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 similar to 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 CB, 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.We thank all members of P. Grandes laboratory for their helpful comments, suggestions, and discussions during the performance of this study. The authors thank Giovanni Marsicano (INSERM, U1215 Neurocentre Magendie, Endocannabinoids and Neuroadaptation, Bordeaux, France. University de Bordeaux, France), Beat Lutz (Institute of Physiological Chemistry and German Resilience Center, University Medical Center of the Johannes Gutenberg University Mainz, Germany) and Susana Mato (Achucarro Basque Center for Neuroscience, Science Park of the UPV/EHU, Leioa, Vizcaya, Spain) for providing the CB1 receptor knock-out mice. This work was supported by MINECO/FEDER, UE (grant number SAF2015-65034-R to PG); The Basque Government (grant number BCG IT764-13 to PG); Red de Trastornos Adictivos, Instituto de Salud Carlos III (ISC-III) and European Regional Development Funds-European Union (ERDF-EU; grant RD16/0017/0012 to PG); PhD contract from MINECO (BES-2013-065057 to SP); Vanier Canada Graduate Scholarship (NSERC to CJF)