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”

“Disparities between the results of studies investigating the role of COMT and DRD4 in cognitive control may relate to the use of psychiatric populations (Bertolino et al. 2004; Ehlis et al. 2007; Eroglu and Barres 2010; Stefanis et al. 2004; Taerk et al. 2004) or to the effects of other interacting genes (Wishart et a…”

“There is a growing evidence that astrocytes play a role in determining where on the cell surface synapses contact neurons (Bolton and Eroglu, 2009; Eroglu and Barres, 2010; Kucukdereli et al., 2011).”

“While this phenomenon has traditionally been attributed to external processes 79 , the current study adds to the growing body of evidence 80,81 , showing pruning as an intrinsic factor of neuronal network growth that seeks to optimize network efficiency.”

“These interactionsare relevant to injury protection, and infection prevention 2,4 .”

“Astrocytes, the most abundant cell type in the human brain, coordinate synapse formation and elimination, neuronal survival, and axon guidance in the developing brain (Allen and Eroglu, 2017; Eroglu and Barres, 2010; Chung et al., 2015; Verkhratsky et al., 2019).”

“Astrocytes are the major CNS components crucial in maintaining synaptic transmission and neuronal health in homeostasis [171].”

“Third, glial cells ensheathe neuronal cells, including synapses (Eroglu and Barres, 2010), yet these cells are largely not infected, as evidenced by an absence of viral gene expression.”

“So far, only two types of glia cells, named Schwann cells, in the neuromuscular junctions, and astrocytes, in the central nervous system (CNS), have been shown to be associated with synapses and participate in synaptic modulation [4, 18].”

“Astrocyte presence increases synapse formation, maturation, and stabilization [20, 27, 55, 56].”

“Postmortem human and animal studies proved that glial cells contribute to the development and progression of psychiatric disorders and can be potential therapeutic targets [190, 191].”

“Additionally, astrocytes appear to play critical roles in neuronal development through their actions on synaptogenesis and synaptic pruning.(5,6) Recent developments in in vivo imaging technologies have significantly advanced our understanding of the extensive roles these cells play in neurophysiology and neuropatholo…”

“The importance of glial cells for synapse formation is well established [47] but, whereas some of the genes of the Synaptic Transmission sub-catalogue are expressed in neurons and other cells, those in the glia catalogue are expressed exclusively in glial cells [38], suggesting that in spite of their different spatial…”

“…abundant cells in the brain, proliferate at a time in development when synapses are forming (De Graff-Peters and Hadders-Algra, 2006; Bernal, 2007; Eroglu and Barres, 2010), and it is increasingly becoming clear that many of the factors that astrocytes release are crucial for the process of…”

“…culture conditions, contain few astrocytes and fail to develop synchronized bursting activity complements the body of work showing that mature glia are required for efficient synaptogenesis and the maturation of network attributes (Banker, 1980; Eroglu and Barres, 2010; Kucukdereli et al., 2011).”

“The major types of glia are astrocytes, microglia, oligodendrocytes, and Schwann cells (Eroglu and Barres, 2010).”

“Neurotransmission occurs at each of the brain’s nearly 100 trillion synapses and governs every aspect of human life from movement to emotional processing to learning and memory (Schweizer and Ryan, 2006; Eroglu and Barres, 2010).”

“Studies have shown that astrocytes play important roles during the early, middle, and late stages of stroke (Ullian et al., 2001; Christopherson et al., 2005; Koehler et al., 2009; Eroglu and Barres, 2010; Allen et al., 2012; Zhou et al., 2019).”

“Finally, increasing evidence suggests that glia interact with neurons directly at synapses to modify synaptic function (Eroglu & Barres, 2010).”

“Recent reports have shown that TSP mediates synaptogenic activity through its neuronal receptor, the calcium channel Cacna2d1 subunit (Eroglu and Barres, 2010).”

“In addition to their supportive roles, astrocytes have also been shown to control the formation, function and removal of synapses (53, 131), they also are important in the control of blood flow and critical for the maintenance of the blood brain barrier (BBB) (13, 80, 87, 103).”

“They link neuronal activity to blood circulation [2, 15], promote synapse formation [5, 8], and determine the properties of the extracellular matrix [9, 16, 27].”

“Gabapentin is thought to block the binding of TSP-1 and α2δ-1, and in turn, inhibit the formation of synapses [57].”

“Their functions include the maintenance of neurotransmitter homeostasis, synapse formation and metabolic and neurotrophic support for neurons (Rouach et al., 2008; Eroglu and Barres, 2010).”

“Astrocytes are involved in regulating the synaptic function [98, 99].”

“These include glia (microglia, astrocytes and oligodendrocytes), endothelial cells, perivascular macrophages and infiltrating peripheral immune cells such as T cells and monocytes/macrophages (Eroglu and Barres, 2010; Grace et al., 2011; Grace et al., 2014).”

“Also, astrocytes have the ability to control synaptogenesis and modulate synaptic activity and function.(12,13) Although astrocytes are implicated and affected in neurodegenerative diseases and brain injuries, their altered function may contribute to further spread of neurodegenerative changes.”

“…microglialderived soluble factors have been implicated in neuronal tau pathology (Metcalfe and Figueiredo-Pereira, 2010), as well as synapse loss (Eroglu and Barres, 2010), suggesting glial activation may also participate in the observed decrease in synaptophysin and PSD-95 protein expression…”

“Astrocytes regulate synaptic formation, modulate network activity, and provide metabolic support to neurons in vivo (Eroglu and Barres, 2010; Perea et al., 2014; Mederos et al., 2018).”

“Previous studies showed that astrocytes could modulate the neuronal activity by uptake and release of neuroactive molecule such as potassium ion and glutamate in the extracellular space (Eroglu and Barres 2010).”

“These specialized cells play a pivotal role in a variety of physiological pathways, encompassing neurogenesis, synaptic maintenance, and molecular homeostasis (Allen & Lyons, 2018; Eroglu & Barres, 2010; McNeill et al., 2021; Verkhratsky & Nedergaard, 2018).”

“…elements of neurons, contributing to the communication between astrocyte and neuron, regulating the synaptic transmission and plasticity (Allen & Barres, 2009; Dityatev & Rusakov, 2011; Eroglu & Barres, 2010; Gruber, 2009; Halassa et al., 2007; Perea et al., 2009; Volterra & Meldolesi, 2005).”

“In addition to the influence on synaptic plasticity [93], there is emerging evidence of the complexities of astrocyte heterogeneity throughout and within brain regions, which could provide further nuance to their physiological role [94].”

“They have a variety of essential roles including glutamate and potassium buffering, axonal guidance, trophic support, astrocyte-mediated inflammatory response, wound healing, formation of the blood-brain barrier, neuronal synapse formation, and plasticity [3,4].”

“Recent studies have revealed new roles of astrocytes (49-52).”

“Also, crosstalk between astrocytes and neurons has been identified to actively control brain homeostasis, neuronal metabolism, and synaptic connectivity [195,196], which align with the functions of these Delayed and Late upregulated DEGs.”

“Astrocytes in particular are well placed to detect changes in neuronal activity and engulf synapses due to the close association of perisynaptic astrocytic processes (PAPs) with the synaptic cleft (Chung, Baldwin, and Allen 2024; Eroglu and Barres 2010; N.- S. Kim and Chung 2023).”

“Within the human brain, astrocytes have different essential roles including support and guidance for migrating neurons, regulation of the cerebral blood flow [4] and maintenance of neurotransmission homeostasis [5].”

“Astrocytes make up the majority of glial cells within the brain (Eroglu and Barres, 2010).”

“A number of studies have established synaptogenic roles for astrocyte-conditioned medium (ACM) by secreting synaptogenic molecules including proteins, lipids, and small molecules (reviewed in [21, 23].”

“…astrocytes, regulate and support neurons at the tripartite synapse, are involved in synaptogenesis, synaptic pruning, neuronal branching, and the release and regulation of metabolites, neuro- and gliotransmitters and neurotrophic factors (Eroglu & Barres, 2010; Harada, Kamiya, & Tsuboi, 2016).”

“…understood, although they are thought to encompass a combination of transcriptional programs and a battery of molecular signals that seem to be regulated both developmentally and regionally, in a cell-specific manner (Jadhav et al, 2009; Eroglu and Barres, 2010; Götz, 2013; Stassart et al, 2013).”

“All these studies have been conceptualized in several important reviews [20,21], which portray astrocytes as the major regulators of synaptic formation, maturation and elimination.”

“…neuronal synapse formation and length, and some glia cells have receptors for neurotransmitters, being able to modulate neuronal activity and synaptic plasticity in both physiological and pathological conditions (Allen 2013, Ben Achour and Pascual 2010, Eroglu and Barres 2010, Haydon 2001).”

“melanogaster have identified specific glial subtypes that are hypothesized to perform functions similar to vertebrate glia, ranging from phagocytosis to neurotrophic support, signifying the important role that these enigmatic cells have within the CNS [10,11].”

“Measurements of glial surface density (Table S1) show that layer 1 of the (69) piriform cortex has a greater number of glial cells and astrocytes (Figs.”

“Astrocytes play a crucial non-cell-autonomous role in supporting neurons by regulating the extracellular environment, providing essential metabolic resources, and clearing extracellular debris and neurotransmitters 1 – 4 .”

“…factors (e.g., cholesterol, integrins, thrombo-spondins), and synaptic maturation and pruning (by supporting the stability of dendritic spines), and dynamic remodelling, which is essential for memory consolidation (Verkhratsky and Nedergaard, 2018; Eroglu and Barres, 2010; Eroglu et al., 2009).”

“Also, as a synaptic gap separates presynaptic and postsynaptic cells, 49 IL separates the two reaction sites in IL-PRD.”

“Astrocytes also secrete a variety of growth factors and extracellular matrix proteins that modulate the direction of axon growth and extent of synapse formation (Eroglu and Barres, 2010).”

“In the brain, a memory affects the formation of another memory in a neural network with accompanying environments of the chemical field by glial cells [22].”

“Astrocytes are a type of glial cell involved in synaptic transmission and the formation and maturation of synapses; thus, they are a constitutive element of the tripartite synapse (Allen and Barres., 2009; Eroglu and Barres, 2010; Perea et al., 2009).”

“Astrocyte processes are known to form intimate contacts with neuronal synapses ensheathing sites of neurotransmitter release and regulating synaptic efficacy and plasticity (Eroglu and Barres, 2010).”

“However, it would be of significant interest to know whether the genotype effect remains as pronounced if NRXN1 hiPS cell-derived neurons were cocultured with astrocytes, which promote neuronal maturation [8,9].”

“While recent studies also point towards roles of astrocytes in the deletion of synapses (Eroglu and Barres, 2010),”

“Glial cells not only are affected by neurotransmitters secreted from neurons, but also impact on synaptic functions by secreting several molecules that modify neuronal activities [63,75].”

“…cues that direct synaptic differentiation at CNS synapses is considerably large (see Waites et al., 2005; Craig et al., 2006; Fox and Umemori, 2006; Eroglu and Barres, 2010; JohnsonVenkatesh and Umemori, 2010; Jones et al., 2011; Kucukdereli et al., 2011; Terauchi and Umemori, 2011), however…”

“In turn, neuronal cues such as synaptic activity and cell-cell adhesion instruct astrocytes ’ morphological and functional maturation, revealing a rich and bidirectional signaling betweenastrocytesandneuronsthatgovernsbraindevelopment 52,59,62 – 68 .”

“8,9 In particular, astrocytes and microglia mediate the pruning of excess synaptic connections to form eye-specific territories in the visual system during the first postnatal week.”

“This targeted stripping of excitatory inputs is thought to mitigate excitotoxicity, thereby promoting neuronal survival and axon regeneration [34, 38, 39].”

“In addition, about 13% of NASA mRNAs were relatively enriched in glia cells ( Figure 6—figure supplement 2 ), which is consistent with the notion that processes of glia cells contribute to formation of the tripartite synapses ( Perea et al., 2009 ; Eroglu and Barres, 2010 ).”

“Glial factors modulate synapse formation, maintenance, and plasticity (Eroglu and Barres, 2010; Allen and Eroglu, 2017; Chung et al., 2024).”

“22, 94 , and glial dysfunction has arisen as a powerful modulator of AD pathogenesis ( reviewed in Our differential gene expression analysis indicated that 6-month mice have smaller target gene log2FC values compared to 12-month mice, a finding independent of the number of nuclei per condition and…”

“Therefore, neurons and astrocytes may have responded to TIS by rewiring their networks at synapses (Eroglu and Barres, 2010).”

“Astrocytes are the most abundant glial cell type in CNS, constitute a heterogeneous cell population and could maintain neural homeostasis [23].”