Endocannabinoids induce lateral long-term potentiation of transmitter release by stimulation of gliotransmission

Marta Gómez-Gonzalo, Marta Navarrete, Gertrudis Perea, Ana Covelo, Mario Martín-Fernández, Ryuichi Shigemoto, Rafael Luján, Alfonso Araque

Research output: Contribution to journalArticlepeer-review

49 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)3699-3712
Number of pages14
JournalCerebral Cortex
Volume25
Issue number10
DOIs
StatePublished - Oct 2015

Keywords

  • Astrocytes
  • Endocannabinoid signaling
  • LTP
  • Nitric oxide
  • mGluRs

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