Elsevier

Cell Calcium

Volume 38, Issues 3–4, September–October 2005, Pages 375-382
Cell Calcium

Glial calcium signaling and neuron–glia communication

https://doi.org/10.1016/j.ceca.2005.06.015Get rights and content

Abstract

The existence of bidirectional signaling between astrocytes and neurons has revealed an important active role of astrocytes in the physiology of the nervous system. As a consequence, there is a new concept of the synaptic physiology—“the tripartite synapse”, where astrocytes exchange information with the pre- and postsynaptic elements and participate as dynamic regulatory elements in neurotransmission. The control of the Ca2+ excitability in astrocytes is a key element in this loop of information exchange. The ability of astrocytes to respond to neuronal activity and discriminate between the activity of different synapses, the modulation of the astrocytic cellular excitability by the synaptic activity, and the expression of cellular intrinsic properties indicate that astrocytes are endowed with cellular computational characteristics that process synaptic information. Therefore, we propose that astrocytes can be considered as cellular elements involved in the information processing by the nervous system.

Introduction

Since the initial studies of the nervous system, neurons were recognized as the cellular elements responsible for the information processing of the nervous system, while glial cells were considered to play a simple supportive role for neurons. The fundamental attribute of neurons is their cellular electrical excitability, which is based on the expression of a plethora of ligand- and voltage-gated membrane channels that give rise to prominent membrane currents and membrane potential variations that represent the biophysical substrate underlying the transfer and integration of information at the cellular level. In contrast, glial cells are non-electrically excitable because, being able to express most of the membrane channels expressed by neurons, the level of expression of some key channels is relatively low to grant active electrical behaviors in response to different stimuli. Nevertheless, glial cells display a form of excitability that is based on variations of the Ca2+ concentration in the cytosol rather than electrical changes in the membrane. This excitability may serve as a cellular information element, which suggest the ability of glia to play more active roles in the nervous system previously thought.

Glial cells in the central nervous system (CNS) have been classified in two major cell groups, macroglia and microglia. Microglia are phagocytic cells involved in inflammatory responses. Macroglia are composed of oligodendrocytes, astrocytes, and ependymoglial cells (a specialized glia that line the ventricles). Oligodendrocytes—and their equivalent in the peripheral nervous system (PNS), Schwann cells—form the myelin ensheaths that enwrap axons. Astrocytes may display different morphologies and phenotypes, such as Müller cells in the retina, Bergmann glia in the cerebellum, protoplasmic astrocytes in the gray matter, fibrous astrocytes in the white matter tracts, perivascular astrocytes that form extensive endfoot that contact with blood vessels, etc. (for a comprehensive description of glial cells, see [1]). Among the different types of glial cells, astrocytes have received special attention, probably because their intimate spatial relationship with neurons and synapses in the CNS. Although the importance of other glial cells on nervous system function must not be diminished, present review will focus on recent findings regarding the characteristics of the intracellular Ca2+ signaling in astrocytes.

In addition to the well-known functions of astrocytes in different physiological processes of the nervous system, such as differentiation, proliferation and trophic support and survival of neurons, new findings have recently proposed the existence of bidirectional communication between astrocytes and neurons, where the astrocyte Ca2+ signal plays a crucial role (for reviews see [2], [3], [4], [5]). We will center our discussion on the synaptic control and the consequences on neuronal physiology of the astrocyte Ca2+ signal, which serving as a key element in this new form of intercellular communication in the nervous system indicates that astrocytes actively participate in brain physiology.

Section snippets

Intracellular Ca2+ variations represent the biophysical substrate of the cellular excitability in astrocytes

Unlike neurons, glial cells are non-electrically excitable, and consequently they were classically considered not to be involved as active elements in the information processing of the nervous system—a function that remained exclusively attributed to neurons. The development and application of imaging techniques that allowed the monitoring of the intracellular Ca2+ was decisive to revive the interest for glial cells, and to establish new investigation pathways in the physiology of astrocytes

Astrocytes display endogenous Ca2+ excitability: spontaneous Ca2+ oscillations

Astrocytes display an endogenous excitability manifested as spontaneous intracellular Ca2+ oscillations that occur in the absence of neuronal activity (Fig. 1D). These spontaneous Ca2+ oscillations have been observed in situ in astrocytes from different brain areas, such as ventrobasal thalamus [12], [18], hippocampus [12], [17], cerebellum [12], [20], and neocortex [12], [21]. They are developmentally regulated and depend on the Ca2+ release from the IP3-sensitive intracellular Ca2+ stores [12]

Intercellular Ca2+ waves: astrocyte-to-astrocyte communication

Pioneering studies performed in cultured astrocytes demonstrated that Ca2+ elevations originated in one astrocyte can propagate non-decrementally to neighboring astrocytes, forming a Ca2+ wave that can extend for several hundreds micrometers [6], [8], [22] (Fig. 1A). Therefore, Ca2+ elevations that form Ca2+ waves may serve as a form of long-range intercellular communication between astrocytes. The mechanisms underlying the propagation of the Ca2+ waves have been extensively investigated and

Astrocyte Ca2+ signal is evoked by synaptic activity: neuron-to-astrocyte communication

Astrocytes express both in vitro and in situ a wide variety of functional receptors for many neurotransmitters (including glutamate, adenosine, norepinephrine, GABA, histamine, ATP, acetylcholine, etc.) (e.g., [1], [19]). Most of the receptors expressed by astrocytes are metabotropic receptors associated with G proteins that upon activation stimulate phospholipase C and the formation of IP3, which increases the intracellular Ca2+ concentration through the Ca2+ release from the IP3-sensitive Ca2+

Intracellular Ca2+ waves in astrocytes

An elegant study of Kettenmann's group [20] that combined ultrastructural analysis, three-dimensional reconstruction and physiological studies showed that the cellular processes of the Bergmann glial cells—a specialized type of astrocytes in the cerebellum—are composed by numerous morphological and functional subcellular compartments called microdomains. These microdomains have a complex surface that wraps synapses between parallel fiber axon terminals and Purkinje neuron spines and may respond

Modulation of the Ca2+ signal: astrocytes process synaptic information

While the neuron-to-astrocyte communication is firmly established by the demonstration of the synaptic control of the astrocyte Ca2+ signal, one relevant question is whether this communication presents properties of complex information processing that are classically considered to be exclusive of neuron-to-neuron communication. In other words, do astrocyte Ca2+ signal simply reflects the synaptic activity level? Or, in contrast, can astrocytes integrate synaptic information, responding with a

Consequences of the astrocyte Ca2+ signal on neuronal physiology: astrocyte-to-neuron communication

One of the most exciting topics on current neurobiology is the functional consequence of the astrocyte Ca2+ signal on neuronal physiology. In addition to respond to synaptically released neurotransmitters, it is well established that astrocytes may release different gliotransmitters such as glutamate, d-serine, TNFα, or ATP. Some of these transmitters have been shown to be released in a Ca2+-dependent manner (for a review see [38]), and to constitute feedback signals from astrocytes that

Conclusions

The evidence obtained by several groups has prompted a reconsideration of the actual role of astrocytes in the physiology of the CNS, based on the demonstration of the existence of reciprocal communication between astrocytes and neurons. The control of the intracellular Ca2+ excitability of astrocytes is a key element in this loop of information exchange. Considering the intricate spatial relationships between astrocytes and synapses, the spatial characteristics of the astrocyte Ca2+ signal,

Acknowledgment

This work was supported by Ministerio de Educación y Ciencia (BFU2004-00448), Spain. G.P. is a CSIC predoctoral fellow.

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