title: Differential regulation of NMDAR and NMDAR-mediated metaplasticity by anandamide and 2-AG in the hippocampus.
abstract: Endocannabinoids (eCBs), including AEA and 2-AG, are endogenous signaling mediators involved in many physiological and pathological events. The G protein-coupled cannabinoid receptor 1 (CB1 R) is an important target for eCBs, however, additional non-CB1 receptor targets have also been identified. Although recent evidence suggests that NMDA receptor function may be regulated by eCBs, the underlying mechanisms remain poorly characterized. Using acutely isolated CA1 neurons and slices from the hippocampus, we found that both AEA and 2-AG potentiate NMDAR-mediated currents independently of CB1 receptors (CB1 Rs) and via distinct signaling pathways. Potentiation by AEA requires the activation of TRPV1 channels. In contrast, potentiation by 2-AG requires the sequential activation of PKC and Src. Additionally, in hippocampal slices, we found that both AEA and 2-AG induce NMDAR-mediated metaplasticity and facilitate the induction of subsequent LTD independently of CB1 Rs. Enhanced LTD by AEA, but not 2-AG, was dependent on TRPV1 channels. Our findings reveal previously unrecognized non-CB1 R-dependent signaling cascades through which the two major eCBs regulate NMDA receptor function and consequently synaptic plasticity.
authors.affiliation: Robarts Research Institute, Molecular Brain Research Group, Western University, London, ON, Canada.
authors.forename: Kai
authors.initials: K
authors.lastname: Yang
authors.forename: Gang
authors.initials: G
authors.lastname: Lei
authors.forename: Yu-Feng
authors.initials: YF
authors.lastname: Xie
authors.forename: John F
authors.initials: JF
authors.lastname: MacDonald
authors.forename: Michael F
authors.initials: MF
authors.lastname: Jackson
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism*; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D063388:Endocannabinoids / Q000378:metabolism*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D005260:Female; D005989:Glycerides / Q000378:metabolism*; D008297:Male; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques; D053284:Polyunsaturated Alkamides / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D050916:TRPV Cation Channels / Q000378:metabolism; D046509:Tissue Culture Techniques
chemical_list: D001095:Arachidonic Acids; D063388:Endocannabinoids; D005989:Glycerides; D053284:Polyunsaturated Alkamides; D043884:Receptor, Cannabinoid, CB1; D016194:Receptors, N-Methyl-D-Aspartate; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; C094503:glyceryl 2-arachidonate; D016392:Proto-Oncogene Proteins pp60(c-src); D011493:Protein Kinase C; D002118:Calcium; C078814:anandamide
keywords: 2-AG; AEA; NMDAR; TRPV1 channels; metaplasticity