MiCaBra · Mitochondrial Cannabinoid Receptors in the Brain

Brain activity critically depends on the high energetic support provided by mitochondria, the cell organelles transformingenergy sources into molecularly usable ATP. The pathological effects of chronic mitochondrial dysfunctions in the brain areunder scrutiny, but the impact of physiological modulation of mitochondrial activity on ongoing brain functions is almostunknown. Cannabinoid type-1 receptors (CB1) are amongst the G Protein-Coupled receptors (GPCR) expressed at highestlevels in the brain, and they are key regulators of behaviour. We recently showed that CB1 receptors are present at brainmitochondrial membranes (mtCB1), where they regulate bioenergetic processes, thereby mediating amnesic effects ofcannabinoids. Thus, the physiological roles of the brain endocannabinoid system formed by CB1 receptors and endogenousligands, 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 atmicro-, meso- and macro-scale levels, MiCaBra will reveal cell biological features, signalling properties and behaviouralimpact of mtCB1 receptors in the brain. First, we will address the cell biology of mtCB1 receptors, determining the structuraland molecular requirements for their mitochondrial trafficking. To define how this GPCR modulate mitochondrial activity andwhat are the functional consequences of these effects, we will study downstream intra-mitochondrial signalling of mtCB1receptors and the eventual impact on cellular processes controlled by the organelle. Finally, we will tackle the role of mtCB1receptors in the (endo)cannabinoid control of brain circuits and behaviour. Thus, MiCaBra has the ambitious aim tounderstand the impact of regulation of bioenergetic processes on ongoing brain functions, thereby determining a novelframework in the study of behavioural pathophysiology.