Trends in Neurosciences
Volume 32, Issue 8, August 2009, Pages 421-431
Journal home page for Trends in Neurosciences

Review
Tripartite synapses: astrocytes process and control synaptic information

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The term ‘tripartite synapse’ refers to a concept in synaptic physiology based on the demonstration of the existence of bidirectional communication between astrocytes and neurons. Consistent with this concept, in addition to the classic ‘bipartite’ information flow between the pre- and postsynaptic neurons, astrocytes exchange information with the synaptic neuronal elements, responding to synaptic activity and, in turn, regulating synaptic transmission. Because recent evidence has demonstrated that astrocytes integrate and process synaptic information and control synaptic transmission and plasticity, astrocytes, being active partners in synaptic function, are cellular elements involved in the processing, transfer and storage of information by the nervous system. Consequently, in contrast to the classically accepted paradigm that brain function results exclusively from neuronal activity, there is an emerging view, which we review herein, in which brain function actually arises from the coordinated activity of a network comprising both neurons and glia.

Introduction

Ten years ago the term ‘tripartite synapse’ was proposed to conceptualize the evidence obtained by many laboratories during the 1990s that revealed the existence of bidirectional communication between neurons and astrocytes (Figure 1). It represents a new concept in synaptic physiology wherein, in addition to the information flow between the pre- and postsynaptic neurons, astrocytes exchange information with the synaptic neuronal elements, responding to synaptic activity and regulating synaptic transmission [1] (Figure 2). The biology of astrocyte–neuron interaction has emerged as a rapidly expanding field and has become one of the most exciting topics in current neuroscience that is changing our vision of the physiology of the nervous system. The classically accepted paradigm that brain function results exclusively from neuronal activity is being challenged by accumulating evidence suggesting that brain function might actually arise from the concerted activity of a neuron–glia network.

Here, we briefly summarize early evidence that led to the establishment of the concept of a tripartite synapse and then discuss more recent data regarding the properties and physiological consequences of the astrocyte Ca2+ signal, which has a fundamental role in neuron–astrocyte communication as the cellular signal triggered by the neuronal activity and responsible for transmitter release from astrocytes and the consequent neuromodulation. Although astrocytes have important roles in key aspects of brain development and function, such as neuronal metabolism, synaptogenesis, homeostasis of the extracellular milieu, or cerebral microcirculation [2], we focus on the role of astrocytes in synaptic physiology, discussing data indicating that astrocytes integrate and process synaptic information and finally regulate synaptic transmission and plasticity through the release of gliotransmitters (i.e. transmitters released by glial cells implicated in rapid glial–neuron and glial–glial communication) [3].

Section snippets

Ca2+-mediated cellular excitability of astrocytes

The astrocytic revolution in current neuroscience began in the early 1990s when pioneering studies used the fluorescence imaging techniques to monitor intracellular Ca2+ levels in living astrocytes. Those studies revealed that cultured astrocytes display a form of excitability based on variations of the intracellular Ca2+ concentration 4, 5. Until then, astrocytes had been considered as nonexcitable cells because, unlike neurons, they do not show electrical excitability (e.g. see Refs 6, 7, 8, 9

Astrocyte Ca2+ signal is controlled by synaptic activity

Astrocyte Ca2+ elevations can occur spontaneously as intrinsic oscillations in the absence of neuronal activity 12, 13, 14, 15, and they can also be triggered by neurotransmitters released during synaptic activity [10] (Table 1), which is of crucial importance because it indicates the existence of neuron-to-astrocyte communication (Figure 3a).

The synaptic control of the astrocyte Ca2+ signal is based on the fact that astrocytes express a wide variety of functional neurotransmitter receptors.

Astrocyte Ca2+ signal in vivo

For many years, technical constraints limited astrocyte Ca2+-signal studies to cultured cells and brain slices. The recent use of novel imaging techniques, that is, two-photon microscopy and specific fluorescent dyes that selectively label astrocytes in vivo [30], which enable the study of astrocyte Ca2+ signals in the whole animal, has revealed important findings (Figure 3b). First, reports from studies of rat, mouse and ferret have demonstrated that astrocytes in vivo exhibit intracellular Ca

Synaptic information processing by astrocytes

In contrast to the view of astrocytes as passive elements that provide the adequate environmental conditions for appropriate neuronal function and that respond to neurotransmitters, simply performing a linear readout of the synaptic activity, experimental evidence supports the idea that astrocytes integrate and process synaptic information elaborating a complex nonlinear response to the incoming information from adjacent synapses (Box 1). As described earlier, it is firmly established that

Gliotransmission and modulation of synaptic transmission

One of the most stimulating topics in current neuroscience is the functional consequences of the astrocyte Ca2+ signal on neuronal physiology. Evidence obtained during the past 15 years has demonstrated that signaling between neurons and astrocytes is a reciprocal communication, where astrocytes not only respond to neuronal activity but also actively regulate neuronal and synaptic activity. Therefore, according to the concept of the tripartite synapse, to fully understand synaptic function,

Astrocytes and synaptic plasticity

Astrocytes operate at lower time scales than synaptic neurotransmission. Whereas fast neurotransmission occurs in milliseconds, astrocytic effects on neuronal physiology last seconds or tens of seconds. In addition, astrocyte regulation of synaptic transmission runs on different time scales, because astrocytes can control transiently the synaptic strength (during seconds), and they can also contribute to long-term synaptic plasticity. Several mechanisms underlying the astrocyte effects on

Astrocytes and animal behavior

The elucidation of the actual impact of astrocyte Ca2+ signaling and gliotransmission on animal behavior represents the ultimate challenge for the concept of the tripartite synapse. The development of transgenic animal models will be useful for this purpose. However, controversial data on this issue have been reported recently using different transgenic mice. Changes in hippocampal neuronal excitability and synaptic transmission were not detected when astrocyte Ca2+ elevations were evoked by

Are all synapses tripartite?

Experiments designed to observe the effects of the astrocyte Ca2+ signal on single hippocampal synapses showed that not all recorded synapses displayed modulation of the synaptic efficacy after astrocyte stimulation, but only a subset of synapses (around 40%) underwent astrocyte-induced potentiation [46]. Experimental conditions might account for some ineffective cases because, owing to the limits of optical resolution, it could not be excluded that the stimulated astrocyte was not in

Concluding remarks

Since the beginning of the ‘glia revolution’ in the 1990s, compelling evidence has been accumulated by many laboratories to firmly establish the concept of the tripartite synapse, in which astrocytes have functionally relevant roles in synaptic physiology. We know now that astrocytes are cellular processors of synaptic information and that they regulate synaptic transmission and plasticity. Consequently, astrocytes are involved in the processing, transfer and storage of information by the

Acknowledgements

The authors are supported by grants from Ministerio de Ciencia e Innovación (BFU2007–064764; http://web.micinn.es), Spain, European Union (HEALTH-F2–2007–202167; http://cordis.europa.eu/fp7) and Cajal Blue Brain (A.A.; http://cajalbbp.cesvima.upm.es). M.N is a predoctoral fellow of the Ministerio de Ciencia e Innovación, Spain.

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