Distinct endocannabinoids specifically signal to astrocytes or neurons in the adult mouse hippocampus

The endocannabinoid (eCB) system is involved in many processes in brain function. eCBs depress synaptic transmission by directly activating presynaptic CB1 receptors (CB1Rs), and they indirectly potentiate adjacent synapses by activating astrocytic CB1Rs. In contrast to other neurotransmitter systems, the brain eCB system involves two endogenous ligands, 2-arachidonoylglycerol (2-AG) and anandamide (AEA), and the receptor CB1R. The meaning of this particularity remains unknown. Here we show that 2-AG selectively signals to neurons, eliciting the depression, which is mediated exclusively by neuronal mechanisms. By contrast, AEA signals to astrocytes, inducing lateral synaptic potentiation. Moreover, AEA, but not 2-AG, and astrocyte-mediated signaling are required for hippocampal spike-timing-dependent long-term potentiation. Hence, while 2-AG selectively signals to neurons, AEA specifically signals to astrocytes, evoking contrasting regulatory phenomena of synaptic transmission and plasticity. These results reveal distinct cell-type-specific signaling pathways that involve unique eCBs selectively signaling to either neurons or astrocytes.