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 GDPβS 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 cholinergic-induced 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. Information processing in the brain was classically thought to rely solely on neurons, whereas astrocytes, the most abundant glial cells in the brain, were considered supportive cells for neurons. However, astrocytes are known to respond to neuronal signals and regulate the function of synapses, so they may indeed serve active roles during information processing and storage in the brain. We investigated whether these phenomena occur in vivo and whether astrocytes participate in synaptic plasticity and long-term potentiation (LTP), which are thought to represent the cellular basis of learning and memory. We found that sensory stimulation in rodents triggers the activity of neurons that release the neurotransmitter acetylcholine and activates astrocytes in the hippocampus, a brain region involved in learning and memory. Acetylcholine elevates intracellular calcium in astrocytes, which then stimulates the release of glutamate, another neurotransmitter. Glutamate released from astrocytes acts on synaptic receptors, increasing synaptic strength and leading to LTP of the efficacy of transmission in synapses. This is the first demonstration of the direct involvement of astrocytes in the generation of in vivo LTP. We suggest that astrocytes are cellular sources of signals underlying synaptic plasticity and are directly involved in memory processes and brain information storage.

Numerous evidence demonstrates that astrocytes, a type of glial cell, are integral functional elements of the synapses, responding to neuronal activity and regulating synaptic transmission and plasticity. Consequently, they are actively involved in the processing, transfer and storage of information by the nervous system, which challenges the accepted paradigm that brain function results exclusively from neuronal network activity, and suggests that nervous system function actually arises from the activity of neuron–glia networks. Most of our knowledge of the properties and physiological consequences of the bidirectional communication between astrocytes and neurons resides at cellular and molecular levels. In contrast, much less is known at higher level of complexity, i.e. networks of cells, and the actual impact of astrocytes in the neuronal network function remains largely unexplored. In the present article, we summarize the current evidence that supports the notion that astrocytes are integral components of nervous system networks and we discuss some functional properties of intercellular signalling in neuron–glia networks.

Experience-dependent plasticity of synaptic transmission, which represents the cellular basis of learning, is accompanied by morphological changes in dendritic spines. Astrocytic processes are intimately associated with synapses, structurally enwrapping and functionally interacting with dendritic spines and synaptic terminals by responding to neurotransmitters and by releasing gliotransmitters that regulate synaptic function. While studies on structural synaptic plasticity have focused on neuronal elements, the structural–functional plasticity of astrocyte–neuron relationships remains poorly known. Here we show that stimuli inducing hippocampal synaptic LTP enhance the motility of synapse-associated astrocytic processes. This motility increase is relatively rapid, starting <5 min after the stimulus, and reaching a maximum in 20–30 min (t_(1/2) = 10.7 min). It depends on presynaptic activity and requires G-protein-mediated Ca²⁺ elevations in astrocytes. The structural remodeling is accompanied by changes in the ability of astrocytes to regulate synaptic transmission. Sensory stimuli that increase astrocyte Ca²⁺ also induce similar plasticity in mouse somatosensory cortex in vivo. Therefore, structural relationships between astrocytic processes and dendritic spines undergo activity-dependent changes with metaplasticity consequences on synaptic regulation. These results reveal novel forms of synaptic plasticity based on structural–functional changes of astrocyte–neuron interactions.