Astrocytes play active roles in brain physiology. They respond to neurotransmitters and modulate neuronal excitability and synaptic function. However, the influence of astrocytes on synaptic transmission and plasticity at the single synapse level is unknown. Ca ²⁺ elevation in astrocytes transiently increased the probability of transmitter release at hippocampal area CA3-CA1 synapses, without affecting the amplitude of synaptic events. This form of short-term plasticity was due to the release of glutamate from astrocytes, a process that depended on Ca ²⁺ and soluble N -ethylmaleimide–sensitive factor attachment protein receptor (SNARE) protein and that activated metabotropic glutamate receptors (mGluRs). The transient potentiation of transmitter release became persistent when the astrocytic signal was temporally coincident with postsynaptic depolarization. This persistent plasticity was mGluR-mediated but N -methyl- d -aspartate receptor–independent. These results indicate that astrocytes are actively involved in the transfer and storage of synaptic information.

The synaptic control of the astrocytic intracellular Ca²⁺is crucial in the reciprocal astrocyte-neuron communication. Using electrophysiological and Ca²⁺imaging techniques in rat hippocampal slices, we investigated the astrocytic Ca²⁺signal modulation induced by synaptic terminals that use glutamate and acetylcholine. Ca²⁺elevations were evoked by glutamate released from Schaffer collaterals and by acetylcholine, but not glutamate, released by alveus stimulation, indicating that astrocytes discriminate the activity of different synapses belonging to different axon pathways. The Ca²⁺signal was modulated bidirectionally by simultaneous activation of both pathways, being depressed at high stimulation frequencies and enhanced at low frequencies. The Ca²⁺modulation was attributable to astrocytic intrinsic properties, occurred at discrete regions of the processes, and controlled the intracellular expansion of the Ca²⁺signal. In turn, astrocyte Ca²⁺signal elicited NMDA receptor-mediated currents in pyramidal neurons. Therefore, because astrocytes discriminate and integrate synaptic information, we propose that they can be considered as cellular elements involved in the information processing by the nervous system.

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.

Cell type–specific glial networks: Glial cells respond to neurotransmitters when nerve cells communicate with each other. Glial cells themselves release gliotransmitters that regulate neural synaptic transmission. Martín et al. studied this reciprocal relationship in a brain region called the dorsal striatum, which has two types of experimentally identifiable neurons and two types of synapses (see the Perspective by Gittis and Brasier). Subpopulations of glial cells selectively responded to the activity of one specific type of neuron. In turn, these specifically activated glial cells signaled only to the same type of neurons but not the other, indicating that glial-nerve signaling is largely cell-type specific. Science , this issue p. 730 ; see also p. 690