Distinct endocannabinoids specifically signal to astrocytes and neurons

Abstract

The endocannabinoid system is an essential intercellular signaling mechanism with a decisive role in many physiological functions of the brain. Endocannabinoids (eCBs), directly acting on presynaptic neuronal CB1 receptors (CB1Rs), can inhibit neurotransmitter release. In addition, they can potentiate adjacent synapses, inducing lateral regulation of synaptic transmission through astrocyte CB1Rs. In contrast to most, if not all, neurotransmitter systems, the eCB system involves two distinct ligands, Anandamide and 2-Arachidonoylglycerol (AEA and 2AG), and a single receptor (CB1R). The physiological meaning of this particularity remains unknown. Here we show that different eCBs are signaling both astrocytes and neurons, inducing distinct and contrasting synaptic regulation. Combining two-photon with pharmacological and optogenetic approaches and transgenic mice for the synthesis enzyme of both eCBs, we have found that the absence of 2-AG synthesis abolished the inhibitory effect, which was mediated exclusively by neuronal mechanisms. However, the absence of AEA synthesis prevents the lateral potentiation mediated by astrocyte calcium mobilization. Together this indicates that 2-AG signals to neurons, decreasing neurotransmitter release, while AEA signals to astrocytes and induces lateral potentiation. Additionally, AEA synthesis is required for the synaptic potentiation induced by spike-timing-dependent plasticity, as well as astrocyte CB1R, indicating that distinct eCBs-signaling influences neuronal plasticity. We conclude that 2-AG and AEA induce distinct and contrasting synaptic regulation through CB1R in different cell types.

Imaging and Genetic Tools for the Investigation of the Endocannabinoid System in the CNS

“…One of the main features of eCBs is that they are likely synthetized "on demand" with precise spatiotemporal coordination. This model implies that the differential distribution of eCB biosynthetic pathways in different brain areas, cell types, and physiological states would dictate their effect in that specific milieu [32][33][34]. For instance, AEA metabolism relies on different sets of enzymes with differential distribution throughout the CNS than those that mediate 2-AG metabolism [35].…”