Astrocytes exert key metabolic, structural and protective functions. Over the past few years, novel features of these cells have emerged pointing to their direct participation in the so-called tripartite synapse, thereby modulating information processing and behavior. Very little is known about the intracellular astroglial mechanisms required to exert these functions, but it is now clear that calcium dynamics at different subcellular astroglial microdomains are key functional elements of the tripartite synapse.

Here we show that the activation of astrocyte mitochondrial-associated CB1 receptors (mtCB1) determines intracellular calcium dynamics and lateral synaptic regulation through specific mechanisms that regulate the activity of the mitochondrial calcium uniporter (MCU) channel. Physiologically, mtCB1-dependent mitochondrial calcium uptake determines the precise dynamics of cytosolic calcium events in astrocytes upon endocannabinoid mobilization.

Accordingly, electrophysiological recordings in hippocampal slices showed that genetic exclusion of mtCB1 receptors or specific astroglial MCU inhibition blocks lateral synaptic potentiation, a key example of astrocyte-dependent integration of distant synapses activity. Altogether, these data reveal an unforeseen link between astroglial mtCB1 and the regulation of brain network functions.

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