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Emerging roles of astrocytes in neural circuit development

Nature Reviews Neuroscience volume 14, pages 311–321 (2013)Cite this article

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An Erratum to this article was published on 02 May 2013

This article has been updated

Key Points

  • Establishment of the correct number and type of synapses is essential for the formation of neural circuits and information processing in the brain. Despite the identification of a diverse range of neuronal mechanisms that regulate neural circuit formation, we are still far from fully understanding the processes involved.

  • New evidence from rodent studies has revealed that astrocytes are key participants in neural circuit development. Astrocytes control synapse formation, maturation, function and elimination by a range of newly identified secreted and contact-mediated signals.

  • Similarly, studies have revealed that human astrocytes can control synapse formation, suggesting that this feature is conserved across species. In fact, human astrocytes can induce the formation of a larger number of synapses than can rodent astrocytes. An understanding of the unique characteristics of human astrocytes might provide new insights into the greater capacity of the human brain to learn and adapt.

  • Astrocytes are also increasingly being implicated in the pathophysiology of neurodevelopmental and neuropsychiatric disorders resulting from synapse defects. In particular, astrocyte dysfunction has been shown to contribute to the developmental defects in synapse development in Rett syndrome, fragile X syndrome and Down's syndrome.

  • This surprising discovery that neurons rely on astrocytes to instruct the formation of their synapses leads to the possibility that astrocytes provide a layer of control that acts in parallel with, and interacts with, the neuronal processes that control circuit formation. A better understanding of the bidirectional signals between neurons and astrocytes should advance our knowledge of neuronal circuit development in health and disease.

Abstract

Astrocytes are now emerging as key participants in many aspects of brain development, function and disease. In particular, new evidence shows that astrocytes powerfully control the formation, maturation, function and elimination of synapses through various secreted and contact-mediated signals. Astrocytes are also increasingly being implicated in the pathophysiology of many psychiatric and neurological disorders that result from synaptic defects. A better understanding of how astrocytes regulate neural circuit development and function in the healthy and diseased brain might lead to the development of therapeutic agents to treat these diseases.

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Figure 1: Astrocytes instruct structural synapse formation by the secretion of several molecules.
Figure 2: Astrocytes secrete signals to induce synapse maturation.
Figure 3: C1q-dependent elimination of synapses by glia.

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Change history

  • 02 May 2013

    In this article, the corresponding author was listed incorrectly. The corresponding author is Laura E. Clarke, lclarke2@stanford.edu. This has been corrected in the online version of the article.

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Authors and Affiliations

  1. Department of Neurobiology, Stanford University School of Medicine, Stanford, 94305, California, USA

    Laura E. Clarke & Ben A. Barres

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  1. Laura E. Clarke
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  2. Ben A. Barres
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Correspondence to Laura E. Clarke.

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Competing interests

B.A.B. is a co-founder of Annexon Inc., a new company that will develop therapeutics for neurological diseases.

Glossary

Silent synapses

Excitatory synapses whose postsynaptic membranes contain NMDA-type glutamate receptors but not AMPA-type glutamate receptors, rendering the synapses inactive under normal physiological conditions.

Type 2 epidermal growth factor-like repeats

Evolutionarily conserved protein sequences that are found in the extracellular domains of several membrane-bound or secreted proteins. Epidermal growth factor-like domains are frequently found in numerous tandem copies of proteins, and these repeats fold together to form a single functional unit.

Von Willebrand factor type A domain

A domain in the large human multimeric von Willebrand factor glycoprotein that is found in blood plasma. This domain is found in various plasma and extracellular proteins and allows these proteins to form multiprotein complexes to participate in numerous biological events (for example, cell adhesion, migration and signal transduction).

Matricellular SPARC family

Matricellular glycoproteins that modulate the interaction of cells with the extracellular matrix primarily through regulation of cell adhesion, cell proliferation and matrix deposition.

Glycosyl-phosphatidylinositol linkages

Post-translational lipid modifications that are found in a diverse range of proteins. The glycosyl-phosphatidylinositol domain serves to anchor these proteins to the membrane. Glycosyl-phosphatidylinositol proteins can be released from the cell membrane upon cleavage by endogenous phospholipases.

Ephrins

Ephrins are ligands that bind to the EPH receptors. Both ephrins and EPH receptors are membrane-bound proteins, so activation of EPH–ephrin signalling pathways can only occur through direct cell–cell contact. Ephrin signalling regulates various biological processes, including the guidance of axon growth cones and cell migration.

Classical complement cascade

This system amplifies the immune response to aid the clearance of pathogens from an organism. The complement system consists of many small proteins found in the blood. When stimulated, proteases in this system cleave proteins to release cytokines and initiate a cascade of further cleavages to amplify the immune response.

Opsonize

To tag a pathogen by the binding of an antibody (or opsonin) to target it for removal by a phagocytic cell.

Polyglutamine repeats

Expanded runs of consecutive trinucleotide CAG repeats, which encode polyglutamine. These repeats are found in the genes of a large number of patients with neurodegenerative diseases such as Huntington's disease, fragile X syndrome and ataxia. Polyglutamine repeats are thought to cause protein aggregation, which is a key feature of these diseases.

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Clarke, L., Barres, B. Emerging roles of astrocytes in neural circuit development. Nat Rev Neurosci 14, 311–321 (2013). https://doi.org/10.1038/nrn3484

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