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Review
. 2013 May;14(5):311-21.
doi: 10.1038/nrn3484. Epub 2013 Apr 18.

Emerging roles of astrocytes in neural circuit development

Laura E Clarke  1 , Ben A Barres
Affiliations
Review

Emerging roles of astrocytes in neural circuit development

Laura E Clarke et al. Nat Rev Neurosci. 2013 May.

Erratum in

  • Nat Rev Neurosci. 2013 Jun;14(6):451

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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Conflict of interest statement

Competing interests statement

B.A.B. declares competing financial interests. See Web version for details. L.E.C. declares no competing financial interests.

Figures

Figure 1
Figure 1. Astrocytes instruct structural synapse formation by the secretion of several molecules
Astrocytes secrete the thrombospondins (purple circles), which are reported to interact with neuroligins, the α2δ-1 voltage-gated calcium channel subunit and integrins to induce excitatory structural synapse assembly. Astrocytes also secrete hevin (orange circles) and SPARC (red circles). Hevin promotes the formation of excitatory synapses, whereas SPARC antagonizes the synaptogenic function of hevin. Both neurexins and neuroligins have been identified as binding partners for hevin, and SPARC can bind integrins. It is thought that the thrombospondins and hevin bind to and cluster trans-synaptic adhesion molecules to induce the formation of structurally normal but postsynaptically silent excitatory synapses. The dashed arrow indicates action potential (AP) propagation, which induces glutamate release from synaptic vesicles. NMDAR, NMDA receptor.
Figure 2
Figure 2. Astrocytes secrete signals to induce synapse maturation
Astrocytes secrete molecules to convert silent synapses (synapses lacking AMPA receptors (AMPARs)) into functional synapses. At the resting potential, NMDA receptors (NMDARs) barely pass any current (not shown) in response to activation by glutamate (blue circles). This is because NMDARs are subject to a voltage-dependent magnesium block. Therefore, NMDARs rely on AMPAR activation to produce sufficient depolarization to allow cations to flow through the channel and to produce an excitatory postsynaptic current (which in turn generates an action potential (AP) that propagates along the axon, as indicated by the dashed arrow). Astrocytes secrete glypicans (green circles) to increase the surface levels and clustering of the GluA1 subunit of the AMPAR and thereby to induce excitatory synapse functionality. The neuronal receptor for the glypicans has yet to be identified, but studies in Drosophila melanogaster indicate that the protein tyrosine phosphatase receptor leukocyte antigen-related receptor (LAR) could be involved.
Figure 3
Figure 3. C1q-dependent elimination of synapses by glia
Astrocytes secrete an unidentified signal (purple) that upregulates the expression of the complement component C1q at synapses. Expression of C1q triggers the activation of downstream classical complement components including C3 and C3b. Microglia are the resident immune cells of the brain and express complement receptors. Activation of microglial complement receptors triggers the phagocytosis of synapses. Interestingly, C1q-dependent phagocytosis is regulated by neural activity and thus provides a mechanism by which weak synapses (as respresented by the red action potential (AP)) that generate weak synaptic signals can be targeted for removal during neural circuit remodelling.
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References

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