Synaptic information processing by astrocytes

doi:10.1016/j.jphysparis.2005.12.003

Journal of Physiology-Paris

Volume 99, Issues 2–3, March–May 2006, Pages 92-97

https://doi.org/10.1016/j.jphysparis.2005.12.003 Get rights and content

Abstract

Glial cells were classically considered as supportive cells that do not contribute to information processing in the nervous system. However, considerable amount of evidence obtained by several groups during the last few years has demonstrated the existence of a bidirectional communication between astrocytes and neurons, which prompted a re-examination of the role of glial cells in the physiology of the nervous system. This review will discuss recent advances in the neuron-to-astrocyte communication, focusing on the recently reported properties of the synaptically evoked astrocyte Ca²⁺ signal that indicate that astrocytes show integrative properties for synaptic information processing. Indeed, we have recently shown that hippocampal astrocytes discriminate between the activity of different synapses, and respond selectively to different axon pathways. Furthermore, the astrocyte Ca²⁺ signal is modulated by the simultaneous activity of different synaptic inputs. This Ca²⁺ signal modulation depends on cellular intrinsic properties of the astrocytes, is bidirectionally regulated by the level of synaptic activity, and controls the spatial extension of the intracellular Ca²⁺ signal. Consequently, we propose that astrocytes can be considered as cellular elements involved in information processing by the nervous system.

Introduction

During the last few years, a considerable amount of evidence has revealed a more active role of astrocytes in the physiology of the central nervous system (CNS) than previously believed. In addition to the well-known functions of astrocytes in differentiation, proliferation and trophic support and survival of neurons, new findings have demonstrated that astrocytes may sense the activity of neighboring synapses, responding to neurotransmitters released by synaptic terminals. Furthermore, astrocytes may in turn release neuroactive substances that may influence synaptic transmission, suggesting that astrocytes actively participate in brain physiology (for reviews see references Araque et al., 2001, Araque et al., 1999, Carmignoto, 2000, Castonguay et al., 2001, Haydon, 2001).

Section snippets

Astrocytic intracellular Ca²⁺ is controlled by the synaptic activity

Astrocytes are excitable cells that base their excitability on intracellular Ca²⁺ variations (Charles and Giaume, 2002, Haydon, 2001, Haydon and Araque, 2002, Nedergaard et al., 2003, Pasti et al., 1997, Verkhratsky et al., 1998). These Ca²⁺ elevations can occur spontaneously (Aguado et al., 2002, Nett et al., 2002, Parri et al., 2001), and they may also be triggered by different stimuli, such as mechanical stimulation, exogenous application of transmitters and neurotransmitters released by

The synaptically evoked astrocyte Ca²⁺ signal is modulated by interaction between different neurotransmitters

One of the most relevant properties of neurons is their ability to integrate synaptic information from multiple synaptic inputs. Neuronal intrinsic properties account for the complex non-linear input/output relationships that are responsible for the integrative properties of neurons (Agmon-Snir et al., 1998, Llinas and Sugimori, 1980). Accordingly, the neuronal electrical excitability may be non-linearly regulated by the simultaneous activity of converging synaptic inputs.

As described above, it

Concluding remarks

A considerable amount of 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 complex properties of the neuron–astrocyte intercellular signaling, which may have extremely important implications in the physiology of the brain, have only begun to be appreciated.

Recent evidence indicates that astrocytes display some

Acknowledgments

We thank Dr. W. Buño for helpful comments on the manuscript. This work was supported by Ministerio de Educación y Ciencia (BFU2004-00448), Spain. GP is a CSIC predoctoral fellow.

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Some types of glia play an active role in neuronal signaling by modifying their activity although little is known about their role in sensory information signaling at the receptor level. In this research, we report a functional role for the glia that surround the soma of the olfactory receptor neurons (OSNs) in adult Drosophila. Specific genetic modifications have been targeted to this cell type to obtain live individuals who are tested for olfactory preference and display changes both increasing and reducing sensitivity. A closer look at the antenna by Ca²⁺ imaging shows that odor activates the OSNs, which subsequently produce an opposite and smaller effect in the glia that partially counterbalances neuronal activation. Therefore, these glia may play a dual role in preventing excessive activation of the OSNs at high odorant concentrations and tuning the chemosensory window for the individual according to the network structure in the receptor organ.
Local energy on demand: Are ‘spontaneous’ astrocytic Ca<sup>2+</sup>-microdomains the regulatory unit for astrocyte-neuron metabolic cooperation?
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Importantly, besides the excitatory neurotransmitter glutamate, also the inhibitory neurotransmitter GABA has been reported to induce Ca2+ − signals in astrocytes (Meier et al., 2008; Mariotti et al., 2016), as do many other neurotransmitters or neuromodulators acting on a plethora of astrocyte GPCRs. One concept that has emerged from these early observations is that astrocytes might act as integrators of neuronal activity, across many synapses and involving different types of neurotransmitters converging on GPCR pathways (Perea and Araque, 2006; Perea and Araque, 2010), and that astrocytes hence would somehow ‘read-out’ bulk neuronal activity within their territory and transduce this neuronal feed-forward signal into a metabolic ‘energy-on-demand’ response (Belanger et al., 2011; Pellerin and Magistretti, 2012; Escartin and Rouach, 2013). Besides its elegance and simplicity, this idea was comforted by the observation that the degree of intercellular coupling among astrocytes often mirrors the anatomofunctional compartmentalization of the brain.
Astrocytes are a neural cell type critically involved in maintaining brain energy homeostasis as well as signaling. Like neurons, astrocytes are a heterogeneous cell population. Cortical astrocytes show a complex morphology with a highly branched aborization and numerous fine processes ensheathing the synapses of neighboring neurons, and typically extend one process connecting to blood vessels. Recent studies employing genetically encoded fluorescent calcium (Ca²⁺) indicators have described ‘spontaneous’ localized Ca²⁺-transients in the astrocyte periphery that occur asynchronously, independently of signals in other parts of the cells, and that do not involve somatic Ca²⁺ transients; however, neither it is known whether these Ca²⁺-microdomains occur at or near neuronal synapses nor have their molecular basis nor downstream effector(s) been identified. In addition to Ca²⁺ microdomains, sodium (Na⁺) transients occur in astrocyte subdomains, too, most likely as a consequence of Na⁺ co-transport with the neurotransmitter glutamate, which also regulates mitochondrial movements locally – as do cytoplasmic Ca²⁺ levels.
In this review, we cover various aspects of these local signaling events and discuss how structural and biophysical properties of astrocytes might foster such compartmentation. Astrocytes metabolically interact with neurons by providing energy substrates to active neurons. As a single astrocyte branch covers hundreds to thousands of synapses, it is tempting to speculate that these metabolic interactions could occur localized to specific subdomains of astrocytes, perhaps even at the level of small groups of synapses. We discuss how astrocytic metabolism might be regulated at this scale and which signals might contribute to its regulation. We speculate that the astrocytic structures that light up transiently as Ca²⁺-microdomains might be the functional units of astrocytes linking signaling and metabolic processes to adapt astrocytic function to local energy demands. The understanding of these local regulatory and metabolic interactions will be fundamental to fully appreciate the complexity of brain energy homeostasis as well as its failure in disease and may shed new light on the controversy about neuron-glia bi-directional signaling at the tripartite synapse.
Astrocyte transplantation for spinal cord injury: Current status and perspective
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Citation Excerpt :
They exert pivotal structural and physiological functions in the healthy spinal cord (Kimelberg and Nedergaard, 2010; Sofroniew and Vinters, 2010). These include essential roles in synaptic transmission, provision of suitable glial substrates (Fallon, 1985; Noble et al., 1984), blood flow regulation and blood–spinal barrier (BSB) formation (Abbott, 2002; Gordon et al., 2007; Haseloff et al., 2005; Koehler et al., 2006), and production of multiple neurotrophic factors (Bozoyan et al., 2012; Perea and Araque, 2006; Powell and Geller, 1999). Astrocytes respond to injuries through reactive astrogliosis, a pathologic hallmark of SCI that in severe cases results in the formation of glial scars (Seifert et al., 2006; Sofroniew, 2009; Sofroniew and Vinters, 2010).
Spinal cord injury (SCI) often causes incurable neurological dysfunction because axonal regeneration in adult spinal cord is rare. Astrocytes are gradually recognized as being necessary for the regeneration after SCI as they promote axonal growth under both physiological and pathophysiological conditions. Heterogeneous populations of astrocytes have been explored for structural and functional restoration. The results range from the early variable and modest effects of immature astrocyte transplantation to the later significant, but controversial, outcomes of glial-restricted precursor (GRP)-derived astrocyte (GDA) transplantation. However, the traditional neuron-centric view and the concerns about the inhibitory roles of astrocytes after SCI, along with the sporadic studies and the lack of a comprehensive review, have led to some confusion over the usefulness of astrocytes in SCI. It is the purpose of the review to discuss the current status of astrocyte transplantation for SCI based on a dialectical view of the context-dependent manner of astrocyte behavior and the time-associated characteristics of glial scarring. Critical issues are then analyzed to reveal the potential direction of future research.
Astrocyte domains and the three-dimensional and seamless expression of consciousness and explicit memories
2013, Medical Hypotheses
Citation Excerpt :
Similarly, multiple tripartite synapses from diverse origins, and expressing a variety of neurotransmitters and neuromodulators, are incorporated into individual domains. Astrocytes sense the level of neuronal activity at any given time [24,29,43] and integrate information conveyed at each synapse [4,7,27–29,62]. Therefore, synaptic information is simultaneously expressed in a dynamic global matrix of innumerable astrocyte domains [6,63].
The expression of consciousness and the site of memory storage within the brain are unknown despite over a century of intense empirical scrutiny. Recent anatomical studies show that human protoplasmic astrocytes form innumerable uniform polyhedral tessellating domains that are arranged three-dimensionally. This complex geometric structure provides a matrix for seamless and three-dimensional expression of consciousness and explicit memories. These studies, in conjunction with physiological data, demonstrate how this may be achieved:
- 1.
  Individual protoplasmic astrocytes occupy separate three-dimensional non overlapping (i.e., tessellating) territories known as domains. Thus, billions of contiguous and continuous domains tile mammalian cortical gray matter.
- 2.
  Each domain subtends approximately 90,000 rodent and 2,000,000 human tripartite synapses that signal to perisynaptic astrocyte processes which encode and integrate synaptic information. Neuron to astrocyte signalling is as rapid as neuron to neuron signaling.
- 3.
  Astrocytes are exquisitely sensitive to neural activity and distinguish synapse from numerous afferent pathways with different neurotransmitters or neuromodulators. Therefore, synaptic information is dynamically integrated within a global matrix of tessellating astrocyte domains.
- 4.
  Astrocytes of the sensory cortex respond to peripheral stimulation in vivo, and some have the ability to distinguish sensory input in more refined detail than surrounding neurons (e.g., visual cortex). Additionally, astrocytes of the cortex and cerebellum react in concert with activity of awake and behaving animals.
- 5.
  Domains are extensively interconnected by gap junctions that transmit molecules, many important for information processing and transcription, through complex syncytial networks. This adds an additional level of complexity to interactions between astrocyte domains that may extend over large areas including the entire neocortex.
Hypothesis: Consciousness is seamlessly expressed in a three-dimensional matrix consisting of billions of tessellating cortical astrocyte domains that bind attended sensory information. The temporal sequence (stream of consciousness) depends on the global distribution of sequential neural activity. The matrix may also be utilized to encode and store explicit memories.
Normal delay eyeblink conditioning in mice devoid of astrocytic S100B
2011, Neuroscience Letters
S100B is a small calcium binding protein synthesized and secreted mostly by astrocytes. Mice devoid of S100B (S100B-KO) develop without detectable anatomic abnormalities of the brain, but exhibit enhanced hippocampal long-term potentiation and enhanced performance in hippocampus-dependent learning and memory tasks, indicating that S100B has a crucial role in hippocampal neuronal plasticity. In the present study, we examined whether S100B has a similar role in the cerebellar regions, because Bergmann glia, a specialized subset of astrocytes in the cerebellar cortex, express a particularly large amount of S100B under physiologic conditions. Unlike in the hippocampus-dependent tasks, S100B-KO mice were indistinguishable from wild-type mice in both cerebellum-dependent motor coordination and delay eyeblink conditioning, a well-established paradigm for cerebellum-dependent learning and memory. These results suggest that S100B has differential roles in the hippocampus and cerebellum.
Glia: The many ways to modulate synaptic plasticity
2010, Neurochemistry International
Synaptic plasticity consists in a change in synaptic strength that is believed to be the basis of learning and memory. Synaptic plasticity has been for a very long period of time a hallmark of neurons. Recent advances in physiology of glial cells indicate that astrocyte and microglia possess all the features to participate and modulate the various form of synaptic plasticity. Indeed beside their respective supportive and immune functions an increasing number of study demonstrate that astrocytes and microglia express receptors for most neurotransmitters and release neuroactive substances that have been shown to modulate neuronal activity and synaptic plasticity. Because glial cells are all around synapses and release a wide variety of neuroactive molecule during physiological and pathological conditions, glial cells have been reported to modulate synaptic plasticity in many different ways. From change in synaptic coverage, to release of chemokines and cytokines up to dedicated “glio” transmitters release, glia were reported to affect synaptic scaling, homeostatic plasticity, metaplasticity, long-term potentiation and long-term depression.

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Synaptic information processing by astrocytes

Abstract

Introduction

Section snippets

Astrocytic intracellular Ca2+ is controlled by the synaptic activity

The synaptically evoked astrocyte Ca2+ signal is modulated by interaction between different neurotransmitters

Concluding remarks

Acknowledgments

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Astrocytic intracellular Ca²⁺ is controlled by the synaptic activity

The synaptically evoked astrocyte Ca²⁺ signal is modulated by interaction between different neurotransmitters

Synaptically-released acetylcholine evokes Ca²⁺ elevations in astrocytes in hippocampal slices

Prostaglandins stimulate Ca²⁺-dependent glutamate release in astrocytes