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

• Published in: Neuropharmacology Vol. 153; pp. 32 - 40
• Main Authors: Peñasco, Sara, Rico-Barrio, Irantzu, Puente, Nagore, Gómez-Urquijo, Sonia María, Fontaine, Christine J., Egaña-Huguet, Jon, Achicallende, Svein, Ramos, Almudena, Reguero, Leire, Elezgarai, Izaskun, Nahirney, Patrick C., Christie, Brian R., Grandes, Pedro
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 15.07.2019
• Subjects: 2-AG; Animals; CB1 receptor; Dentate Gyrus - drug effects; Dentate Gyrus - physiology; Electrophysiology; Endocannabinoids - pharmacology; Excitatory synapses; Hippocampus; Long-term depression; Long-Term Synaptic Depression - drug effects; Long-Term Synaptic Depression - physiology; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Organ Culture Techniques; Perforant Pathway - drug effects; Perforant Pathway - physiology; Receptor, Cannabinoid, CB1 - agonists; Receptor, Cannabinoid, CB1 - physiology; Synapses - drug effects; Synapses - physiology; Electrophysiology; CB1 receptor; Long-term depression; 2-AG; Excitatory synapses; Hippocampus; CB receptor
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2019.04.020

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. [Display omitted] •CB1 receptor inhibits excitatory medial perforant path (MPP) synaptic transmission.•MPP stimulation triggers CB1-dependent excitatory long-term depression (eCB-eLTD).•∼26% of the MPP excitatory terminals contain CB1 receptors.•eCB-eLTD is group I metabotropic glutamate receptor dependent.•eCB-eLTD requires 2-arachydonoyl-glycerol (2-AG) synthesis.