ERC Advanced Grant pour Giovanni Marsicano
Giovanni Marsicano, DR1 at Inserm has obtained the ERC advanced grant MiCaBra. During the previous ERC Starting grant EndoFood (2011), his team discovered that the type-1 cannabinoid receptor CB1 is partially localised at brain mitochondrial membranes (mtCB1), where it regulates bioenergetic processes. MiCaBra (Mitochondrial Cannabinoid Receptors in the Brain) is now fully dedicated to the study of the impacts of this novel and surprising function of a G Protein Coupled Receptor in brain processes.
Brain activity critically depends on the high energetic support provided by mitochondria, the cell organelles transforming energy sources into molecularly usable ATP. The pathological effects of chronic mitochondrial dysfunctions in the brain are under scrutiny, but the impact of physiological modulation of mitochondrial activity on ongoing brain functions is almost unknown. Cannabinoid type-1 receptors (CB1) are amongst the G Protein-Coupled receptors (GPCR) expressed at highest levels in the brain, and they are key regulators of behaviour. We recently showed that CB1 receptors are present at brain mitochondrial membranes (mtCB1), where they regulate bioenergetic processes, thereby mediating amnesic effects of cannabinoids.
Thus, the physiological roles of the brain endocannabinoid system formed by CB1 receptors and endogenous ligands, and the pharmacological effects of cannabinoid drugs (e.g. the psychotropic compound of the plant cannabis sativa, Δ9-tetrahydrocannabinol) partially rely on the regulation of brain mitochondrial activity. Using a bottom-up approach at micro-, meso- and macro-scale levels, MiCaBra will reveal cell biological features, signalling properties and behavioural impact of mtCB1 receptors in the brain. First, we will address the cell biology of mtCB1 receptors, determining the structural and molecular requirements for their mitochondrial trafficking. To define how this GPCR modulate mitochondrial activity and what are the functional consequences of these effects, we will study downstream intra-mitochondrial signalling of mtCB1 receptors and the eventual impact on cellular processes controlled by the organelle.
Finally, we will tackle the role of mtCB1 receptors in the (endo)cannabinoid control of brain circuits and behaviour. Thus, MiCaBra has the ambitious aim to understand the impact of regulation of bioenergetic processes on ongoing brain functions, thereby determining a novel framework in the study of behavioural pathophysiology.