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Review
, 96 (3), 697-708

Cell Biology of Astrocyte-Synapse Interactions

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Review

Cell Biology of Astrocyte-Synapse Interactions

Nicola J Allen et al. Neuron.

Abstract

Astrocytes, the most abundant glial cells in the mammalian brain, are critical regulators of brain development and physiology through dynamic and often bidirectional interactions with neuronal synapses. Despite the clear importance of astrocytes for the establishment and maintenance of proper synaptic connectivity, our understanding of their role in brain function is still in its infancy. We propose that this is at least in part due to large gaps in our knowledge of the cell biology of astrocytes and the mechanisms they use to interact with synapses. In this review, we summarize some of the seminal findings that yield important insight into the cellular and molecular basis of astrocyte-neuron communication, focusing on the role of astrocytes in the development and remodeling of synapses. Furthermore, we pose some pressing questions that need to be addressed to advance our mechanistic understanding of the role of astrocytes in regulating synaptic development.

Keywords: astrocyte; glia; synapse.

Figures

Figure 1
Figure 1. Perisynaptic astrocyte processes are structural and functional components of synapses
A) A membrane-associated fluorescent protein expressing cortical protoplasmic astrocyte from postnatal day 21 mouse cortex, showing the morphological complexity of astrocytes in vivo. Scale bar, 20 µm. Image courtesy of Dr. J.A. Stogsdill (Eroglu Lab). B) An Electron Micrograph of the tripartite synapse in the mouse visual cortex (V1). The pre-(Axon) and postsynaptic (Dendrite) structures are highlighted in red and green, respectively. An astrocyte process, which makes contacts with pre and postsynaptic boutons, is labeled in blue (Astro). Scale bar, 250nm. C) Astrocytes are also functionally linked to synapses as they possess the ability to sense synaptic activity and respond to it through intracellular Ca2+ transients, and by releasing neuroactive molecules that can signal back to synapses.
Figure 2
Figure 2. Astrocytes control synapse formation, maturation and elimination
A) Astrocytes secrete synaptogenic Thrombospondins (TSP) and hevin, to induce structural synapses, which are presynaptically active but postsynaptically silent due to lack of AMPARs. However, these structural synapses have postsynaptic NMDARs (grey). TSPs induce synapse formation by interacting with their neuronal receptor calcium channel subunit α2δ-1. Hevin induces formation of a subset of excitatory synapses by bridging two interaction-incompatible synaptic receptors, neurexin1-a and neuroligin 1. B) Astrocyte-secreted glypican 4 induces functional synapse formation by signaling through presynaptic RPTPδ, leading to release of the AMPA receptor clustering factor NP1 from the presynaptic terminal, and binding of NP1 to GluA1 AMPARs (red) on the dendrite. C) Astrocytes control synapse elimination in two different ways. First astrocytes eliminate unwanted synapses by phagocytosis through the functions of MERTK and MEGF10 receptors. Second, astrocytes release TGFβ, which induces complement protein C1q expression by neurons. C1q is localized to weak/unwanted synapses through an unknown mechanism and recruits microglia, which express complement receptors (CRs) for elimination of these unwanted synapses by phagocytosis.
Figure 3
Figure 3. Models of differential astrocyte expression of synaptogenic factors
A) Homogenous astrocytes – all astrocytes express the same synaptogenic factors. B) Regionally restricted astrocytes – astrocytes in different brain regions express different synaptogenic factors. C) Locally specialized astrocytes – neighboring astrocytes within brain regions express different synaptogenic factors. D) Within astrocyte specialization – one astrocyte expresses multiple synaptogenic factors, and targets them to different synaptic domains.

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