PhD Tifany Desprez

Role(s) of mitochondrial type-1 cannabinoid receptors in the brain

Soutenue le 13 mai 2015

Team of Giovanni Marsicano: “Endocannabinoïdes et Neuroadaptation”

Type-1 cannabinoid receptor CB1 is a G protein-coupled receptor (GPCR), widely expressed in the brain, which regulates numerous physiological processes. However, the cellular mechanisms of CB1-mediated control of these functions are poorly understood. Although CB1 are known to signal at the plasma membrane, a portion of these receptors are also present in mitochondria (mtCB1), where mtCB1 activation decreases mitochondrial activity. The goal of this thesis was to dissect the impact of brain mtCB1 signaling in known behavioral effects induced by cannabinoids. To distinguish the functions of mtCB1 from other receptor pools, we developed tools based on the characterization of the intra-mitochondrial molecular cascade induced by mtCB1 receptors. In isolated brain mitochondria, we found that intra-mitochondrial decrease of soluble-adenylyl cyclase (sAC) activity links mtCB1- dependent activation of Gαi/o proteins to decrease cellular respiration. Local brain inhibition of sAC activity blocks cannabinoid-induced amnesia, catalepsy and contributes to the hypolocomotor effect of cannabinoids. In addition, we generated a functional mutant CB1 protein (DN22-CB1) lacking the first 22 amino acid of CB1 and its mitochondrial localization. Differently from CB1, activation of DN22-CB1 does not affect mitochondrial activity. Hippocampal in vivo expression of DN22-CB1 abolished both cannabinoid-induced impairment of synaptic transmission and amnesia in mice. Together, these studies couple mitochondrial activity to behavioral performances. The involvement of mtCB1 in the effects of cannabinoids on memory and motor control highlights the key role of bioenergetic processes as regulators of brain functions.

Key words: , MtCB1 receptors, Mitochondria, Soluble adenylyl cyclase, Oxidative phosphorylation, Bioenergetic, Object recognition memory, Motor control, Hippocampus, Substantia Nigra pars reticulata

Jury

  • M. KRAMER, Ijsbrand Pr. Université de Bordeaux, France, Président
  • M. GALVE-ROPERH, Ismael Pr. Universidad Complutense de Madrid, Espagne
    Rapporteur
  • M. WOTJAK, Carsten Dr. Max Planck Institute of Psychiatry Munich, Allemagne
    Rapporteur
  • M. BARROS, Felipe Dr. Centro de Estudios Cientificos, Santiago, Chilie
    Examinateur
  • Mme COTA, Daniela Dr. Université de Bordeaux, France
    Examinateur
  • M. ROSSIGNOL, Rodrigue Dr. Université de Bordeaux, France
    Examinateur
  • M. MARSICANO, Giovanni Dr. Université de Bordeaux, France
    Invité

Directeur de thèse

Giovanni  Marsicano
VD, PhD
NeuroCentre Magendie
U862 INSERM
Université de  Bordeaux
Group “Endocannabinoids and Neuroadaptation”

Last update: 9 April 2018