Mitochondrial Cannabinoid Receptors in the Brain

Ziel

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.