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

The endocannabinoid system modulates synaptic plasticity in the hippocampus, but a link between long-term synaptic plasticity and the type 1 cannabinoid (CB₁) 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 CB₁ receptors, and field excitatory postsynaptic potentials evoked by MPP stimulation were inhibited by CB₁ receptor activation. In addition, MPP stimulation at 10 Hz for 10 min triggered CB₁ receptor-dependent excitatory long-term depression (eCB-eLTD) at MPP synapses of wild-type mice but not on CB₁-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 CB₁ receptors with eCB-eLTD at DML MPP synapses and further involve these receptors in memory processing within the adult brain.