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Thesis defense – Pierre-Louis Raux

4 December 2023 / 14:00

Venue: Neurocentre Magendie

Pierre-Louis Raux
Team: Physiopathology and therapeutic approaches of stress-related diseases
Neurocentre Magendie

Thesis supervisor:  Monique Vallée


Development and characterization of the CB1-E134G transgenic mouse model to study the role of endogenous pregnenolone in modulating the endocannabinoid system


The endocannabinoid system (ECS) is a complex neuromodulatory network that has attracted tremendous research interest over the past 50 years. The vast majority of our knowledge of ECS-mediated signaling is associated with the type 1 cannabinoid receptor (CB1R), a seven-transmembrane domain G-protein coupled receptor. CB1R is expressed in various organs and tissues, with the highest levels found in the brain, where it is the most abundant metabotropic receptor in mammals and is intimately involved in the regulation of a plethora of biological functions. Because CB1R controls such a broad range of physiological processes, dysregulation of CB1-mediated signaling has been implicated in the pathogenesis of many central and peripheral disorders. Thus, CB1R represents an exciting therapeutic target for the development of pharmacotherapies in the context of neuropsychiatric and metabolic diseases. From this perspective, the discovery of endogenous regulatory mechanisms to prevent an imbalance in CB1R activity represents promising therapeutic strategies to restore the CB1R-associated homeostatic load. In particular, the steroid pregnenolone (PREG) has been identified as an endogenous CB1 negative allosteric modulator with neuroprotective effects. Interestingly, CB1 overactivation by the exogenous CB1 agonist Δ9- tetrahydrocannabinol (THC), the primary psychoactive component of Cannabis sativa, has been shown to upregulate central PREG levels, establishing an endogenous negative feedback loop between the steroid and the CB1R. Indeed, PREG is able to bind to the TMH1/TMH8/Hx8 region of the CB1R and selectively inhibit CB1-mediated signaling pathways to protect against the acute and toxic effects of THC. However, our current knowledge of the interaction between PREG and CB1R remains elusive, and the limited pharmacological tools available are insufficient to identify novel roles for PREG in modulating CB1-mediated signaling and functions. To further explore this topic, we report the development and characterization of a novel transgenic mouse line carrying a missense point mutation in the CB1-encoding gene (Cnr1), resulting in the amino acid substitution E134G, aimed at disrupting the PREG allosteric binding site on CB1. The general objectives of this work are to describe the phenotypes of male and female CB1-E134G mice at baseline, under experimental conditions known to induce endogenous CB1R activation, and in response to exogenous cannabinoid administration. Analyses show little to no changes in behavior of mutant CB1-E134G mice compared to their wild-type (WT) littermates, at baseline and after endogenous CB1 activation, suggesting that endogenous PREG does not regulate this CB1 activity. However, CB1 protein was found to be drastically downregulated in the brain of naive CB1-E134G mutants, suggesting a compensatory mechanism to prevent CB1R activation overload and a role for PREG in CB1R dynamics in vivo. In addition, CB1-E134G mice exhibited enhanced efficacy of exogenous cannabinoids at the behavioral, somatic and neurochemical levels compared to WT mice. Interestingly, PREG was found to preferentially regulate striatonigral mitochondria-associated CB1R over plasma membrane-associated CB1R involved in cannabinoid-mediated locomotor effects and antinociception, respectively. Collectively, these data confirm that PREG represents a defense mechanism against CB1 overactivation and suggest that this regulatory loop may involve specific intracellular subsets of receptors to maintain homeostasis. Furthermore, it can be hypothesized that PREG represents a molecular switch to bias the action of cannabinoids towards therapeutically relevant analgesia by inhibiting motor side effects, suggesting the therapeutic potential of PREG in cannabis use disorders. Finally, future use of this model may provide new opportunities to elucidate the mechanism of action of PREG as a CB1 negative allosteric modulator and new therapeutic prospects.


Francis CHAOULOFF, DR INSERM U1215, Université de Bordeaux ; Président

Elena MARTIN-GARCIA, Professeur, Université Pompeu Fabra ; Rapportrice

Giuseppe GANGAROSSA, Professeur, Université Paris Cité ; Rapporteur

Yvette AKWA, Chargée de recherche, INSERM 1195 ; Examinatrice

Roberto FRAU, Prof Associate, Université de Cagliari ; Examinateur

Monique VALLÉE, CR CNRS, Université de Bordeaux ; Directrice de thèse


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4 December 2023
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