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Cereb Cortex. 2015 Oct;25(10):3699-712. doi: 10.1093/cercor/bhu231. Epub 2014 Sep 26.

Endocannabinoids Induce Lateral Long-Term Potentiation of Transmitter Release by Stimulation of Gliotransmission.

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Instituto Cajal, CSIC, Madrid 28002, Spain.
Instituto Cajal, CSIC, Madrid 28002, Spain Current address: Department of Neurobiology, Centro de Biología Molecular "Severo Ochoa," (CSIC/UAM), Madrid, Spain.
Department of Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA.
Division of Cerebral Structure, National Institute for Physiological Sciences, Okazaki 444-8787, Japan.
Instituto de Investigación en Discapacidades Neurológicas (IDINE), Departamento de Ciencias Médicas, Facultad de Medicina, Universidad Castilla-La Mancha, Albacete 02006, Spain.
Instituto Cajal, CSIC, Madrid 28002, Spain Department of Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA.


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.


LTP; astrocytes; endocannabinoid signaling; mGluRs; nitric oxide

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