Opinion
The tripartite synapse: roles for gliotransmission in health and disease

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In addition to being essential supporters of neuronal function, astrocytes are now recognized as active elements in the brain. Astrocytes sense and integrate synaptic activity and, depending on intracellular Ca2+ levels, release gliotransmitters (e.g. glutamate, d-serine and ATP) that have feedback actions on neurons. Recent experimental results have raised the possibility that quantitative variations in gliotransmission might contribute to disorders of the nervous system. Here, we discuss targeted molecular genetic approaches that have demonstrated that alterations in protein expression in astrocytes can lead to serious changes in neuronal function. We also introduce the concept of ‘astrocyte activation spectrum’ in which enhanced and reduced gliotransmission might contribute to epilepsy and schizophrenia, respectively. The results of future experimental tests of the astrocyte activation spectrum, which relates gliotransmission to neurological and psychiatric disorders, might point to a new therapeutic target in the brain.

Introduction

For much of the past century, astrocytes (see Glossary) have been considered passive bystanders that merely provide support to neuronal networks. Research that has been carried out over the past decade is changing this view, and astrocytes are now sharing the limelight with neurons because these cells have been shown to have important roles in the regulation of synaptic transmission. Astrocytes detect neuronal activity and can release chemical transmitters, which in turn control synaptic activity. This new understanding has led to the idea that astrocytes are intimately involved in the regulation of neuronal network function in vivo and, thus, are crucial determinants of higher brain functions and, consequently, of behavior 1, 2, 3.

For decades, it has been known that, following injury to the nervous system or in conditions such as Parkinson's disease, Alzheimer's disease, epilepsy, schizophrenia and depression, the structure and protein expression of the astrocyte are altered 1, 4, 5. However, it was not known whether this structural change represents a reaction to injury, in which the astrocyte is performing a supportive function in an attempt to prevent further injury, or whether the astrocyte is providing detrimental signals that contribute to the disorder. Because it has been assumed that many disorders of the nervous system are rooted in alterations of synaptic transmission and it is now understood that gliotransmission regulates synaptic transmission, it becomes important to ask whether astrocytes contribute to synaptic abnormalities and, thus, to disorders.

Here, we discuss the scientific breakthroughs that have led to the concept that astrocytes are intimately involved, along with neurons, in the control of brain function. We then consider the notion that dysfunctional astrocytes might underlie certain neurological disorders and psychiatric states. In particular, we focus on epilepsy and schizophrenia because astrocytes are known to control synchronized neuronal activity and N-methyl-d-aspartic acid (NMDA)-receptor function, two processes that are related to these disorders.

Section snippets

A brief history of the study of astrocytes

After the discovery of glial cells and the subsequent definition of the different classes of glia (Box 1), the structure of astrocytes provided the first clues to their function in the nervous system. The processes of the astrocyte are contained within a distance of ∼100 μm, and processes of the same cell contact neuronal membranes and the vasculature, where they form endfeet around the endothelia and smooth muscle [6]. On the neuronal side, astrocytes make contact with synapses in several

Ca2+ excitability and gliotransmission

In the early 1990s, the research groups of Stephen Smith and Michael Sanderson provided new insights into astrocytic function by using Ca2+ imaging to study cultured glial cells 19, 20. Smith's research team showed that cultured astrocytes respond to the chemical transmitter glutamate with oscillations in their internal Ca2+ level, and Ca2+ oscillations can travel as waves between adjacent astrocytes. Sanderson's research team focally stimulated a single astrocyte and showed that astrocytes are

Neuronal synchronization

An important consequence of glutamate action is the synchronization of neuronal activity. The Ca2+-dependent release of astrocytic glutamate activates extrasynaptic neuronal NMDA receptors. Paired recordings and Ca2+ imaging have shown that glutamatergic gliotransmission can synchronously excite groups of pyramidal neurons that are located within ∼100 μm 24, 33; presumably a dendrite of each synchronously excited neuron is co-innervated by the same astrocyte. Although synchronous excitation has

Synaptic modulation

Because astrocyte-dependent regulation of synaptic transmission has been the focus of several recent review articles 1, 2, 34, we discuss this issue only briefly to provide the necessary basis for the hypothesis relating gliotransmission to disorders of the brain.

Glutamate and ATP have been demonstrated to exert synaptic modulatory actions. Glutamate can have presynaptic effects that are mediated either by metabotropic glutamate (mGlu) receptors [35] or by kainate receptors that induce an

Control of NMDA-receptor function and metaplasticity

In addition to direct modulatory actions, astrocytes regulate the degree of function of NMDA receptors by releasing d-serine, a co-agonist for this receptor [42]. Serine racemase is expressed in astrocytes and is responsible for the conversion of l- into d-serine [43]. Ca2+ elevations in astrocytes evoke the exocytotic release of d-serine, which can then act on neuronal NMDA receptors [44]. NMDA receptors are crucial for the induction of long-term synaptic plasticity [45]. Unlike most

Coordination of synaptic networks

During the past three years, three research teams have shown that astrocyte-dependent regulation of synapses is mediated through adenosine and that this gliotransmitter enables the astrocyte to act as an intermediary in signaling between networks of synapses 38, 39, 40. It is well known that there is a tonic level of extracellular adenosine in the brain, which causes presynaptic inhibition of transmitter release from certain excitatory synapses [50]. Using molecular genetic strategies applied

Antagonism between gliotransmitters

As neurons use different transmitters to mediate opposing actions in synaptic transmission, astrocytes exert excitatory and inhibitory effects. Most studies performed in different regions of the CNS support the notion that gliotransmission is based on the use of glutamate and adenosine (which accumulates via the hydrolysis of released ATP), whereas neurons use glutamate and γ-aminobutyric acid (GABA). Regardless of the gliotransmitters that are used by the astrocyte, it is not known whether the

Astrocytic changes correlate with brain disorders

Because many of the synapses in the CNS are tripartite in nature, disruption of astrocytic supportive functions and/or of gliotransmission has the potential to disrupt synaptic transmission, synaptic plasticity and neuronal excitability. On a system level, this might translate into disruption of brain physiology and behavioral abnormalities. Over the past few years, several studies have validated this idea. For example, counting the number of astrocytes has led to the idea that in patients

The astrocyte activation spectrum: a biological model

Although alterations in many of the biological functions of the astrocyte, including pH regulation, control of K+ homeostasis and metabolic coupling, might have deleterious effects in the nervous system, it is worth considering the potential of a role for gliotransmission in disorders. It is intriguing that enhanced excitatory gliotransmission, for example in terms of Ca2+ oscillations and glutamate release, can contribute to epileptiform activity and seizures, whereas reduced gliotransmission

Future directions

For the past decade, considerable basic research has focused on the study of the regulation of astrocytic Ca2+ signaling and gliotransmission. As a consequence, it is now possible to speculate about how quantitative differences in these signaling processes might contribute to disorders of the nervous system. A future task is to test experimentally the validity of the astrocytic activation spectrum, which we propose in Figure 4. To make such an experimental test will require the integration of

Concluding remarks

The application of microscopy to the study of astrocytes has provided a new insight into the function of these non-neuronal cells of the nervous system. As a result, we now know that astrocytes exhibit Ca2+ excitability, and that Ca2+ oscillations can induce the release of gliotransmitters including glutamate and d-serine. In addition to their potential physiological roles in the control of neuronal excitability and synaptic transmission is their possible contribution to disorders of the

Acknowledgements

Due to space constraints, we were unable to cite all the relevant primary literature and apologize in advance to those whose work has not been cited. The authors thank members of the Haydon laboratory for their helpful discussions. Our work is supported by grants from the NINDS and NIMH of the NIH, and by the Epilepsy Foundation through the generous support of the American Epilepsy Society and UCB Pharma, Inc.

Glossary

Astrocytes
a subtype of glial cell that contacts synapses and the vasculature. Astrocytes are often identified based on the expression of GFAP.
Glial fibrillary acidic protein (GFAP)
an astrocyte-specific protein that is used to identify this type of glial cell.
Gliotransmission
the process of release of chemical transmitters (gliotransmitters) from astrocytes.
Metaplasticity
the process of plasticity of synaptic plasticity. By regulating the availability of d-serine to NMDA receptors, astrocytes

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