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Long-term potentiation (LTP) of synaptic transmission represents the cellular basis of learning and memory. Astrocytes have been shown to regulate synaptic transmission and plasticity. However, their involvement in specific physiological processes that induce LTP in vivo remains unknown. Here we show that in vivo cholinergic activity evoked by sensory stimulation or electrical stimulation of the septal nucleus increases Ca2+ in hippocampal astrocytes and induces LTP of CA3-CA1 synapses, which requires cholinergic muscarinic (mAChR) and metabotropic glutamate receptor (mGluR) activation. Stimulation of cholinergic pathways in hippocampal slices evokes astrocyte Ca2+ elevations, postsynaptic depolarizations of CA1 pyramidal neurons, and LTP of transmitter release at single CA3-CA1 synapses. Like in vivo, these effects are mediated by mAChRs, and this cholinergic-induced LTP (c-LTP) also involves mGluR activation. Astrocyte Ca2+ elevations and LTP are absent in IP3R2 knock-out mice. Downregulating astrocyte Ca2+ signal by loading astrocytes with BAPTA or GDPbS also prevents LTP, which is restored by simultaneous astrocyte Ca2+ uncaging and postsynaptic depolarization. Therefore, cholinergic-induced LTP requires astrocyte Ca2+ elevations, which stimulate astrocyte glutamate release that activates mGluRs. The cholinergicinduced LTP results from the temporal coincidence of the postsynaptic activity and the astrocyte Ca2+ signal simultaneously evoked by cholinergic activity. Therefore, the astrocyte Ca2+ signal is necessary for cholinergic-induced synaptic plasticity, indicating that astrocytes are directly involved in brain storage information ; Supported by grants from Ministerio de Ciencia e Innovacio´n (BFU2010-15832, BFU2008-03488, BFU2008-04196, CSD2010-00045), Spain, European Union (HEALTH-F2-2007-202167) and Cajal Blue Brain. G.P. is supported by a Marie Curie Fellowship (FP7-253635). E.D.M. is supported by INCRECyT project from European Social Fund and JCCM.