Abstract
Neuronal plasticity is critical for the maintenance and modulation of brain activity. Emerging evidence indicates that glial cells actively shape neuroplasticity, allowing for highly flexible regulation of synaptic transmission, neuronal excitability, and network synchronization. Astrocytes regulate synaptogenesis, stabilize synaptic connectivity, and preserve the balance between excitation and inhibition in neuronal networks. Microglia, the brain-resident immune cells, continuously monitor and sculpt synapses, allowing for the remodeling of brain circuits. Glia-mediated neuroplasticity is driven by neuronal activity, controlled by a plethora of feedback signaling mechanisms and crucially involves extracellular matrix remodeling in the central nervous system. This review summarizes the key findings considering neurotransmission regulation and metabolic support by astrocyte-neuronal networks, and synaptic remodeling mediated by microglia. Novel data indicate that astrocytes and microglia are pivotal for controlling brain function, indicating the necessity to rethink neurocentric neuroplasticity views.
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Introduction
Neuroplasticity is a key to understanding brain development, learning, and homeostatic regulation in the central nervous system (CNS). In a broad sense, the term “neuroplasticity” refers to the ability of nervous tissue to change during normal functioning or in pathology. The mechanisms of neuronal plasticity include modulation of synaptic strength (i.e., synaptic plasticity), structural remodeling, and adjustment of intrinsic neuronal properties such as excitability or firing rate. Although neuroplasticity is traditionally associated with neuron-based pathways, recent experimental data emphasize the role of regulatory mechanisms involving glial cells and the brain extracellular matrix (ECM). In the mature brain, neurogenesis and axonal sprouting are inhibited by the ECM [1], but gliogenesis remains active [2]. Ample evidence indicates that glia (meaning “glue” in Greek) are vividly interacting brain cells that communicate via gap junctions and cytokines in health and disease [3]. The four major glial cell populations in the CNS are NG2-glia, oligodendrocytes, astrocytes, and microglia. NG2-glia is essential for the renewal of glial cells (for review, see [4]), and oligodendrocytes are required for myelin formation (for review, see [5]). Neurons and glial cells collectively shape the brain ECM [6], which is an important mediator of intercellular signaling in the extracellular space [7]. ECM is mainly composed of polysaccharides and proteoglycans that act as extracellular scaffolds and provide a highly regulated environment for intercellular communication by regulating the diffusion of metabolites and signaling molecules [8]. ECM components regulate the hydrodynamics of the extracellular space, compartmentalize cell surfaces, and bind signaling mediators. The conventional classification of ECM in the brain parenchyma includes synaptic, interstitial, and condensed matrices of perineuronal nets [9, 10]. The different neuroplasticity-regulating properties of these matrices may vary based on their molecular composition and localization. While astrocytes produce a major part of ECM components, microglia remodel the ECM during neuroinflammation and physiological immune surveillance in the brain. In this review, we highlight the critical role of astrocytes, microglia, and ECM in the regulation of neuronal activity and plasticity at different organizational levels—from single synapses to networks.
Astrocytic cradle of the synapse
Astrocytes received their name in the late nineteenth century because of the stellate appearance that was revealed by Camillo Golgi and Santiago Ramón y Cajal using the silver-chromate and gold chloride-sublimate techniques, correspondingly [11]. Today, immunohistochemical labeling of glial acidic fibrillary protein (GFAP), which remains one of the most widely used astrocytic marker proteins, shows similar star-like morphology. However, dye-filling techniques and genetic labeling of astrocytic membrane proteins reveal a dense pattern of highly ramified branches [12]. Therefore, the ground truth is that astrocytes are rather dandelion like than stellate. The thin astrocytic processes enwrap presynaptic terminals and dendritic spines of excitatory synapses [13], creating the spongiform microdomains [14] that provide the structural background for local astrocyte-synapse communication. Emphasizing the intimate proximity between the astrocyte and the synapse, astrocytic perisynaptic processes are called astrocytic cradles [15]. The essential role of astrocytic cradles for controlling synaptic transmission is reflected by the tripartite synapse concept [16] and summarized in Fig. 1.
Graphical summary of neuroplasticity mechanisms mediated by glia. Intimate interactions between astrocytes, microglia, and ECM allow for dynamic control of neuronal activity and synaptic transmission. While astrocytes regulate neuronal function by providing metabolic support, modulating neurotransmission, and producing ECM, microglia can sculpt neuronal synapses in an activity-dependent manner. Abbreviations: αKG, α-ketoglutarate; ATP/ADP, adenosine tri- and diphosphate; AMPAR, AMPA receptor; D-ser, D-serine; EAAT, excitatory amino acid transporter; ECM, extracellular matrix; EPSC, excitatory postsynaptic current; IPSC, inhibitory postsynaptic current; G6P, glucose-6-phosphate; GABAAR, ionotropic GABA receptor A; GABABR, metabotropic GABA receptor B; GAT3, GABA transporter 3; Glu, glutamate; Gln, glutamine; GLUT1, glucose transporter 1; IL33, interleukin 33; mGluR, metabotropic glutamate receptor; MMPs, matrix metalloproteases; MCT, monocarboxylate transporter; NMDAR, NMDA receptor; OXPHOS, oxidative phosphorylation; P2YR, purinergic P2Y receptor; SNAT, sodium-coupled neutral amino acid transporter; SS, succinic semialdehyde; TCA cycle, tricarboxylic acid cycle (Krebs cycle)
In tripartite synapses, astrocytes enhance the adhesion between pre- and postsynaptic membranes. While the key synaptic adhesion molecules of the neurexin-neuroligin complex are predominantly synthesized by neurons, astrocytes produce ephrins, integrins, and cadherins, and promote the expression of other cell adhesion molecules of the immunoglobulin superfamily (IgCAMs) including SynCAMs and NCAMs to further stabilize the synapse. The adhesion molecules released by astrocytes promote the formation and stabilize synapses, which makes them essential for maintaining synaptic transmission [17]. Astrocytes also produce glypicans, the heparan sulfate proteoglycans that induce the formation of functional synapses and modulate synaptic plasticity by promoting glutamate receptor clustering [18]. In addition, astrocytes produce other ECM proteins such as thrombospondins and hevin, which have been shown to regulate synapse formation and stability. For a more exhaustive review of cell adhesion in the tripartite synapse, see [19]. The synaptic ECM components produced by astrocytes have long lifetimes [20, 21] and actively modulate synaptic activity [22]. The implications of ECM in synaptic activity regulation have led to the emergence of the more recent tetrapartite synapse concept [23].
On a functional level, astrocytic cradles dynamically control neurotransmitter concentration. Perisynaptic astrocytic membranes create diffusion barriers that limit the spillover of neurotransmitters [24] and express excitatory amino acid transporters (EAATs). EAAT1 (also known as GLAST1 and SLC1A3) and EAAT2 (also known as GLT1 and SLC1A2) mediate rapid reuptake of glutamate, thereby shaping postsynaptic current responses [25]. The expression and uptake capacity of these transporters depend on neuronal activity [26, 27] and are regulated by astrocytic Ca/calmodulin-dependent kinase CaMKII [28, 29]. Interestingly, EAATs 1 and 2 can be synthesized locally in the astrocytic processes [30], which allows for the fast upregulation of glutamate reuptake if necessary.
Inhibitory synapses are predominantly established directly on neuronal somas or dendritic shafts and rarely localize to dendritic spines [31]. To the best of our knowledge, there is no direct evidence of astrocytic cradle formation around inhibitory synapses. However, astrocytes actively sequester GABA from the perisynaptic space via the high-affinity GABA transporter GAT3 [32], providing a reuptake mechanism similar to those for glutamate. Thus, neurotransmitter uptake by astrocytes regulates both excitatory and inhibitory signaling in neuronal networks.
Gliotransmission and neuronal activity regulation
Astrocytes regulate neuronal activity not only by removing neurotransmitters from the extracellular space but also by releasing them in an activity-dependent manner. To describe this mechanism, the term “gliotransmission” has been coined, and the neurotransmitters released from astrocytes are commonly called gliotransmitters [33]. Astrocytes express membrane receptors for the vast majority of mammalian neurotransmitters [34], and, although they do not generate neuron-like action potentials, astrocytes respond to neurotransmitter application and neuronal stimulation (e.g., after sensory stimuli) with transient elevations of intracellular Ca2+ concentrations [35, 36]. Analyzing Ca2+ signals, also called Ca2+ events, is currently the key method for understanding the physiology of astrocyte-neuronal interactions [37, 38]. Depending on the strength of neuron-to-astrocyte stimulation, Ca2+ events may localize to the peripheral astrocytic processes (microdomain activity) or spread over the entire cell and its neighbors (global events or waves). While the microdomain Ca2+ activity can be triggered by membrane transporters and ion channels [39], the major Ca2+ events are mediated by inositol triphosphate (IP3) signaling and store-operated Ca2+ release [40]. In the seminal works [41, 42], the Ca2+ waves were detected in cultured astrocytes after norepinephrine (NE) application or after prolonged electrical stimulation. More recent in vivo experiments identified the critical importance of astrocytic calcium signaling for neuronal activity regulation [43,44,45].
Ca2+ events trigger the release of gliotransmitters, which regulate synapse activity locally, heterosynaptically, or globally by potentiating or inhibiting synaptic transmission and neuronal excitability (for review, see [33, 46]). Interestingly, astrocytes use similar molecular machinery for the vesicular release of gliotransmitters [47, 48]. In excitatory synapses, the release of astrocytic glutamate and D-serine mediates synaptic potentiation [48,49,50] and stimulates the barrage firing of inhibitory interneurons [51]. On the other hand, ATP/adenosine release from astrocytes stimulated by both excitatory and inhibitory activity induces heterosynaptic suppression of glutamatergic synapses [43, 52]. In inhibitory synapses, GABA stimulates astrocytic GABAB receptors, induces long-lasting Ca2+ oscillations [53], and stimulates excitatory neurotransmission via glutamate release [54]. Conversely, GAT3 transporter activity following GABAergic stimulation induces astrocytic ATP release and inhibitory synapse potentiation [55]. Gliotransmission therefore can act as a jack of all trades in neuronal activity regulation. However, the selection mechanisms determining astrocytic responses to neuronal stimulation remain largely unknown.
The described mechanisms of neuron-glia interactions provide flexible modulation of neuroplasticity and indicate a high capability of brain networks for self-regulation. Due to technical difficulties, most experimental studies that we reviewed here were conducted on the sub-cellular and cellular levels, making it yet challenging to conclude how the key neuroplasticity mechanisms mediated by glia integrate on the functional network level. Emerging evidence indicates that astrocytic signaling is essential for neuronal synchronization and inhibitory network refinement [56, 57]. Astrocytes can modulate the efficacy of both excitatory and inhibitory synapses, thereby extending the dynamic range of neuroplasticity and increasing the computational power of local circuits [57] by tuning the excitation-inhibition balance. Recently, it was shown that astrocytes encode spatial information, and the expected reward location can be decoded from their activity in an awake mouse brain [58]. Based on the available data, we propose that multicellular interactions in neuron-glial networks promote ranged propagation of inhibition and excitation and support excitation-inhibition balance in local neuronal networks (Fig. 2).
Although single astrocytes occupy distinct territories and establish non-intersecting islands of synaptic regulation [59], they are functionally connected into a syncytium-like network by gap junctions [60]. Astrocytic coupling via connexin 43 and 30 channels allows for intercellular Ca2+ signaling and metabolic coupling, which is necessary for preventing epileptiform activity [61, 62].
Through gap junctions, the traveling Ca2+ events may transfer excitatory or inhibitory stimuli from the territory of one astrocyte to another. Thereby, astrocytic networks can regulate neuronal synchronization on a slower time scale than provided by synaptic neurotransmission. Neurotransmitter release from the astrocytes is less area restricted than synaptic release and can therefore affect extrasynaptic receptors of multiple neurons within the astrocytic territory [56], thereby regulating the excitation-inhibition balance without remodeling synaptic connectivity. Tonic inhibition by astrocytic GABA release [63, 64] and the efflux of chloride via astrocytic GABAA channels [65] efficiently modulates network inhibition. Similarly, excitatory gliotransmission and stimulation of extrasynaptic AMPA and NMDA receptors [33, 46] can contribute to spreading excitation.
Potassium buffering in astrocytes and perineuronal nets
While the control over neurotransmitter concentrations regulates the amplitude, frequency, and dynamics of postsynaptic responses, neuronal excitability, and firing patterns depend on the astrocytic capacity for buffering K+ ions. Extracellular K+ concentration changes the equilibrium potential for this ion, thereby affecting the repolarization and hyperpolarization phases of the action potential. In absence of astrocytes, accumulation of extracellular K+ during neuronal activity will depolarize the neuronal membrane, inducing tonic spike firing and eventually blocking neuronal activity and conductivity. To prevent these detrimental effects, astrocytes buffer up to 80% of the released K+ via Kir4.1 channels [66]. Ki4.1-mediated K+ buffering works in concert with astrocytic glutamate transporters and Na+/K+-ATPases [67], thereby maintaining ionic homeostasis in the extracellular space.
In a subpopulation of fast-spiking interneurons, the interstitial brain ECM condensates into peculiar structures known as perineuronal nets [9]. Neuronal activity consolidates the diffusely expressed polyanionic macromolecules into densely packed lattice-shaped layers that can sequester K+ ions extracellularly [68, 69]. The reduced synthesis of hyaluronan, which is one of the largest anionic polysaccharides in the extracellular space, causes altered neuronal activity and seizures [8]. Therefore, both astrocytic Kir4.1 channels and polyanionic ECM are critical for K+ buffering and neuronal activity maintenance.
Metabolic regulation of neuronal activity
Neurons are arguably the most energy-demanding cells of the body that do not maintain their own consumption of metabolites. Neuronal metabolism is dominated by mitochondrial oxidative phosphorylation (OXPHOS), which has the highest ATP production efficiency among known metabolic pathways [70]. Glycolysis is strongly downregulated in mature neurons, making them dependent on the import of lactate via the astrocyte-neuron lactate shuttle pathway (Fig. 1). In contrast, astrocytes predominantly use glycolysis that supports the biosynthesis of lipids, nucleotides, and amino acids, and produce ample amounts of lactate [71]. Under normal conditions, astrocytic glycolysis is fueled by glucose uptake from the blood via glucose transporter GLUT1. Astrocytic glycolysis is pivotal for brain function, and, in case of altered glucose supply from the blood (e.g., in stroke), astrocytes can temporarily sustain glycolysis by deriving glucose-6-phosphate (G6P) from glycogen granules in their cytoplasm [72]. At the last step of glycolysis, astrocytes convert most of the produced pyruvate into lactate, which is released into the extracellular space by the monocarboxylate transporters MCT1 and MCT4. Neurons import extracellular lactate using MCT2 and convert it back to pyruvate for fueling the mitochondrial tricarboxylic acid (TCA) cycle and OXPHOS. Thereby, astrocyte-neuron lactate proves the key source of energy for the maintenance of neuronal activity.
In postsynaptic neurons, lactate potentiates NMDAR-mediated currents [73] by increasing NADH/NAD+ ratio. NMDAR potentiation by lactate depends on the redox sensitivity of the NR1 subunit [74] and is required for long-term memory formation [75]. Therefore, the transfer of lactate by the astrocyte-neuron lactate shuttle is an essential metabolic mechanism of neuroplasticity.
Neurotransmitters released during neuronal activity provide another crucial substrate for astrocytic metabolism. Following the uptake of glutamate via EAATs, glutamine synthase (GS) catalyzes the condensation of glutamate and ammonia to form glutamine. The importance of this reaction is evidenced by the ample expression of GS in astrocytes. With minor limitations, GS can be considered an astrocytic marker protein [76]. Astrocytic glutamine can be transferred to neurons by several transporter systems (for review, see [77]), of which sodium-coupled neutral amino acid transporters SNAT3 and SNAT5 (also known as SN1 and SN2, correspondingly) localize on the astrocytic membranes, and SNAT1 (also known as SAT1) and SNAT7 are predominantly neuronal [78]. In neurons, glutamine is converted back to glutamate by phosphate-activated glutaminase (PAG), thereby creating the astrocyte-neuronal glutamate-glutamine cycle [79], as shown in Fig. 1. GABA enters the glutamate-glutamine cycle via the TCA cycle through conversion to succinic semialdehyde (SS) and succinate in astrocytic mitochondria [80]. Glutamate is then synthesized from α-ketoglutarate and converted to glutamine by GS. In inhibitory neurons, astrocytic glutamine is one of the main precursors of GABA synthesis [81].
Glutamine transport supports synaptic plasticity by providing the essential substrate for neurotransmitter synthesis in both glutamate- and GABAergic neurons [82]. Genetic disruption of SNAT1 hampered neuronal GABA synthesis and impaired neurotransmission, plasticity, and cortical processing [83] in mice. Inhibition of GS results in reduced synaptic efficacy and altered long-term potentiation (LTP) [84]. Conclusively, the astrocyte-neuronal glutamate-glutamine cycle is critical for neurotransmission and neuroplasticity regulation.
Remodeling synaptic connectivity in the adult brain
Neuronal networks generate complex activity patterns that require not only the adjustment of synaptic strengths but also the dynamic remodeling of synaptic connectivity. Essential connectivity is established in the juvenile brain before the end of the critical plasticity period [85], which is signified by the maturation of excitatory and inhibitory neuronal networks [86] and the enrichment of plasticity-restricting components of the ECM [87]. Removing and establishing synapses in the mature CNS is mediated by microglia, the immune cells of the brain, and requires their coordinated interaction with astrocytes and ECM.
In the adult brain, both interstitial matrix and perineuronal nets contain axon-repelling chondroitin sulfate glycosaminoglycans (CSPGs) and semaphorins, which restrict new synapse formation [88, 89]. Thereby, CSPG-rich zones such as perineuronal nets compartmentalize neuronal surfaces and create permissive and restrictive microdomains that allow for highly precise targeting of the newly formed synapses. At the same time, ECM integrity is essential for maintaining inhibitory control in neuronal networks, and the depletion of ECM triggers excessive synchronization of neuronal activity [90]. Therefore, retaining excitation-inhibition balance during synaptic reorganization requires restricted ECM degradation that is confined by the area of remodeling. This locality can be achieved through the controlled release of matrix metalloproteases (MMPs) by glial cells [91] and highly accurate synapse elimination by microglia [92, 93].
Microglia are brain-resident macrophages [94] that continually survey the microenvironment [95] and rapidly detect tissue damage [96] or neuronal activity changes [97]. Neuronal activity promotes microglial surveillance via norepinephrine [98] and GABA signaling [99]. Microglial processes establish intercellular junction contacts with neuronal bodies [97]. Within these contacts, microglial purinergic receptors are co-clustered with neuronal potassium channels, creating a specialized nano-architecture optimized for purinergic cell-to-cell communication. Since the activity of a neuron highly correlates with mitochondrial ATP production, the microglia-neuron junctions allow for the rapid stimulation of microglia via ATP/ADP signaling. In stimulated microglia, Ca2+ signaling attunes to neuronal activity [100]. Neuronal interleukin 33 (IL33) regulates microglial activity under physiological conditions and promotes the phagocytosis of ECM components by microglia [101]. Neuronal activity regulates microglial phagocytosis [92], but, to the best of our knowledge, evidence for activity-dependent ECM remodeling by microglia is lacking currently. Although further studies are required to decipher the role of microglia-ECM interactions in synaptic remodeling, the available data suggests that microglia can locally remodel ECM, eliminate synapses, and promote synaptic plasticity depending on neuronal activity. Of note, inhibitory synapses are preferentially sculpted by GABA-receptive microglia involving GABABR-mediated signaling [102].
The specificity of activity-dependent synapse elimination is ensured by the phagocytic complement components C1q and C3 in microglia [92] and by exposure of phosphatidyl serine and pentraxins on presynaptic membranes [103, 104]. While the expression of microglial C1q/C3 can be induced by neuronal and astrocytic IL33 release [101, 105], the regulatory mechanisms of presynaptic expression of pentraxins and phosphatidyl serine remain to be understood.
As key mediators of synaptic remodeling, microglia cells contribute to the maintenance of excitation-inhibition balance on the network level. The patrolling function of microglia is regulated by extracellular chemokines including ATP [106, 107] and fractalkine [108, 109], which allow these cells to travel significant distances in the brain parenchyma [95, 110]. Due to the high mobility, a single stimulated microglia cell can potentially remodel multiple synapses and contribute to ranged modulation of excitation and inhibition. Microglia shape the developing neural circuits by engulfing excessive immature synapses via the complement receptor 3(CR3)/C3-dependent phagocytosis [92], a mechanism that is essential for normal synaptogenesis during brain development [111]. Interestingly, a similar mechanism contributes to pathological synapse loss due to upregulated microglial phagocytosis in Alzheimer’s disease [112]. In a healthy brain, microglia can also shape synaptic connectivity using complement-independent mechanisms including trogocytosis [93] and TWEAK signaling [113].
While the possibility of establishing new synapses in mature neuronal networks can be attributed to the local ECM degradation and synapse elimination by microglia, the capability of establishing new synapses is defined by the regulatory molecules produced by astrocytes [114]. Thrombospondin 1 (TSP1) induces the formation of structurally complete but functionally silent synapses. The establishment of active synapses requires the enrollment of glypicans 4 and 6 (GPC4/6) and hevin (also known as secreted protein acidic and rich in cysteine (SPARC) like 1, or SP1). The synaptogenic function of hevin is antagonized by SPARC [115], which is locally synthesized in astrocytic processes [30], allowing for the dynamic control of new synapse formation.
Collectively, the available evidence suggests that synaptic remodeling is likely orchestrated in three steps: local ECM degradation, synapse elimination by microglia, and astrocyte-mediated synapse formation. To support this hypothesis, further research is needed.
Neuroinflammation and neuroplasticity
The mechanisms of homeostatic brain activity regulation that we reviewed here can be severely altered by inflammatory signaling in multiple neurological diseases. For example, in stroke, neuroinflammation contributes to both damage and remodeling of brain tissue [116]. In both acute and chronic stroke phases, peripheral blood immune cells invade the ischemic brain parenchyma [117, 118], and preclinical studies indicate that immunomodulatory treatments can promote neurological recovery post stroke [119]. After the onset of cerebral ischemia, the release of alarmins [120] and cytokines triggers the pro-inflammatory microglia phenotype [121], which, in turn, can promote the neurotoxic phenotype in reactive astrocytes [122]. A recent study [123] has demonstrated that the neurotoxicity of ischemic astrocytes involves metabolic switching mediated by STAT3 activation. Post-stroke reactive gliosis alters interstitial ECM composition in the brain, which includes the upregulation of short-chain hyaluronan [124] and tenascin-C [125]. As an endogenous ligand of toll-like receptor 4 and inflammatory regulator, tenascin-C regulates morphological alterations in reactive glia [125, 126]. Post-stroke ECM remodeling also involves perineuronal nets [127, 128], and their transient degradation may support neurological recovery.
Neuroinflammation induces similar alterations in reactive glia and ECM in multiple neurodegenerative diseases including Alzheimer’s, Huntington’s, and multiple sclerosis. In Alzheimer’s disease, the release of amyloid-b induces microglial reprogramming and activation [129], which causes synaptic degeneration by complement-mediated microglial phagocytosis [112]. Activated microglia upregulate multiple ECM-degrading enzymes during neuroinflammation [130]. Most likely, the release of extracellular proteases from reactive microglia contributes to the decomposition of perineuronal nets in Alzheimer’s and Huntington’s diseases [131, 132]. Multiple studies using the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis demonstrated that the prolonged reactivity in microglia and astrocytes induces neurodegeneration [133, 134]. A recent study demonstrated that ECM composition in EAE altered due to the compromised glycosaminoglycan metabolism [135], showing that multiple sclerosis progression is associated with the reduced expression of 4-sulfated chondroitin sulfates and the increased synthesis of hyaluronic acid.
The lack of an in-depth mechanistic understanding of ECM-glia interactions during neuroinflammation hinders the development of novel therapies for neurodegenerative diseases. However, we believe that the ongoing studies in the field will propose promising translational approaches in the future.
Concluding remarks
Interactions between neurons, glia, and ECM allow for highly flexible modulation of neuronal plasticity. Ample evidence indicates that neuroplasticity is not restricted to neurons, and, in certain cases, can be dominated by glia. With multiple questions that remain open, future research on glia-mediated neuroplasticity will extend the current understanding of brain activity regulation.
References
Fawcett JW (2015) The extracellular matrix in plasticity and regeneration after CNS injury and neurodegenerative disease. Prog Brain Res 218:213–226
Rusznak Z, Henskens W, Schofield E, Kim WS, Fu Y (2016) Adult neurogenesis and gliogenesis: possible mechanisms for neurorestoration. Exp Neurobiol 25(3):103–112
Domingues HS, Portugal CC, Socodato R, Relvas JB (2016) Oligodendrocyte, astrocyte, and microglia crosstalk in myelin development, damage, and repair. Front Cell Dev Biol 4:71
Dimou L, Gallo V (2015) NG2-glia and their functions in the central nervous system. Glia 63(8):1429–1451
Bergles DE, Richardson WD (2015) Oligodendrocyte development and plasticity. Cold Spring Harb Perspect Biol 8(2):a020453
Dzyubenko E, Gottschling C, Faissner A (2016) Neuron-glia interactions in neural plasticity: contributions of neural extracellular matrix and perineuronal nets. Neural Plast 2016:5214961
Nicholson C, Hrabětová S (2017) Brain extracellular space: the final frontier of neuroscience. Biophys J 113(10):2133–2142
Arranz AM, Perkins KL, Irie F, Lewis DP, Hrabe J, Xiao F, Itano N, Kimata K, Hrabetova S, Yamaguchi Y (2014) Hyaluronan deficiency due to Has3 knock-out causes altered neuronal activity and seizures via reduction in brain extracellular space. J Neurosci 34(18):6164–6176
Fawcett JW, Oohashi T, Pizzorusso T (2019) The roles of perineuronal nets and the perinodal extracellular matrix in neuronal function. Nat Rev Neurosci 20(8):451–465
Frischknecht R, Seidenbecher CI (2008) The crosstalk of hyaluronan-based extracellular matrix and synapses. Neuron Glia Biol 4(3):249–257
Hubbard JA, Binder DK (2016) History of Astrocytes. In: Hubbard JA, Binder DK (eds) Astrocytes and epilepsy. Academic Press, San Diego, pp 1–38
Lanjakornsiripan D, Pior BJ, Kawaguchi D, Furutachi S, Tahara T, Katsuyama Y, Suzuki Y, Fukazawa Y, Gotoh Y (2018) Layer-specific morphological and molecular differences in neocortical astrocytes and their dependence on neuronal layers. Nat Commun 9(1):1623
Gavrilov N, Golyagina I, Brazhe A, Scimemi A, Turlapov V, Semyanov A (2018) Astrocytic coverage of dendritic spines, dendritic shafts, and axonal boutons in hippocampal neuropil. Front Cell Neurosci 12:248
Arizono M, Inavalli V, Panatier A, Pfeiffer T, Angibaud J, Levet F, Ter Veer MJT, Stobart J, Bellocchio L, Mikoshiba K, Marsicano G, Weber B, Oliet SHR, Nagerl UV (2020) Structural basis of astrocytic Ca(2+) signals at tripartite synapses. Nat Commun 11(1):1906
Verkhratsky A, Nedergaard M (2014) Astroglial cradle in the life of the synapse. Philos Trans R Soc Lond B Biol Sci 369(1654):20130595
Perea G, Navarrete M, Araque A (2009) Tripartite synapses: astrocytes process and control synaptic information. Trends Neurosci 32(8):421–431
Dalva MB, McClelland AC, Kayser MS (2007) Cell adhesion molecules: signalling functions at the synapse. Nat Rev Neurosci 8(3):206–220
Allen NJ, Bennett ML, Foo LC, Wang GX, Chakraborty C, Smith SJ, Barres BA (2012) Astrocyte glypicans 4 and 6 promote formation of excitatory synapses via GluA1 AMPA receptors. Nature 486(7403):410–414
Hillen AEJ, Burbach JPH, Hol EM (2018) Cell adhesion and matricellular support by astrocytes of the tripartite synapse. Prog Neurobiol 165-167:66–86
Fornasiero EF, Mandad S, Wildhagen H, Alevra M, Rammner B, Keihani S, Opazo F, Urban I, Ischebeck T, Sakib MS, Fard MK, Kirli K, Centeno TP, Vidal RO, Rahman RU, Benito E, Fischer A, Dennerlein S, Rehling P et al (2018) Precisely measured protein lifetimes in the mouse brain reveal differences across tissues and subcellular fractions. Nat Commun 9(1):4230
Dankovich TM, Rizzoli SO (2022) The synaptic extracellular matrix: long-lived, stable, and still remarkably dynamic. Front Synaptic Neurosci 14:854956
Dityatev A, Schachner M, Sonderegger P (2010) The dual role of the extracellular matrix in synaptic plasticity and homeostasis. Nat Rev Neurosci 11(11):735–746
Dityatev A, Rusakov DA (2011) Molecular signals of plasticity at the tetrapartite synapse. Curr Opin Neurobiol 21(2):353–359
Sykova E (2001) Glial diffusion barriers during aging and pathological states. Prog Brain Res 132:339–363
Murphy-Royal C, Dupuis JP, Varela JA, Panatier A, Pinson B, Baufreton J, Groc L, Oliet SH (2015) Surface diffusion of astrocytic glutamate transporters shapes synaptic transmission. Nat Neurosci 18(2):219–226
Benediktsson AM, Marrs GS, Tu JC, Worley PF, Rothstein JD, Bergles DE, Dailey ME (2012) Neuronal activity regulates glutamate transporter dynamics in developing astrocytes. Glia 60(2):175–188
Poitry-Yamate CL, Vutskits L, Rauen T (2002) Neuronal-induced and glutamate-dependent activation of glial glutamate transporter function. J Neurochem 82(4):987–997
Ashpole NM, Chawla AR, Martin MP, Brustovetsky T, Brustovetsky N, Hudmon A (2013) Loss of calcium/calmodulin-dependent protein kinase II activity in cortical astrocytes decreases glutamate uptake and induces neurotoxic release of ATP *. J Biol Chem 288(20):14599–14611
Underhill SM, Wheeler DS, Amara SG (2015) Differential regulation of two isoforms of the glial glutamate transporter EAAT2 by DLG1 and CaMKII. J Neurosci 35(13):5260–5270
Sakers K, Lake AM, Khazanchi R, Ouwenga R, Vasek MJ, Dani A, Dougherty JD (2017) Astrocytes locally translate transcripts in their peripheral processes. Proc Natl Acad Sci U S A 114(19):E3830–E3838
Boivin JR, Nedivi E (2018) Functional implications of inhibitory synapse placement on signal processing in pyramidal neuron dendrites. Curr Opin Neurobiol 51:16–22
Minelli A, DeBiasi S, Brecha NC, Zuccarello LV, Conti F (1996) GAT-3, a high-affinity GABA plasma membrane transporter, is localized to astrocytic processes, and it is not confined to the vicinity of GABAergic synapses in the cerebral cortex. J Neurosci 16(19):6255–6264
Araque A, Carmignoto G, Haydon PG, Oliet SH, Robitaille R, Volterra A (2014) Gliotransmitters travel in time and space. Neuron 81(4):728–739
Porter JT, McCarthy KD (1997) Astrocytic neurotransmitter receptors in situ and in vivo. Prog Neurobiol 51(4):439–455
Covelo A, Araque A (2018) Neuronal activity determines distinct gliotransmitter release from a single astrocyte. Elife 7:e32237. https://doi.org/10.7554/eLife.32237
Schipke CG, Haas B, Kettenmann H (2008) Astrocytes discriminate and selectively respond to the activity of a subpopulation of neurons within the barrel cortex. Cereb Cortex 18(10):2450–2459
Dzyubenko E, Prazuch W, Pillath-Eilers M, Polanska J, Hermann DM (2021) Analysing intercellular communication in astrocytic networks using “astral”. Front Cell Neurosci 15:689268
Wang Y, DelRosso NV, Vaidyanathan TV, Cahill MK, Reitman ME, Pittolo S, Mi X, Yu G, Poskanzer KE (2019) Accurate quantification of astrocyte and neurotransmitter fluorescence dynamics for single-cell and population-level physiology. Nat Neurosci 22(11):1936–1944
Rungta RL, Bernier L-P, Dissing-Olesen L, Groten CJ, LeDue JM, Ko R, Drissler S, MacVicar BA (2016) Ca2+ transients in astrocyte fine processes occur via Ca2+ influx in the adult mouse hippocampus. Glia 64(12):2093–2103
Verkhratsky A, Rodriguez JJ, Parpura V (2012) Calcium signalling in astroglia. Mol Cell Endocrinol 353(1-2):45–56
Duffy S, MacVicar BA (1995) Adrenergic calcium signaling in astrocyte networks within the hippocampal slice. J Neurosci 15(8):5535–5550
Nedergaard M (1994) Direct signaling from astrocytes to neurons in cultures of mammalian brain cells. Science 263(5154):1768–1771
Boddum K, Jensen TP, Magloire V, Kristiansen U, Rusakov DA, Pavlov I, Walker MC (2016) Astrocytic GABA transporter activity modulates excitatory neurotransmission. Nat Commun 7:13572
Perea G, Yang A, Boyden ES, Sur M (2014) Optogenetic astrocyte activation modulates response selectivity of visual cortex neurons in vivo. Nat Commun 5(1):3262
Poskanzer KE, Yuste R (2016) Astrocytes regulate cortical state switching in vivo. Proc Natl Acad Sci U S A 113(19):E2675–E2684
Volterra A, Meldolesi J (2005) Astrocytes, from brain glue to communication elements: the revolution continues. Nat Rev Neurosci 6(8):626–640
Malarkey EB, Parpura V (2008)Mechanisms of glutamate release from astrocytes. Neurochem Int 52(1-2):142-54
Perea G, Araque A (2007) Astrocytes potentiate transmitter release at single hippocampal synapses. Science 317(5841):1083–1086
Neame S, Safory H, Radzishevsky I, Touitou A, Marchesani F, Marchetti M, Kellner S, Berlin S, Foltyn VN, Engelender S, Billard JM, Wolosker H (2019) The NMDA receptor activation by d-serine and glycine is controlled by an astrocytic Phgdh-dependent serine shuttle. Proc Natl Acad Sci U S A 116(41):20736–20742
Yang Y, Ge W, Chen Y, Zhang Z, Shen W, Wu C, Poo M, Duan S (2003) Contribution of astrocytes to hippocampal long-term potentiation through release of D-serine. Proc Natl Acad Sci U S A 100(25):15194–15199
Deemyad T, Luthi J, Spruston N (2018) Astrocytes integrate and drive action potential firing in inhibitory subnetworks. Nat Commun 9(1):4336
Zhang JM, Wang HK, Ye CQ, Ge W, Chen Y, Jiang ZL, Wu CP, Poo MM, Duan S (2003) ATP released by astrocytes mediates glutamatergic activity-dependent heterosynaptic suppression. Neuron 40(5):971–982
Mariotti L, Losi G, Sessolo M, Marcon I, Carmignoto G (2016) The inhibitory neurotransmitter GABA evokes long-lasting Ca(2+) oscillations in cortical astrocytes. Glia 64(3):363–373
Perea G, Gomez R, Mederos S, Covelo A, Ballesteros JJ, Schlosser L, Hernandez-Vivanco A, Martin-Fernandez M, Quintana R, Rayan A, Diez A, Fuenzalida M, Agarwal A, Bergles DE, Bettler B, Manahan-Vaughan D, Martin ED, Kirchhoff F, Araque A (2016) Activity-dependent switch of GABAergic inhibition into glutamatergic excitation in astrocyte-neuron networks. Elife 5:e20362. https://doi.org/10.7554/eLife.20362
Matos M, Bosson A, Riebe I, Reynell C, Vallee J, Laplante I, Panatier A, Robitaille R, Lacaille JC (2018) Astrocytes detect and upregulate transmission at inhibitory synapses of somatostatin interneurons onto pyramidal cells. Nat Commun 9(1):4254
Fellin T, Pascual O, Gobbo S, Pozzan T, Haydon PG, Carmignoto G (2004) Neuronal synchrony mediated by astrocytic glutamate through activation of extrasynaptic NMDA receptors. Neuron 43(5):729–743
Mederos S, Perea G (2019) GABAergic-astrocyte signaling: a refinement of inhibitory brain networks. Glia 67(10):1842–1851
Doron A, Rubin A, Benmelech-Chovav A, Benaim N, Carmi T, Refaeli R, Novick N, Kreisel T, Ziv Y, Goshen I (2022) Hippocampal astrocytes encode reward location. Nature 609(7928):772–778
Halassa MM, Fellin T, Takano H, Dong JH, Haydon PG (2007) Synaptic islands defined by the territory of a single astrocyte. J Neurosci 27(24):6473–6477
Anders S, Minge D, Griemsmann S, Herde MK, Steinhauser C, Henneberger C (2014) Spatial properties of astrocyte gap junction coupling in the rat hippocampus. Philos Trans R Soc Lond B Biol Sci 369(1654):20130600
Bedner P, Dupper A, Huttmann K, Muller J, Herde MK, Dublin P, Deshpande T, Schramm J, Haussler U, Haas CA, Henneberger C, Theis M, Steinhauser C (2015) Astrocyte uncoupling as a cause of human temporal lobe epilepsy. Brain 138(Pt 5):1208–1222
Rouach N, Koulakoff A, Abudara V, Willecke K, Giaume C (2008) Astroglial metabolic networks sustain hippocampal synaptic transmission. Science 322(5907):1551–1555
Pandit S, Neupane C, Woo J, Sharma R, Nam MH, Lee GS, Yi MH, Shin N, Kim DW, Cho H, Jeon BH, Kim HW, Lee CJ, Park JB (2020) Bestrophin1-mediated tonic GABA release from reactive astrocytes prevents the development of seizure-prone network in kainate-injected hippocampi. Glia 68(5):1065–1080
Woo J, Min JO, Kang DS, Kim YS, Jung GH, Park HJ, Kim S, An H, Kwon J, Kim J, Shim I, Kim HG, Lee CJ, Yoon BE (2018) Control of motor coordination by astrocytic tonic GABA release through modulation of excitation/inhibition balance in cerebellum. Proc Natl Acad Sci U S A 115(19):5004–5009
Egawa K, Yamada J, Furukawa T, Yanagawa Y, Fukuda A (2013) Cl(-) homeodynamics in gap junction-coupled astrocytic networks on activation of GABAergic synapses. J Physiol 591(16):3901–3917
Olsen ML, Sontheimer H (2008) Functional implications for Kir4.1 channels in glial biology: from K+ buffering to cell differentiation. J Neurochem 107(3):589–601
Larsen BR, Stoica A, MacAulay N (2016) Managing brain extracellular K(+) during neuronal activity: the physiological role of the Na(+)/K(+)-ATPase subunit isoforms. Front Physiol 7:141
Bruckner G, Brauer K, Hartig W, Wolff JR, Rickmann MJ, Derouiche A, Delpech B, Girard N, Oertel WH, Reichenbach A (1993) Perineuronal nets provide a polyanionic, glia-associated form of microenvironment around certain neurons in many parts of the rat brain. Glia 8(3):183–200
Dityatev A, Bruckner G, Dityateva G, Grosche J, Kleene R, Schachner M (2007) Activity-dependent formation and functions of chondroitin sulfate-rich extracellular matrix of perineuronal nets. Dev Neurobiol 67(5):570–588
Bauernfeind AL, Barks SK, Duka T, Grossman LI, Hof PR, Sherwood CC (2014) Aerobic glycolysis in the primate brain: reconsidering the implications for growth and maintenance. Brain Struct Funct 219(4):1149–1167
Lunt SY, Vander Heiden MG (2011) Aerobic glycolysis: meeting the metabolic requirements of cell proliferation. Annu Rev Cell Dev Biol 27:441–464
Belanger M, Allaman I, Magistretti PJ (2011) Brain energy metabolism: focus on astrocyte-neuron metabolic cooperation. Cell Metab 14(6):724–738
Yang J, Ruchti E, Petit JM, Jourdain P, Grenningloh G, Allaman I, Magistretti PJ (2014) Lactate promotes plasticity gene expression by potentiating NMDA signaling in neurons. Proc Natl Acad Sci U S A 111(33):12228–12233
Choi Y, Chen HV, Lipton SA (2001) Three pairs of cysteine residues mediate both redox and zn2+ modulation of the nmda receptor. J Neurosci 21(2):392–400
Suzuki A, Stern SA, Bozdagi O, Huntley GW, Walker RH, Magistretti PJ, Alberini CM (2011) Astrocyte-neuron lactate transport is required for long-term memory formation. Cell 144(5):810–823
Anlauf E, Derouiche A (2013) Glutamine synthetase as an astrocytic marker: its cell type and vesicle localization. Front Endocrinol (Lausanne) 4:144
Leke R, Schousboe A (2016) The glutamine transporters and their role in the glutamate/GABA-glutamine cycle. Adv Neurobiol 13:223–257
Hagglund MG, Sreedharan S, Nilsson VC, Shaik JH, Almkvist IM, Backlin S, Wrange O, Fredriksson R (2011) Identification of SLC38A7 (SNAT7) protein as a glutamine transporter expressed in neurons. J Biol Chem 286(23):20500–20511
Schousboe A, Scafidi S, Bak LK, Waagepetersen HS, McKenna MC (2014) Glutamate metabolism in the brain focusing on astrocytes. Adv Neurobiol 11:13–30
Andersen JV, Jakobsen E, Westi EW, Lie MEK, Voss CM, Aldana BI, Schousboe A, Wellendorph P, Bak LK, Pinborg LH, Waagepetersen HS (2020) Extensive astrocyte metabolism of gamma-aminobutyric acid (GABA) sustains glutamine synthesis in the mammalian cerebral cortex. Glia 68(12):2601–2612
Sonnewald U, Westergaard N, Schousboe A, Svendsen JS, Unsgard G, Petersen SB (1993) Direct demonstration by [13C]NMR spectroscopy that glutamine from astrocytes is a precursor for GABA synthesis in neurons. Neurochem Int 22(1):19–29
Schousboe A, Bak LK, Waagepetersen HS (2013) Astrocytic control of biosynthesis and turnover of the neurotransmitters glutamate and GABA. Front Endocrinol (Lausanne) 4:102
Qureshi T, Sorensen C, Berghuis P, Jensen V, Dobszay MB, Farkas T, Dalen KT, Guo C, Hassel B, Utheim TP, Hvalby O, Hafting T, Harkany T, Fyhn M, Chaudhry FA (2019) The glutamine transporter Slc38a1 regulates GABAergic neurotransmission and synaptic plasticity. Cereb Cortex 29(12):5166–5179
Ivens S, Caliskan G, Papageorgiou I, Cesetti T, Malich A, Kann O, Heinemann U, Stork O, Albrecht A (2019) Persistent increase in ventral hippocampal long-term potentiation by juvenile stress: a role for astrocytic glutamine synthetase. Glia 67(12):2279–2293
Hensch TK (2005) Critical period plasticity in local cortical circuits. Nat Rev Neurosci 6(11):877–888
Takesian AE, Hensch TK (2013) Balancing plasticity/stability across brain development. Prog Brain Res 207:3–34
Gundelfinger ED, Frischknecht R, Choquet D, Heine M (2010) Converting juvenile into adult plasticity: a role for the brain’s extracellular matrix. Eur J Neurosci 31(12):2156–2165
Carulli D, Foscarin S, Faralli A, Pajaj E, Rossi F (2013) Modulation of semaphorin3A in perineuronal nets during structural plasticity in the adult cerebellum. Mol Cell Neurosci 57:10–22
Pearson CS, Mencio CP, Barber AC, Martin KR, Geller HM (2018) Identification of a critical sulfation in chondroitin that inhibits axonal regeneration. Elife 7:e37139. https://doi.org/10.7554/eLife.37139
Dzyubenko E, Fleischer M, Manrique-Castano D, Borbor M, Kleinschnitz C, Faissner A, Hermann DM (2021) Inhibitory control in neuronal networks relies on the extracellular matrix integrity. Cell Mol Life Sci 78(14):5647–5663
Huntley GW (2012) Synaptic circuit remodelling by matrix metalloproteinases in health and disease. Nat Rev Neurosci 13(11):743–757
Schafer DP, Lehrman EK, Kautzman AG, Koyama R, Mardinly AR, Yamasaki R, Ransohoff RM, Greenberg ME, Barres BA, Stevens B (2012) Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron 74(4):691–705
Weinhard L, di Bartolomei G, Bolasco G, Machado P, Schieber NL, Neniskyte U, Exiga M, Vadisiute A, Raggioli A, Schertel A, Schwab Y, Gross CT (2018) Microglia remodel synapses by presynaptic trogocytosis and spine head filopodia induction. Nat Commun 9(1):1228
Bennett ML, Bennett FC (2020) The influence of environment and origin on brain resident macrophages and implications for therapy. Nat Neurosci 23(2):157–166
Nimmerjahn A, Kirchhoff F, Helmchen F (2005) Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308(5726):1314–1318
Szalay G, Martinecz B, Lenart N, Kornyei Z, Orsolits B, Judak L, Csaszar E, Fekete R, West BL, Katona G, Rozsa B, Denes A (2016) Microglia protect against brain injury and their selective elimination dysregulates neuronal network activity after stroke. Nat Commun 7:11499
Cserep C, Posfai B, Lenart N, Fekete R, Laszlo ZI, Lele Z, Orsolits B, Molnar G, Heindl S, Schwarcz AD, Ujvari K, Kornyei Z, Toth K, Szabadits E, Sperlagh B, Baranyi M, Csiba L, Hortobagyi T, Magloczky Z et al (2020) Microglia monitor and protect neuronal function through specialized somatic purinergic junctions. Science 367(6477):528–537
Liu YU, Ying Y, Li Y, Eyo UB, Chen T, Zheng J, Umpierre AD, Zhu J, Bosco DB, Dong H, Wu LJ (2019) Neuronal network activity controls microglial process surveillance in awake mice via norepinephrine signaling. Nat Neurosci 22(11):1771–1781
Logiacco F, Xia P, Georgiev SV, Franconi C, Chang YJ, Ugursu B, Sporbert A, Kuhn R, Kettenmann H, Semtner M (2021) Microglia sense neuronal activity via GABA in the early postnatal hippocampus. Cell Rep 37(13):110128
Umpierre AD, Bystrom LL, Ying Y, Liu YU, Worrell G, Wu LJ (2020) Microglial calcium signaling is attuned to neuronal activity in awake mice. Elife 7:9:e56502. https://doi.org/10.7554/eLife.56502
Nguyen PT, Dorman LC, Pan S, Vainchtein ID, Han RT, Nakao-Inoue H, Taloma SE, Barron JJ, Molofsky AB, Kheirbek MA, Molofsky AV (2020) Microglial remodeling of the extracellular matrix promotes synapse plasticity. Cell 182(2):388–403.e15
Favuzzi E, Huang S, Saldi GA, Binan L, Ibrahim LA, Fernandez-Otero M, Cao Y, Zeine A, Sefah A, Zheng K, Xu Q, Khlestova E, Farhi SL, Bonneau R, Datta SR, Stevens B, Fishell G (2021) GABA-receptive microglia selectively sculpt developing inhibitory circuits. Cell 184(15):4048–4063 e32
Kovacs RA, Vadaszi H, Bulyaki E, Torok G, Toth V, Matyas D, Kun J, Hunyadi-Gulyas E, Fedor FZ, Csincsi A, Medzihradszky K, Homolya L, Juhasz G, Kekesi KA, Jozsi M, Gyorffy BA, Kardos J (2020) Identification of neuronal pentraxins as synaptic binding partners of C1q and the involvement of NP1 in synaptic pruning in adult mice. Front Immunol 11:599771
Scott-Hewitt N, Perrucci F, Morini R, Erreni M, Mahoney M, Witkowska A, Carey A, Faggiani E, Schuetz LT, Mason S, Tamborini M, Bizzotto M, Passoni L, Filipello F, Jahn R, Stevens B, Matteoli M (2020) Local externalization of phosphatidylserine mediates developmental synaptic pruning by microglia. EMBO J 39(16):e105380
Vainchtein ID, Chin G, Cho FS, Kelley KW, Miller JG, Chien EC, Liddelow SA, Nguyen PT, Nakao-Inoue H, Dorman LC, Akil O, Joshita S, Barres BA, Paz JT, Molofsky AB, Molofsky AV (2018) Astrocyte-derived interleukin-33 promotes microglial synapse engulfment and neural circuit development. Science 359(6381):1269–1273
Dou Y, Wu H-J, Li H-Q, Qin S, Wang Y-E, Li J, Lou H-F, Chen Z, Li X-M, Luo Q-M, Duan S (2012) Microglial migration mediated by ATP-induced ATP release from lysosomes. Cell Res 22(6):1022–1033
Haynes SE, Hollopeter G, Yang G, Kurpius D, Dailey ME, Gan W-B, Julius D (2006) The P2Y12 receptor regulates microglial activation by extracellular nucleotides. Nat Neurosci 9(12):1512–1519
Harrison JK, Jiang Y, Chen S, Xia Y, Maciejewski D, McNamara RK, Streit WJ, Salafranca MN, Adhikari S, Thompson DA (1998) Role for neuronally derived fractalkine in mediating interactions between neurons and CX3CR1-expressing microglia. Proc Natl Acad Sci 95(18):10896–10901
Hughes PM, Botham MS, Frentzel S, Mir A, Perry VH (2002) Expression of fractalkine (CX3CL1) and its receptor, CX3CR1, during acute and chronic inflammation in the rodent CNS. Glia 37(4):314–327
Eyo UB, Wu LJ (2019) Microglia: lifelong patrolling immune cells of the brain. Prog Neurobiol 179:101614
Paolicelli RC, Bolasco G, Pagani F, Maggi L, Scianni M, Panzanelli P, Giustetto M, Ferreira TA, Guiducci E, Dumas L, Ragozzino D, Gross CT (2011) Synaptic pruning by microglia is necessary for normal brain development. Science 333(6048):1456–1458
Dejanovic B, Huntley MA, De Mazière A, Meilandt WJ, Wu T, Srinivasan K, Jiang Z, Gandham V, Friedman BA, Ngu H, Foreman O, Carano RAD, Chih B, Klumperman J, Bakalarski C, Hanson JE, Sheng M (2018) Changes in the synaptic proteome in tauopathy and rescue of tau-induced synapse loss by C1q antibodies. Neuron 100(6):1322–1336.e7
Cheadle L, Rivera SA, Phelps JS, Ennis KA, Stevens B, Burkly LC, Lee W-CA, Greenberg ME (2020) Sensory experience engages microglia to shape neural connectivity through a non-phagocytic mechanism. Neuron 108(3):451–468.e9
Allen NJ, Eroglu C (2017) Cell biology of astrocyte-synapse interactions. Neuron 96(3):697–708
Kucukdereli H, Allen NJ, Lee AT, Feng A, Ozlu MI, Conatser LM, Chakraborty C, Workman G, Weaver M, Sage EH, Barres BA, Eroglu C (2011) Control of excitatory CNS synaptogenesis by astrocyte-secreted proteins Hevin and SPARC. Proc Natl Acad Sci U S A 108(32):E440–E449
Dzyubenko E, Manrique-Castano D, Kleinschnitz C, Faissner A, Hermann DM (2018) Role of immune responses for extracellular matrix remodeling in the ischemic brain. Ther Adv Neurol Disord 11:1756286418818092
Enzmann G, Mysiorek C, Gorina R, Cheng YJ, Ghavampour S, Hannocks MJ, Prinz V, Dirnagl U, Endres M, Prinz M, Beschorner R, Harter PN, Mittelbronn M, Engelhardt B, Sorokin L (2013) The neurovascular unit as a selective barrier to polymorphonuclear granulocyte (PMN) infiltration into the brain after ischemic injury. Acta Neuropathol 125(3):395–412
Neumann J, Riek-Burchardt M, Herz J, Doeppner TR, Konig R, Hutten H, Etemire E, Mann L, Klingberg A, Fischer T, Gortler MW, Heinze HJ, Reichardt P, Schraven B, Hermann DM, Reymann KG, Gunzer M (2015) Very-late-antigen-4 (VLA-4)-mediated brain invasion by neutrophils leads to interactions with microglia, increased ischemic injury and impaired behavior in experimental stroke. Acta Neuropathol 129(2):259–277
Malone K, Amu S, Moore AC, Waeber C (2019) Immunomodulatory therapeutic strategies in stroke. Front Pharmacol 10:630
Qiu J, Nishimura M, Wang Y, Sims JR, Qiu S, Savitz SI, Salomone S, Moskowitz MA (2008) Early release of HMGB-1 from neurons after the onset of brain ischemia. J Cereb Blood Flow Metab 28(5):927–938
Sun Y, Hei M, Fang Z, Tang Z, Wang B, Hu N (2019) High-mobility group box 1 contributes to cerebral cortex injury in a neonatal hypoxic-ischemic rat model by regulating the phenotypic polarization of microglia. Front Cell Neurosci 13:506
Liddelow SA, Guttenplan KA, Clarke LE, Bennett FC, Bohlen CJ, Schirmer L, Bennett ML, Munch AE, Chung WS, Peterson TC, Wilton DK, Frouin A, Napier BA, Panicker N, Kumar M, Buckwalter MS, Rowitch DH, Dawson VL, Dawson TM et al (2017) Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541(7638):481–487
M. Borbor, D. Yin, U. Brockmeier, C. Wang, M. Doeckel, M. Pillath-Eilers, B. Kaltwasser, D.M. Hermann, E. Dzyubenko, Neurotoxicity of ischemic astrocytes involves STAT3-mediated metabolic switching and depends on glycogen usage, Glia n/a(n/a) (2023).
Al'Qteishat A, Gaffney J, Krupinski J, Rubio F, West D, Kumar S, Kumar P, Mitsios N, Slevin M (2006) Changes in hyaluronan production and metabolism following ischaemic stroke in man. Brain 129(Pt 8):2158–2176
Dzyubenko E, Manrique-Castano D, Pillath-Eilers M, Vasileiadou P, Reinhard J, Faissner A, Hermann DM (2022) Tenascin-C restricts reactive astrogliosis in the ischemic brain. Matrix Biol 110:1–15
Manrique-Castano D, Dzyubenko E, Borbor M, Vasileiadou P, Kleinschnitz C, Roll L, Faissner A, Hermann DM (2021) Tenascin-C preserves microglia surveillance and restricts leukocyte and, more specifically, T cell infiltration of the ischemic brain. Brain Behav Immun 91:639–648
Dzyubenko E, Manrique-Castano D, Kleinschnitz C, Faissner A, Hermann DM (2018) Topological remodeling of cortical perineuronal nets in focal cerebral ischemia and mild hypoperfusion. Matrix Biol 74:121–132
Hartig W, Mages B, Aleithe S, Nitzsche B, Altmann S, Barthel H, Krueger M, Michalski D (2017) Damaged neocortical perineuronal nets due to experimental focal cerebral ischemia in mice, rats and sheep. Front Integr Neurosci 11(15):15
Baik SH, Kang S, Lee W, Choi H, Chung S, Kim JI, Mook-Jung I (2019) A breakdown in metabolic reprogramming causes microglia dysfunction in Alzheimer’s disease. Cell Metab 30(3):493–507 e6
Lively S, Schlichter LC (2013) The microglial activation state regulates migration and roles of matrix-dissolving enzymes for invasion. J Neuroinflammation 10:75
Crapser JD, Ochaba J, Soni N, Reidling JC, Thompson LM, Green KN (2020) Microglial depletion prevents extracellular matrix changes and striatal volume reduction in a model of Huntington’s disease. Brain 143(1):266–288
Crapser JD, Spangenberg EE, Barahona RA, Arreola MA, Hohsfield LA, Green KN (2020) Microglia facilitate loss of perineuronal nets in the Alzheimer’s disease brain. EBioMedicine 58:102919
Rothhammer V, Borucki DM, Tjon EC, Takenaka MC, Chao CC, Ardura-Fabregat A, de Lima KA, Gutierrez-Vazquez C, Hewson P, Staszewski O, Blain M, Healy L, Neziraj T, Borio M, Wheeler M, Dragin LL, Laplaud DA, Antel J, Alvarez JI et al (2018) Microglial control of astrocytes in response to microbial metabolites. Nature 557(7707):724–728
Wheeler MA, Jaronen M, Covacu R, Zandee SEJ, Scalisi G, Rothhammer V, Tjon EC, Chao CC, Kenison JE, Blain M, Rao VTS, Hewson P, Barroso A, Gutierrez-Vazquez C, Prat A, Antel JP, Hauser R, Quintana FJ (2019) Environmental control of astrocyte pathogenic activities in CNS inflammation. Cell 176(3):581–596.e18
Silva RV, Biskup K, Zabala-Jouvin JK, Batzdorf CS, Stellmach C, Morr AS, Sack I, Ludwig A, Blanchard V, Infante-Duarte C (2023) Brain inflammation induces alterations in glycosaminoglycan metabolism and subsequent changes in CS-4S and hyaluronic acid. Int J Biol Macromol 230:123214
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Open Access funding enabled and organized by Projekt DEAL. This work was funded by German Research Foundation (DFG) projects 389030878, 405358801, 428817542, and 505462125 to D.M.H., and 467228103 to E.D.
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Dzyubenko, E., Hermann, D.M. Role of glia and extracellular matrix in controlling neuroplasticity in the central nervous system. Semin Immunopathol 45, 377–387 (2023). https://doi.org/10.1007/s00281-023-00989-1
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DOI: https://doi.org/10.1007/s00281-023-00989-1