Regulation of synaptic connectivity by glia.

“A recent study showed that the classical complement cascade, which is part of the innate immune system, helps to mediate synapse elimination in the developing CN”

“Recent gene-expression analysis of astrocytes in vivo showed that astrocytes produce messenger RNAs that encode several synaptic adhesion proteins, such as neurexins, neuroligins and cadherin”

“The extensive structural and functional association of perisynaptic glia with the synapse gave rise to the concept of the 'tripartite synapse', in which synapses are defined as comprising the presynaptic and postsynaptic specializations of the neurons and the glial process that ensheaths the”

“Interestingly, even though TNF-α increased the cell-surface expression of AMPA receptors, long-term potentiation and long-term depression were not affected in its absenc”

“For example, the human brain contains several more populations of astrocytes than the rodent brain, and human astrocytes are up to threefold larger and more ramified than their rodent counterpart”

“Under these conditions, RGCs show little spontaneous synapse activity and form few synapses, whereas RGCs cultured in the presence of a feeding layer of astrocytes or astrocyte-conditioned medium show about tenfold more excitatory synapse activity and a fivefold to sevenfold increase in the number of synapse”

“There are several types in the central nervous system (CNS), including astrocytes, oligodendrocytes and microgli”

“Astrocytes constitute the most abundant glial cells in the human brain [1].”

““Given its ability to interact with multiple molecule types, it is possible that TSPs can not only induce synapse formation but can also modulate presynaptic and postsynaptic function” [111].”

“Glial activity plays an important role in neuroprotection and maintaining tissue homeostasis by regulating metabolism (6), pruning neurites and synapses (7), and clearing pathogens such as the hallmark AD protein, amyloid-beta (Aβ) (8).”

“This idea has been supported by reports using various secreted factors to drive glutamatergic differentiation, where more pure populations of excitatory hPSNs are capable of network bursting [49, 64].”

“…are involved in the healthy development of the central nervous system (CNS), and play an important role in various neurological diseases (Eroglu and Barres, 2010; Höftberger et al., 2010; Jakovcevski et al., 2009; Nedergaard et al., 2003; Saijo and Glass, 2011; Stefanits et al., 2012;…”

“Astrocyte heterogeneity in the CNS has recently been described to influence neuronal synaptogenesis and maturation through secretion of several extracellular matrix proteins (Eroglu and Barres, 2010).”

“Moreover, glial cells in the hippocampus have been shown to be important in LTP and hippocampus-dependent memory tasks (Carmona, Murai, Wang, Roberts, & Pasquale, 2009; Eroglu & Barres, 2010; Yang et al., 2003).”

“As described in the Introduction, integrins—while regulating the astrocytecerebral endothelial cell interactions that occur in the neurovascular unit—also play a role in mediating neuronto-neuron, as well as astroglia-to-neuron, interactions in the CNS [13, 16].”

“The phagocytosis and synaptic pruning abilities of astrocytes are critical for neuronal circuit maturation 3,55,56 .”

“…molecule leads Please cite this article in press as: Spejo, A.B., Oliveira, A.L.R., Synap Neuropharmacology (2014), http://dx.doi.org/10.1016/j.neuropharm.2014 to an aberrant stripping response by microglia, that also removes inhibitory synapses (Eroglu and Barres, 2010; Oliveira et al., 2004).”

“Astrocytes recently shown to be involved in synaptic plasticity at the so-called tripartite synapse (Eroglu and Barres, 2010; Min and Nevian, 2012).”

“…both synaptic assembly (Elmariah, Oh, Hughes, & Balicegordon, 2005; Ullian, 2001) and synaptic physiology in the adult brain (Allen & Barres, 2009; Eroglu & Barres, 2010; Yang, Higashimori, & Morel, 2013), our studies reveal a new role for astrocytes in the circuit modulation of sensory response…”

“Noteworthy, the simulated cholesterol effect on membrane thickness is a realistic biophysical effect consistent with experimental data [57–60].”

“Astrocytes make up a significant portion of the cell population in the CNS and are crucial to the brain’s normal functioning (B elanger, Allaman, & Magistretti, 2011; Eroglu & Barres 2010; Stobart & Anderson 2013).”

“Under normal conditions, products of these genes are necessary for the formation, maturation and stability of synapses and dendritic spines [95, 96].”

“Astrocytes also critically mediate the formation and function of synapses (Ullian et al., 2001; Eroglu and Barres, 2010) and are implicated in the hormone-dependent regression of synapses underlying female receptivity (Garcia-Segura et al., 1999; Garcia-Segura and Melcangi, 2006).”

“Regulation of synapses (12), the clearance of extracellular ions and transmitters (16,17), the control of neuronal metabolism and migration (18–20), the regulation of brain energy supplies (15), neurotrophic factor synthesis and release (21), angiogenesis and immune function in the CNS (22), coping with brain insults…”

“in development and disease [3, 14, 15] and modulate synaptic transmission via glutamate uptake [16].”

“…to information processing within the central nervous system (Haydon and Carmignoto, 2006; Martineau et al., 2006; Iadecola and Nedergaard, 2007; Eroglu and Barres, 2010; Halassa and Haydon, 2010; Pfrieger, 2010; Di Castro et al., 2011; Panatier et al., 2011), including the hypothalamus (Hatton…”

“…they actively contribute to information processing, by shaping and regulating synaptic connectivity and plasticity, as well as by releasing neurotransmitters and gliotransmitters themselves (Ballabh et al , 2004; Attwell et al , 2010; Eroglu & Barres, 2010; Araque et al , 2014; Chung et al , 2016).”

“Astrocytes are involved not only in neuronal support, such as synapse formation and removal under healthy conditions [16,17] but also in the onset and exacerbation of CNS diseases including traumatic brain injury and spinal cord injury.”

“…pruning during development or pathological elimination/loss of synapses during disease, depending on the neuronal network (Perry and O’Connor, 2008; Eroglu and Barres, 2010; Verkhratsky and Nedergaard, 2014; Chung et al., 2013; Tröscher et al., 2019; Kreutzfeldt et al., 2013; Di Liberto et al.,…”

“, 2015), synaptic connectivity (Eroglu and Barres, 2010), and neuronal excitability (Tan et al.”

“The astrocytes contribute to the neuron-neuron signaling by releasing glial transmitters that bind to receptors on both pre- and postsynaptic neuronal structures (Eroglu and Barres, 2010).”

“These observations suggest a crucial role for astrocytes in the experience-dependent structural synaptic changes that underlie learning and memory (Eroglu & Barres, 2010).”

“Synaptic loss is an early hallmark of AD (Hamos et al., 1989; Eroglu and Barres, 2010).”

“29 One study in healthy males found gabapentin increased gamma-aminobutyric acid (GABA) levels—potentially via stimulating glutamic acid decarboxylase activity and inhibiting GABA trans-aminase.”

“It has long been known that the correct formation of the right type and numbers of synaptic connections in the hippocampus constitute the pivotal basis for proper cognitive function [29].”

“…6 June 2016 | Volume 10 | Article 165 We consider that these fragment analyses in a twodimensional image reflect the three-dimensional complexity of astrocytic fine processes; the finer and more complex the astrocytic processes became, the more frequently the GFPpositive fragments occurred.”

“The reduction in glia cell number resulted in a low level of basal AMPAR expression, probably attributable to a lack of glial-released factors that are known to promote AMPAR expression (Ullian et al., 2004; Pfrieger, 2009; Eroglu and Barres, 2010).”

“Astrocytes can, therefore, actively control the activity of neurons (Eroglu and Barres, 2010; Khakh and Sofroniew, 2015).”

“Glial cells are involved in diverse processes at the heart of many neuropsychiatric disorders, from synapse formation, maturation, and pruning to neuroinflammation and blood-brain barrier (BBB) formation (Barres, 2008; Eroglu and Barres, 2010).”

“That said, little is known about the mechanisms underly- ing destabilization and elimination of unnecessary synapses (Eroglu and Barres, 2010; Sanes and Lichtman, 1999).”

“Astrocytes also play important roles in synapsis formation, and plasticity (Clarke and Barres, 2013; Eroglu and Barres, 2010; Papa et al., 2014; Sloan and Barres, 2014), modulating extracellular excitatory neurotransmitter levels (Bergles and Jahr, 1997; Carmignoto, 2000; Domingues et al., 2010;…”

“This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited.”

“, 2012), modulation of synaptic transmission (Simard and Nedergaard, 2004), neuronal connectivity (Eroglu and Barres, 2010), and uptake of potentially pathogenic proteins (Lee et al.”

“…high expression of astrocytic synaptic cell adhesion molecules, including neurexins (Nrxn1), neuroligins (Nlgn1, Nlgn3), and leucine-rich repeat transmembrane proteins (Lrrc4, Lrrc4b), with direct evidence from both common and rare variant associations to schizophrenia 4,5 (Figures 5, 6, and 7).”

“Since astrocytes act as a bridge between blood vessels and neurons [72], ginseng- and ginsenosides-induced increase in healthy astrocytes may facilitate the crosstalk among neurovascular cells, and thus promote angiogenesis, neurogenesis, and synaptogenesis.”

“Interestingly, glial cells also sense and modulate the synaptic activity (19, 20) in addition to the above-mentioned maintenance functions.”

““fncel-08-00012” — 2014/1/29 — 13:42 — page 1 — #1 METHODS ARTICLE published: 30 January 2014 doi: 10.3389/fncel.2014.00012 Novel cell separation method for molecular analysis of neuron-astrocyte co-cultures”

“Astrocytes are the most abundant glial cells in the CNS, representing, with their processes, a critical component of the BBB together with endothelial cells [25].”

“2 responsible for preserving homeostasis as well as many other functions, including the support to neurons, modification of synapse signaling, recycling of neurotransmitters, blood-brain barrier (BBB) regulation and glymphatic clearance (Eroglu and Barres, 2010; Sofroniew and Vinters, 2010).”

“They have been demonstrated to actively participate in, for example, the blood-brain barrier control, neuronal development, neuro-transmitter turnover, synaptogenesis, and immunological response [1,3,11,12].”

“Macrophage infiltration from the periphery into the CNS is minimal under normal physiological conditions; however, greater infiltration has been shown to occur during peak EAE disease coinciding with increased inflammation and symptoms (Jiang et al., 2014).”

“Astrocytes have been well known for the establishment and maintenance of proper synaptic connectivity and networks [12].”

“During this process, microglial processes invade the clefts of axosomatic synapses and disconnect presynaptic input from the surface of the injured neurons (Kreutzberg, 1993; Schiefer et al., 1999), presumably reducing their excitotoxicity (Eroglu and Barres, 2010).”

“…network efficiency in MS. Astrocytes have been described to be powerful controllers of synapse formation, function, plasticity and elimination, and reactive astrocytes in brain injury express molecules that affect synapse formation and, thus, impair neuronal connectivity (Eroglu and Barres, 2010).”

“The brain is made up of trillions of synaptic connections that together form neural networks that underpin whole brain function and behavior (Eroglu and Barres, 2010).”

“…into the functional importance of glial plasticity in circadian timing are derived from knowledge on their role as active partners of neurons in information processing and in regulation of synaptic connections and expression of brain plasticity (Theodosis et al., 2006; Eroglu and Barres, 2010).”

“Astrocytes have many functions in the CNS (recently reviewed by [9–11]), such as regulation of local vasodilation and blood flow, provision of energy metabolites to neurons, participation in synaptic function and plasticity, modulation of neuronal communication, and maintenance of the extracellular balance of ions, fl…”

“Reactive astrocytes were verified to control formation, maintenance, function, and the removal of neuronal synapses (Eroglu and Barres, 2010; Koizumi et al., 2018).”

“INTRODUCTION Glia provide neurons with metabolic and structural support as well as playing a direct role in guiding neuronal development (Eroglu and Barres, 2010; Freeman and Doherty, 2006; Parker and Auld, 2006).”

“[195] C.”

“Astrocytes are glial cells with a variety of homeostatic, synaptic, and neuroprotective functions (Araque et al., 1999; Eroglu and Barres, 2010; Verkhratsky et al., 2019).”

“Astrocytes reportedly participate in inorganic ion homeostasis maintenance, neurotransmitter clearance, metabolic support, blood‐ brain barrier development, response to injury or disease, and synaptic transmission (Barres, 2008; Eroglu & Barres, 2010; Freeman & Rowitch, 2013).”

“To date, glial-derived factors are the best example of synaptogenic cues that act in paracrine fashion (Eroglu and Barres, 2010; Allen and Eroglu, 2017).”

“In addition to these problems, the increasing evidence for the role of glial cells in synaptic firing (e.g., Allen & Barnes, 2005; Auld & Robitaille, 2003; Eroglu & Barres, 2010) suggests that models based solely on neurons and their connections are at best incomplete.”

“Although motor neurons and muscle fibers are the fundamental units of NMJs, terminal Schwann cells also play an essential role in the microenvironment by being involved in synaptogenesis, synaptic activity, regeneration of damaged synapses, and synaptic maturation of NMJs (Eroglu and Barres, 2010; Thomson et al., 2012…”

“Several lines of evidence illustrate the key participation of glial cells during neuronal network formation, in neurogenesis [3,4], neuroblast proliferation [5], neuron migration [6,7], neurite growth and guidance [8,9,10,11,12], as well as in myelination and synapse establishment [13,14,15,16].”