Endocannabinoid long-term depression revealed at medial perforant path excitatory synapses in the dentate gyrus

Abstract The endocannabinoid system modulates synaptic plasticity in the hippocampus, but a link between long-term synaptic plasticity and the type 1 cannabinoid (CB 1 ) receptor at medial perforant path (MPP) synapses remains elusive. Here, immuno-electron microscopy in adult mice showed that ∼26% of the excitatory synaptic terminals in the middle 1/3 of the dentate molecular layer (DML) contained CB 1 receptors, and field excitatory postsynaptic potentials evoked by MPP stimulation were inhibited by CB 1 receptor activation. In addition, MPP stimulation at 10 Hz for 10 min triggered CB 1 receptor-dependent excitatory long-term depression (eCB-eLTD) at MPP synapses of wild-type mice but not on CB 1 -knockout mice. This eCB-eLTD was group I mGluR-dependent, required intracellular calcium influx and 2-arachydonoyl-glycerol (2-AG) synthesis but did not depend on N -methyl- d -aspartate (NMDA) receptors. Overall, these results point to a functional role for CB 1 receptors with eCB-eLTD at DML MPP synapses and further involve these receptors in memory processing within the adult brain.