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Sciencedirect.Com Available online at www.sciencedirect.com ScienceDirect Glial regulation of synapse maturation and stabilization in the developing nervous system Marion R Van Horn and Edward S Ruthazer The dynamic interaction between neurons and glia is a Structural plasticity of the tripartite synapse promotes fundamental aspect of developmental neurobiology. Astrocytic neural circuit development processes are extremely complex and can physically surround Synapses are the primary points of communication neuronal synapses where they are involved in regulating between neurons. During development, appropriate syn- neuronal activity and synaptic plasticity. This review describes apses are strengthened and inappropriate synapses are important roles glial cells play in synapse maturation and lost. This process of synapse selection is essential for the stabilization in the developing central nervous system. We formation of neural circuits, effective information proces- highlight recent evidence showing that the motility of astrocytic sing and overall brain function. and radial glial processes is modulated by neuronal signals and is important for normal synapse maturation and function. Astrocytes have diffuse, arborized branches with a myriad Examples of glia-derived molecules that influence synapse of nanoscopic protusions, known as perisynaptic astro- maturation and stabilization are presented. We close by cytic processes (PAPs) that extend and associate with touching on recent and future trends in neuron-glia research. synapses. While PAPs are found in all brain areas, the number of synapses covered by PAPs, and the degree to Address which an individual synapse is covered, varies signifi- Montreal Neurological Institute, McGill University, Montreal, QC, H3A cantly. During development, astrocyte process motility 2B4, Canada and as well as coverage of synapses has been found to be Corresponding author: Ruthazer, Edward S ([email protected]) quite dynamic [2,3]. In the cerebellum, ensheathment of dendritic spines by Bergmann glia increases during per- iods of synaptogenesis [3]. Furthermore, in the develop- Current Opinion in Neurobiology 2019, 54:113–119 ing Xenopus tadpole, two-photon in vivo time-lapse imag- This review comes from a themed issue on Neurobiology of learning ing of radial glial cells, which are thought to be and plasticity functionally analogous to mammalian stellate astrocytes Edited by Scott Waddell and Jesper Sjotrom [4,5], shows radial glia processes are significantly more dynamic during early periods of development when cir- cuits are undergoing extensive synaptic remodeling [2]. https://doi.org/10.1016/j.conb.2018.10.002 0959-4388/ã 2018 Published by Elsevier Ltd. We recently investigated the functional significance of glial motility on the development of neural circuits and neuronal function. We found that suppressing the filopo- dial dynamics of radial glia during a period of extensive synapse development, by interfering with cGMP-depen- dent protein kinase 1, Rac1 and RhoA signaling, impaired Introduction normal synaptic maturation. In particular, miniature Measuring changes in electrical activity of neurons has excitatory postsynaptic current (mEPSC) frequencies provided an important foundation for understanding were significantly decreased in optic tectal neurons neigh- how information is processed and encoded throughout boring glia with impaired filopodial dynamics. This could the brain. However, advanced imaging techniques, in indicate either a decrease in the total number of synapses particular those based on intracellular calcium dynamics formed or a failure to traffic a-amino-3-hydroxy-5- and intravital imaging of cellular morphology, have methyl-4-isoxazolepropionic acid receptors (AMPARs) begun to provide experimental evidence that glial cells to the synaptic cleft of immature N-methyl-D-aspartate are also dynamic cells that respond to changes in neu- receptor (NMDAR)-only ‘silent’ synapses, suggesting ronal activity and engage in bi-directional communica- that glial process motility plays an important role in tion with neurons and other glial cells. In some cases promoting normal synaptic maturation of these neurons these interactions comprise a physical ‘tripartite during development. synapse’ consisting of presynaptic, postsynaptic and glia components [1]. Accordingly, in order to have a com- The functional significance of astrocyte process coverage plete picture of how information is processed in the of synapses during development has also been reported in brain it is important to jointly consider the contributions the cerebellum. When glia sheath retraction was induced of both neurons and glia. by expressing GluA2 subunits to render AMPARs www.sciencedirect.com Current Opinion in Neurobiology 2019, 54:113–119 114 Neurobiology of learning and plasticity 2+ Ca -impermeable in Bergmann glia, there was a signifi- showing that astrocytic contacts with dendritic spines cant increase in synaptic puncta and dendritic spine promote both the lifetime and morphological maturation density [6]. This observation is consistent with an earlier of dendritic protrusions [13]. study that reported a deficit in the developmental pruning of climbing fiber inputs onto Purkinje cells, resulting in While these results highlight that the fact that neuronal greater poly-innervation [7]. activity can signal to astrocytes and influence interactions with synapses, the mechanism and signaling pathways Neuronal signals promote structural plasticity of mediating these changes need to be further investigated. astrocyte processes and influences synapse Notably, expression of mGluR5, which has been identi- stabilization fied in a number of studies as an important regulator of Examining the morphology and motility of astrocytic and astrocyte motility, has been found to be developmentally radial glial processes has shown that the plasticity of PAPs regulated and not expressed in the adult brain [14]. and their proximity to synapses is influenced by a number Accordingly, mechanisms mediating astrocyte process of physiological conditions. A particularly striking dem- motility during development may differ from those in onstration of the functional consequences of the remo- adulthood. deling of astrocytic coverage takes place at synapses in the hypothalamus during lactation and dehydration [5]. Astro- Astrocytic motility may regulate synaptic availability of cyte processes are physically retracted from synapses, glutamate and gliotransmitters resulting in reduced clearance of glutamate [6], changes Synaptic remodeling that occurs during development in the diffusion properties of the extracellular space [7], as relies on changes in synaptic strength akin to those well as significant changes in synaptic transmission [8]. implicated in learning and memory such as long-term potentiation (LTP) [15,16]. A fundamental mechanism While there is accumulating evidence showing that astro- underlying changes in synaptic strength is the delivery cyte proximity to synapses is critical for synaptic function, and removal of AMPARs at synapses through a process we are just beginning to understand the mechanisms that has been shown to be in part dependent on the mediating astrocyte process plasticity. Recent experi- activation of NMDARs [17,18]. ments have begun to examine how neuronal activity influences astrocyte process motility [8,9–11,12]. In vivo Astrocytic processes contain glutamate transporters, live imaging of radial glial cell processes in the neuropil of which are necessary for clearing synaptic glutamate and the developing tadpole optic tectum has revealed that preventing widespread excitotoxicity [19]. A recent study their dynamics is significantly increased when measured has shown that connexin 30, an astrocyte gap-junction 5 min after visual stimulation, a phenomenon that was protein, is important for controlling astrocyte process prevented by MK801 blockade of NMDARs, which are motility. Mice that are deficient in connexin 30 have expressed on tectal neurons but not on radial glial cells an increase in astrocytic coverage at synapses resulting [10]. Furthermore, in vivo imaging of somatosensory in enhanced glutamate clearance and a decrease in syn- cortex in mice has found that a greater proportion of aptic glutamate concentration [20] (Figure 1). astrocytic processes are displaced after whisker stimula- tion compared to unstimulated mice [8,12]. Notably, Interestingly, the mobility of glutatmate transporters on the increase in stimulation-induced motility was pre- the astroglial cell membrane has been found to be driven vented by group I metabotropic glutamate receptor by neuronal activity [21,22]. Diffusion of GLT-1 (also (mGluR) antagonists, but not by NMDAR blockade. It known as Excitatory Amino Acid Transporter 2) in astro- / was also absent in IP3R2À À mice, which have impair- cytic membranes has been found to slow down near ments in G-protein-mediated calcium transients in astro- synapses, and impairing GLT-1 diffusion mobility results cytes [12]. This last experiment raised important ques- in slowed kinetics of excitatory postsynaptic currents [21] tions about the possible relationship between (Figure 1). Glutamate uncaging at synapses increased intracellular calcium release and astrocytic motility. GLT-1 diffusion, suggesting rapid turnover of transporter at actively releasing synapses. This highlights the fact To further examine the mechanisms mediating astrocyte that astrocytic processes at synapses play an active role in plasticity, activation
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