ER-mitochondria contacts underline cannabinoid regulation of calcium signaling in astrocytes

Abstract Intracellular calcium signaling underlies the astroglial control of brain functions. However, the cellular mechanisms regulating calcium handling by astrocytes are far from being understood. Mitochondria-endoplasmic reticulum contacts (MERCs) are key determinants of calcium dynamics, but their functional impact on astroglial regulation of brain information processing is currently unexplored. Here we show that the activation of astrocyte mitochondrial-associated CB1 receptors (mtCB1) regulates MERCs-dependent intracellular calcium signaling, thereby determining the synaptic functions of these cells. In vitro and in vivo stimulation of mtCB1 receptors promotes calcium transfer from the endoplasmic reticulum to mitochondria through a specific molecular cascade, involving AKT signaling, IPR3 receptors and different components of the mitochondrial calcium uniporter complex (MCU). Physiologically, mtCB1-dependent mitochondrial calcium uptake determines the dynamics of cytosolic calcium events in astrocytes upon endocannabinoid mobilization. Accordingly, electrophysiological recordings in hippocampal slices showed that astrocyte-specific mtCB1 receptors exclusion or dominant negative MCU expression blocks lateral synaptic potentiation, through which astrocytes integrate the activity of distant synapses. Altogether, these data reveal a cellular endocannabinoid link between astroglial MERCs and the regulation of brain network functions.