psychotic pathology so the neuronal cytoskeleton may represent a potential new therapeutic target for acute andchronic treatment of psychosis.To test the validity of this hypothesis, we develop an interdisciplinary approach to study in detail the molecular mechanisms and thedynamics of cannabinoid-induced rapid remodeling of the neuronal and glial cytoskeleton and to identify resulting changes in neuronalfunction, such as altered synaptic connectivity, both in vitro and in vivo. Our experimental methods range from imaging-basedquantitative measurements (videomicroscopy, FRET microscopy, superresolution microscopy) of cellular structure and dynamics invitro, to a novel paradigm of functional brain imaging, recently validated in collaboration with Dr Mickael Tanter, ESPCI-ParisTech.This method, Ultrafast Functional Ultrasound or fUS, through achieving parallel measurement of functional parameters with sensitivity,spatiotemporal resolution and operating simplicity unmatched by current imaging modalities (Osmanski et al. Nature Communications,2014), will open access to previously unexplored aspects of brain function.