title: Endocannabinoids Induce Lateral Long-Term Potentiation of Transmitter Release by Stimulation of Gliotransmission.
abstract: Endocannabinoids (eCBs) play key roles in brain function, acting as modulatory signals in synaptic transmission and plasticity. They are recognized as retrograde messengers that mediate long-term synaptic depression (LTD), but their ability to induce long-term potentiation (LTP) is poorly known. We show that eCBs induce the long-term enhancement of transmitter release at single hippocampal synapses through stimulation of astrocytes when coincident with postsynaptic activity. This LTP requires the coordinated activity of the 3 elements of the tripartite synapse: 1) eCB-evoked astrocyte calcium signal that stimulates glutamate release; 2) postsynaptic nitric oxide production; and 3) activation of protein kinase C and presynaptic group I metabotropic glutamate receptors, whose location at presynaptic sites was confirmed by immunoelectron microscopy. Hence, while eCBs act as retrograde signals to depress homoneuronal synapses, they serve as lateral messengers to induce LTP in distant heteroneuronal synapses through stimulation of astrocytes. Therefore, eCBs can trigger LTP through stimulation of astrocyte-neuron signaling, revealing novel cellular mechanisms of eCB effects on synaptic plasticity.
authors.affiliation: Instituto Cajal, CSIC, Madrid 28002, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Gómez-Gonzalo
authors.affiliation: Instituto Cajal, CSIC, Madrid 28002, Spain Current address: Department of Neurobiology, Centro de Biología Molecular "Severo Ochoa," (CSIC/UAM), Madrid, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Navarrete
authors.affiliation: Instituto Cajal, CSIC, Madrid 28002, Spain.
authors.forename: Gertrudis
authors.initials: G
authors.lastname: Perea
authors.affiliation: Department of Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Ana
authors.initials: A
authors.lastname: Covelo
authors.affiliation: Department of Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Mario
authors.initials: M
authors.lastname: Martín-Fernández
authors.affiliation: Division of Cerebral Structure, National Institute for Physiological Sciences, Okazaki 444-8787, Japan.
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Shigemoto
authors.affiliation: Instituto de Investigación en Discapacidades Neurológicas (IDINE), Departamento de Ciencias Médicas, Facultad de Medicina, Universidad Castilla-La Mancha, Albacete 02006, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Luján
authors.affiliation: Instituto Cajal, CSIC, Madrid 28002, Spain Department of Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Araque
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D063388:Endocannabinoids / Q000378:metabolism*; D019706:Excitatory Postsynaptic Potentials; D006624:Hippocampus / Q000378:metabolism / Q000502:physiology*; D017774:Long-Term Potentiation; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D017966:Pyramidal Cells / Q000378:metabolism / Q000502:physiology*; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism; D015398:Signal Transduction; D013569:Synapses / Q000378:metabolism
chemical_list: D063388:Endocannabinoids; D018094:Receptors, Metabotropic Glutamate; D009569:Nitric Oxide; D011493:Protein Kinase C; D002118:Calcium
keywords: LTP; astrocytes; endocannabinoid signaling; mGluRs; nitric oxide