Abstract Electrical activity is essential for brain function. However, neurons, the electrically active cells, are less numerous than the non-electrical glial cells in the central nervous system. The non-electrical components modify the function of neural circuits, depending on the electrical neuronal activity, by wrapping synapses, myelinating axons and phagocytozing the neuronal components. Moreover, recent evidence has suggested that they contribute to neurological and psychiatric disease by regulating neuronal circuits, ultimately affecting their behaviour. In this review, we highlight the physiological functions of glial cells, particularly the electrical activity-dependent processes, to provide further insight into their role in brain function. astrocyte, glial cell, microglia, NG2 cell, oligodendrocyte In the central nervous system (CNS), glial cells, originally termed ‘nervenkitt’, are classified into four main subtypes: astrocytes, microglia, NG2 (nerve/glia antigen 2) cells and oligodendrocytes. Astrocytes, NG2 cells and oligodendrocytes originate from the ectoderm (1, 2), along with neurons. In contrast, microglial cells originate from the mesoderm and, in mice, are derived from the yolk sac at embryonic day 7.5 (E7.5) (3). Recently, accumulating evidence has suggested that these cells respond to neuronal activity to actively modify brain components, such as synapses, axons and blood vessels, and nerve functions via their numerous processes. Astrocytic processes wrap around the synapses, form the blood−brain barrier (BBB), and make contact with the nodes of Ranvier in the white matter to regulate the generation of action potentials. Microglia continuously extend and retract their processes, making and breaking contact with synapses and blood vessels. NG2 cells form synapse-like structures with axons and are involved in neuronal circuits; neuronal activity affects the differentiation and proliferation of NG2 cells, which become mature oligodendrocytes. Thus, the numerous processes of glial cells are crucial for activity-dependent glial functions to regulate neuronal structures and activities (Fig. 1). Fig. 1 View largeDownload slide Activity-dependent process of glial cells. Glial cells communicate with neurons. Astrocytes (blue) expand their end feet to synapses. Microglial processes (green) also make contact with synaptic elements. NG2 cells (red) form a synapse-like structure. Oligodendrocytes (lime green) synthesize the myelin sheath and wrap it around axons. Neural activity from activated neurons (orange) modulates glial cells functions (middle) and then activity-dependent functions of glial cells (myelination, synapse modulation, etc.) regulate neural activity of non-activated neurons (black), consequently changing from the resting state (left) to functional state (right). Fig. 1 View largeDownload slide Activity-dependent process of glial cells. Glial cells communicate with neurons. Astrocytes (blue) expand their end feet to synapses. Microglial processes (green) also make contact with synaptic elements. NG2 cells (red) form a synapse-like structure. Oligodendrocytes (lime green) synthesize the myelin sheath and wrap it around axons. Neural activity from activated neurons (orange) modulates glial cells functions (middle) and then activity-dependent functions of glial cells (myelination, synapse modulation, etc.) regulate neural activity of non-activated neurons (black), consequently changing from the resting state (left) to functional state (right). Non-Active Glial Cells and Their Neurotransmitter Receptors Astrocytes (4), microglia (5) and oligodendrocytes (6) do not elicit action potentials, but certain types of NG2 cells (7) generate action potentials. However, glial cells express functional neurotransmitter receptors; such as the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) (8–11), the N-methyl-d-aspartate receptor (NMDAR) (7, 12), metabotropic glutamate receptor (mGluR) (13–15), purinoreceptor (16–18), the gamma-aminobutyric acid (GABA) A receptor (19–21), the GABA B receptor (22–24), acetylcholine receptor (25–27), adrenergic receptor (28–31) and glycine receptor (32). The fact that glial cells express receptors for neurotransmitters indicates that these cells participate in neurotransmission. Astrocytes and Neuronal Activity The original hypothesis of ‘activity’ of non-electrical components in the brain arose from the observations of astrocytic Ca2+ responses (33). Astrocytes are not electrically active cells; however, they extend their numerous lamellar processes to the nodes of Ranvier, blood vessels and synapses to receive information from their numerous lamellar processes, which elicits intracellular Ca2+ response in both astrocytic processes and cell somas to receive the information from those components. Those astrocytic Ca2+ responses are mainly mediated by activation of Gq protein-coupled receptors, as observed in cell culture (34) and in acute brain slices (35, 36). Neuronal glutamate release triggers increases in intracellular Ca2+ levels in astrocytes, via mGluRs (37). These Ca2+ responses in astrocytic somas have also been observed with in vivo two-photon microscopy (38) after sensory stimulation (39). Various types of sensory stimulation, such as hind limb stimulation (40), whisker stimulation (39), visual stimulation (41) and odour stimulation (42), can trigger astrocytic Ca2+ level elevations in vivo. Ca2+ responses in astrocytes depend on the frequency of whisker stimulation (39), while visually evoked Ca2+ transients in astrocytes have the stimulus feature of selectivity (41). In addition, a cerebellar subtype of astrocytes, the Bergman glia, can cause three different types of Ca2+ responses during motor behaviour (43). These Ca2+ waves in the Bergman glia correlate with Ca2+ waves in cortical astrocytes during locomotion, which are induced by noradrenergic alpha-1 pathways (28, 30). Thus, astrocytic activities correlate with neuronal activities in vitro and in vivo. However, these astrocytic activities that are evoked by sensory stimulation affect neuronal function remain unknown. Since astrocytes can release several gliotransmitters in response to neuronal activities in cultured cells and brain slices (44), activated astrocytes might contribute to the regulation of neuronal function (45). Fig. 2 View largeDownload slide Activity-dependent functions of glial cells. (A) Astrocytes form the BBB, along with endothelial cells and pericytes, to supply nutritional elements and maintain brain homeostasis. These cells express various types of neurotransmitter receptors, including glutamate receptors, GABA receptors and purinoreceptors, which wrap around the synapse as part of a tripartite synapse, and thus they contribute to neural circuits. Motor behaviour and various types of sensory stimulation, including hind limb, whisker, visual and odder stimulation can induce Ca2+ elevation in astrocyte. Vascular dilation induced by neuronal activity depends on astrocytic Ca2+ elevation, mediated through mGluR activation, to regulate brain microcirculation. (B) Microglia regulate synaptic function and number, thereby regulating synaptic plasticity and pruning through activity-dependent surveillance. The dynamic movement of microglia processes depends on the neuronal activity–mediated ATP release and those processes make interactions with neuronal elements to regulate neuronal function. (C) NG2 cells proliferate and differentiate, thus regulating myelination in the adult brain. Alterations in neural activity, voluntary exercise and sensory deprivation modulate NG2 cell proliferation and differentiation, ultimately regulating myelination. (D) Changes depending on neuronal activity including behaviour and learning also promote myelination. Fig. 2 View largeDownload slide Activity-dependent functions of glial cells. (A) Astrocytes form the BBB, along with endothelial cells and pericytes, to supply nutritional elements and maintain brain homeostasis. These cells express various types of neurotransmitter receptors, including glutamate receptors, GABA receptors and purinoreceptors, which wrap around the synapse as part of a tripartite synapse, and thus they contribute to neural circuits. Motor behaviour and various types of sensory stimulation, including hind limb, whisker, visual and odder stimulation can induce Ca2+ elevation in astrocyte. Vascular dilation induced by neuronal activity depends on astrocytic Ca2+ elevation, mediated through mGluR activation, to regulate brain microcirculation. (B) Microglia regulate synaptic function and number, thereby regulating synaptic plasticity and pruning through activity-dependent surveillance. The dynamic movement of microglia processes depends on the neuronal activity–mediated ATP release and those processes make interactions with neuronal elements to regulate neuronal function. (C) NG2 cells proliferate and differentiate, thus regulating myelination in the adult brain. Alterations in neural activity, voluntary exercise and sensory deprivation modulate NG2 cell proliferation and differentiation, ultimately regulating myelination. (D) Changes depending on neuronal activity including behaviour and learning also promote myelination. Recently, genetically encoded green fluorescent protein (GFP)-based calcium indicators that target the cell membrane, such as Lck-GCaMP, have allowed to study Ca2+ responses in astrocytic processes (46). Ca2+ responses in processes are not necessarily associated with the responses in cell soma, indicating the distinct function of Ca2+ responses in processes and cell soma. Additionally, local Ca2+ responses, as detected by Lck-GCaMP, was found to be mediated by transient receptor potential A1 (TRPA1) channels. TRPA1-mediated decreases in resting Ca2+ concentrations in astrocytes reduced inhibitory synaptic efficacy (47). These studies suggest that activities in astrocytic processes are also important for modulating neuronal activities. Further studies are needed to understand the spatial pattern and temporal correlation of the Ca2+ responses in these processes and how those Ca2+ responses could be integrated into the somatic response. Such information could contribute to understanding how the glial network affects brain function. Astrocytic processes extending to the blood vessels form the BBB, along with endothelial cells and pericytes that regulate the microcirculation, in a manner dependent on neural activity mediated by mGluR signalling (48). This regulation of the microcirculation is directly involved in sensory processing. Sensory stimuli trigger neuronal firing, which is followed by mGluR-mediated Ca2+ responses in astrocytes; this, in turn, induces vasodilation (42). The expression of neurotransmitter receptors in astrocyte indicates that astrocytic Ca2+ responses that are associated with neuronal transmission and vasodilation could coordinate these types of information to regulate synaptic activity and oxygen supply (Fig. 2A). Microglia Functions Associated With Neuronal Activity Traditional approaches have shown that the morphological changes in microglia (microglia activation) have a ‘neuroprotective role’ or ‘neurotoxic role’ in terms of neuronal pathology (49), through the receptors expressed on the microglia (50). Upon nerve injury, activated microglia invade the synaptic cleft of excitatory neurons to ‘strip off’ their synapses (51). These neuron−microglial interactions prevent neuronal excitatory responses after nerve injury (51, 52). Recent advances in light microscopy have revealed that microglia in the physiological brain state are highly motile, extending and retracting their processes to survey the brain parenchyma (53, 54). The extension of the microglia processes is regulated by the metabotropic purinergic receptor (P2Y12) (55), suggesting that their motility and the polarity, and thus the dynamic movement of microglial processes, depends on neuronal activity. NMDAR-mediated elevation in neuronal Ca2+ level induces adenosine triphosphate (ATP) release from pannexin channels, resulting in subsequent extension of microglial processes, and their contacting of neuronal elements (56). In fact, microglia make contacts with the synapse, depending on synaptic activity and sensory input (57, 58). Presynaptic terminals in the lateral geniculate nucleus expresses C3, and microglia detect the ‘weakly active’ synapses through the traditional complement pathway (59, 60). Furthermore, increased immature spine density has been observed upon genetic deletion of fractalkine receptor (CX3CR1) in microglia (61), suggesting that microglia phagocytize synapses by fractalkine signalling, and are thus involved in synapse elimination during development. These findings indicate the correlation between immune status and function of neuronal circuits and that dysfunction of microglia, the mediator for immune function and regulator of neuronal circuits may contribute to a subset of neurological and psychiatric disorders (62). In addition to synapse surveillance, microglia processes are attracted to the neuronal soma by neuronal activity through the ATP released from hemi-channels to reduce neuronal activity (63). Thus, the motility of the microglia processes depends on neuronal activity and those processes make contact with neuronal elements in order to modify their function. Brain-derived neurotrophic factor (BDNF) is one of the key molecules involved in the modification of neuronal function. Microglia release BDNF during both motor learning (64) and chronic pain (65, 66), consequently regulating neural activity. Several cytokines and chemokines induce the Ca2+ response in microglia in vitro (67). Focal laser ablation, which attracts microglia processes, causes Ca2+ responses in in vivo (68). Further in vivo experiments are needed to identify how microglial responses are associated with temporal and spatial changes in activity of neurons and how these contribute to disease (Fig. 2B). Activity-Dependent NG2 Cells and Oligodendrocyte Functions Activity-dependent processes of proliferation and differentiation of oligodendrocyte progenitor cells (OPCs; e.g. NG2 cells, which express specific antigens and NG2 chondroitin sulphate) have long been debated. Traditional experiments have shown that the reduced neural activity that follows intraocular injection of tetrodotoxin (TTX) suppressed OPC proliferation in the optic nerve, suggesting activity-dependent regulation of the number of oligodendrocytes (69). Electrical stimulation of the rat corticospinal tract promoted OPC proliferation and differentiation through the NMDAR (70). Voluntary exercise (i.e. wheel running) enhanced OPC differentiation, thus reducing OPC proliferation in the motor cortex (71). OPCs in the developing barrel cortex receive glutamatergic projections from the thalamus. Sensory deprivation (i.e. whisker removal during developmental stages) resulted in the reduction of thalamo-cortical inputs on OPCs, thus inhibiting OPC proliferation and altering OPC distribution in the barrel cortex (72). Furthermore, in Thy1-channelrhodopsin-2 transgenic mice, neuronal activity induced by optogenetic stimulation regulated OPC proliferation, differentiation and myelination (73). The synapse-like structures between OPCs and presynaptic elements have been shown to vary between different brain regions, including the hippocampal CA3 region (10), cerebral cortex (74), cerebellum (75) and white matter (11). Moreover, functional responses through these structures regulate OPC proliferation and differentiation, mediated by Ca2+ signals through neurotransmitter receptors, such as the AMPAR (10, 11, 76), NMDAR (7) and GABAR (20, 77). Such activity-dependent OPC proliferation and differentiation modify neuronal circuit activity, which affects behaviour by regulating neuronal circuit activity or myelination. Indeed, oligodendrocytes newly generated from OPCs synthesize myelin in the young adult brain (78) and inhibition of OPC differentiation impairs motor learning (79, 80), suggesting the contribution of OPC differentiation to myelin synthesis in the adult brain. However, the existence of mature oligodendrocytes without myelination and the extent of myelination in the adult corpus callosum correlate with the number of mature oligodendrocytes, indicating that OPC differentiation and myelination are distinct processes (81). It has also been long been debated whether oligodendrocytes myelinate axons in a manner dependent on their neural activity. The axonal initial segment (AIS) is a characteristic region of axons that is the initiation site for action potentials. Prolonged depolarization by high extracellular K+ levels induced changes in the position of the AIS in cultured hippocampal neurons (82). The reduction in neural activity that is induced by ocular TTX injections decreased the number of myelinated axon segments (83); in contrast, the repetitive propagation of the action potential (84) led to increases in the extent of myelin formation. Additionally, a recent study demonstrated that activity-dependent axonal secretion of neurotransmitters is required for maintenance of the myelin sheath in vivo (85). Moreover, recent magnetic resonance imaging (MRI) studies using diffusion tensor imaging (DTI) in humans showed that increased fractional anisotropy (FA) in white matter was associated with juggling (86), reading (87) and piano playing (88), indicating the contribution of neuronal activity to myelination in the adult brain (89). These findings suggest that myelin and axon morphology are dependent on neural activity, but the mechanisms underlying these changes remain unclear. In co-cultures of dorsal root ganglion (DRG) neurons and OPCs, ATP released from the neuronal axons in response to electrical stimulation promoted OPC differentiation and formation of the myelin sheath (90). Axonal glutamate released from DRG neurons increased local myelin basic protein (MBP) synthesis in OPCs specifically at the non-synaptic (91, 92) junction sites of DRG neurons and OPCs, through Fyn kinase activity (91). In addition, neuregulin and BDNF signals promoted NMDAR-dependent myelination of active axons (93). Furthermore, several in vivo studies have demonstrated that neuronal activation caused by motor behaviour and motor learning promotes myelination, while impaired myelination has been observed in the prefrontal cortex after social isolation (94, 95). A study using DTI MRI in rodents has shown that increased FA with forelimb motor learning is correlated with the MBP signal detected by immunohistochemistry, suggesting an association between changes in the white matter structure detected by MRI and myelin formation (96). The newly formed myelin is essential for motor learning. Genetic deletion of myelin regulatory factor prevents new oligodendrocyte production, resulting in impaired motor learning (79, 80). This suggests that active myelination occurs in mature mice and contributes to motor learning. However, the activity dependence of myelination is still under debate. In oligodendrocyte monocultures, expression of myelin-related proteins and formation of myelin sheath-like structures have been observed (97). OPCs can also form myelin around axons that have been fixed with paraformaldehyde (98), as well as around nanofibres (99), indicating that OPC differentiation and myelination are possible in the absence of the dynamic signalling between axons and OPCs. Disruption of myelin regulation can result in abnormal information processing, which could cause psychiatric and neurological disorders (100). In fact, genome-wide analysis has demonstrated differences in myelin-related gene expression in patients with schizophrenia (101). In addition, abnormal signals detected by MRI in white matter have been associated with cognitive decline in elderly people (102). These findings suggest that myelin regulation contributes to information processing in an activity-dependent manner and its disruption results in psychiatric and neurological diseases (Fig. 2C and D). Conclusion In this review, we have summarized the activity-dependent functions of non-electrical glial cells. Glial cells actively receive neuronal information and exert their functions in an activity-dependent manner. Disruption of these physiological functions may result in developmental and psychiatric disorders. In addition, abnormal activity pattern of neurons present in developmental and psychiatric disorders may impair glial cell functions, which may have an effect on disease progression. Rescuing the physiological functions of glial cells could be a therapeutic target for these diseases. Funding This work was supported by the Japan Science and Technology Agency for Core Research for Evolutional Science and Technology (to J.N.and H.W.), the Japan Science and Technology Agency for Precursory Research for Embryonic Science and Technology (to H.W.), Grant-in-Aids for Scientific Research on Scientific Research on Innovative Areas 15H01300 (to H.W.) and 17H05747 ( to H.W.), and 16H01346 (to H.W.) and 25110732 (to H.W.) and Grant-in-Aids for Young Scientists (A) 26710004 (to H.W.) from the Ministry of Education, Culture, Sports, Science and Technology. Conflict of Interest None declared. References 1 Garman R.H. ( 2011 ) Histology of the central nervous system . Toxicol. Pathol. 39 , 22 – 35 Google Scholar CrossRef Search ADS PubMed 2 Nishiyama A. ( 2007 ) Polydendrocytes: NG2 cells with many roles in development and repair of the CNS . Neuroscientist 13 , 62 – 76 Google Scholar CrossRef Search ADS PubMed 3 Ginhoux F. , Greter M. , Leboeuf M. , Nandi S. , See P. , Gokhan S. , Mehler M.F. , Conway S.J. , Ng L.G. , Stanley E.R. , Samokhvalov I.M. , Merad M. ( 2010 ) Fate mapping analysis reveals that adult microglia derive from primitive macrophages . Science 330 , 841 – 845 Google Scholar CrossRef Search ADS PubMed 4 Sontheimer H. , Waxman S.G. ( 1993 ) Expression of voltage-activated ion channels by astrocytes and oligodendrocytes in the hippocampal slice . J. Neurophysiol. 70 , 1863 – 1873 Google Scholar CrossRef Search ADS PubMed 5 Wu L.J. , Zhuo M. ( 2008 ) Resting microglial motility is independent of synaptic plasticity in mammalian brain . J. Neurophysiol . 99 , 2026 – 2032 Google Scholar CrossRef Search ADS PubMed 6 Kukley M. , Dietrich D. ( 2009 ) Kainate receptors and signal integration by NG2 glial cells . Neuron Glia Biol . 5 , 13 – 20 Google Scholar CrossRef Search ADS PubMed 7 Karadottir R. , Hamilton N.B. , Bakiri Y. , Attwell D. ( 2008 ) Spiking and nonspiking classes of oligodendrocyte precursor glia in CNS white matter . Nat. Neurosci. 11 , 450 – 456 Google Scholar CrossRef Search ADS PubMed 8 Holzwarth J.A. , Gibbons S.J. , Brorson J.R. , Philipson L.H. , Miller R.J. ( 1994 ) Glutamate receptor agonists stimulate diverse calcium responses in different types of cultured rat cortical glial cells . J. Neurosci . 14 , 1879 – 1891 Google Scholar CrossRef Search ADS PubMed 9 Noda M. , Nakanishi H. , Nabekura J. , Akaike N. ( 2000 ) AMPA-kainate subtypes of glutamate receptor in rat cerebral microglia . J. Neurosci. 20 , 251 – 258 Google Scholar CrossRef Search ADS PubMed 10 Bergles D.E. , Roberts J.D. , Somogyi P. , Jahr C.E. ( 2000 ) Glutamatergic synapses on oligodendrocyte precursor cells in the hippocampus . Nature 405 , 187 – 191 Google Scholar CrossRef Search ADS PubMed 11 Kukley M. , Capetillo-Zarate E. , Dietrich D. ( 2007 ) Vesicular glutamate release from axons in white matter . Nat. Neurosci. 10 , 311 – 320 Google Scholar CrossRef Search ADS PubMed 12 Lalo U. , Pankratov Y. , Kirchhoff F. , North R.A. , Verkhratsky A. ( 2006 ) NMDA receptors mediate neuron-to-glia signaling in mouse cortical astrocytes . J. Neurosci . 26 , 2673 – 2683 Google Scholar CrossRef Search ADS PubMed 13 Ding S. , Fellin T. , Zhu Y. , Lee S.Y. , Auberson Y.P. , Meaney D.F. , Coulter D.A. , Carmignoto G. , Haydon P.G. ( 2007 ) Enhanced astrocytic Ca2+ signals contribute to neuronal excitotoxicity after status epilepticus . J. Neurosci . 27 , 10674 – 10684 Google Scholar CrossRef Search ADS PubMed 14 Pasti L. , Volterra A. , Pozzan T. , Carmignoto G. ( 1997 ) Intracellular calcium oscillations in astrocytes: a highly plastic, bidirectional form of communication between neurons and astrocytes in situ . J. Neurosci . 17 , 7817 – 7830 Google Scholar CrossRef Search ADS PubMed 15 Fellin T. , Pascual O. , Gobbo S. , Pozzan T. , Haydon P.G. , Carmignoto G. ( 2004 ) Neuronal synchrony mediated by astrocytic glutamate through activation of extrasynaptic NMDA receptors . Neuron 43 , 729 – 743 Google Scholar CrossRef Search ADS PubMed 16 Kirischuk S. , Moller T. , Voitenko N. , Kettenmann H. , Verkhratsky A. ( 1995 ) ATP-induced cytoplasmic calcium mobilization in Bergmann glial cells . J. Neurosci . 15 , 7861 – 7871 Google Scholar CrossRef Search ADS PubMed 17 Sun W. , McConnell E. , Pare J.F. , Xu Q. , Chen M. , Peng W. , Lovatt D. , Han X. , Smith Y. , Nedergaard M. ( 2013 ) Glutamate-dependent neuroglial calcium signaling differs between young and adult brain . Science 339 , 197 – 200 Google Scholar CrossRef Search ADS PubMed 18 Walz W. , Ilschner S. , Ohlemeyer C. , Banati R. , Kettenmann H. ( 1993 ) Extracellular ATP activates a cation conductance and a K+ conductance in cultured microglial cells from mouse brain . J. Neurosci . 13 , 4403 – 4411 Google Scholar CrossRef Search ADS PubMed 19 Fraser D.D. , Duffy S. , Angelides K.J. , Perez-Velazquez J.L. , Kettenmann H. , MacVicar B.A. ( 1995 ) GABAA/benzodiazepine receptors in acutely isolated hippocampal astrocytes . J. Neurosci . 15 , 2720 – 2732 Google Scholar CrossRef Search ADS PubMed 20 Lin S.C. , Bergles D.E. ( 2004 ) Synaptic signaling between GABAergic interneurons and oligodendrocyte precursor cells in the hippocampus . Nat. Neurosci. 7 , 24 – 32 Google Scholar CrossRef Search ADS PubMed 21 Blankenfeld G. , Trotter J. , Kettenmann H. ( 1991 ) Expression and developmental regulation of a GABAA receptor in cultured murine cells of the oligodendrocyte lineage . Eur. J. Neurosci. 3 , 310 – 316 Google Scholar CrossRef Search ADS PubMed 22 Ding S. , Wang T. , Cui W. , Haydon P.G. ( 2009 ) Photothrombosis ischemia stimulates a sustained astrocytic Ca2+ signaling in vivo . Glia 57 , 767 – 776 Google Scholar CrossRef Search ADS PubMed 23 Kuhn S.A. , van Landeghem F.K. , Zacharias R. , Farber K. , Rappert A. , Pavlovic S. , Hoffmann A. , Nolte C. , Kettenmann H. ( 2004 ) Microglia express GABA(B) receptors to modulate interleukin release . Mol. Cell. Neurosci . 25 , 312 – 322 Google Scholar CrossRef Search ADS PubMed 24 Kang J. , Jiang L. , Goldman S.A. , Nedergaard M. ( 1998 ) Astrocyte-mediated potentiation of inhibitory synaptic transmission . Nat. Neurosci. 1 , 683 – 692 Google Scholar CrossRef Search ADS PubMed 25 Araque A. , Martin E.D. , Perea G. , Arellano J.I. , Buno W. ( 2002 ) Synaptically released acetylcholine evokes Ca2+ elevations in astrocytes in hippocampal slices . J. Neurosci . 22 , 2443 – 2450 Google Scholar CrossRef Search ADS PubMed 26 Takata N. , Mishima T. , Hisatsune C. , Nagai T. , Ebisui E. , Mikoshiba K. , Hirase H. ( 2011 ) Astrocyte calcium signaling transforms cholinergic modulation to cortical plasticity in vivo . J. Neurosci . 31 , 18155 – 18165 Google Scholar CrossRef Search ADS PubMed 27 Navarrete M. , Perea G. , de Sevilla D.F. , Gómez-Gonzalo M. , Núñez A. , Martín E.D. , Araque A. ( 2012 ) Astrocytes mediate in vivo cholinergic-induced synaptic plasticity . PLoS Biol. 10 , e1001259 Google Scholar CrossRef Search ADS PubMed 28 Paukert M. , Agarwal A. , Cha J. , Doze V.A. , Kang J.U. , Bergles D.E. ( 2014 ) Norepinephrine controls astroglial responsiveness to local circuit activity . Neuron 82 , 1263 – 1270 Google Scholar CrossRef Search ADS PubMed 29 Srinivasan R. , Huang B.S. , Venugopal S. , Johnston A.D. , Chai H. , Zeng H. , Golshani P. , Khakh B.S. ( 2015 ) Ca(2+) signaling in astrocytes from Ip3r2(-/-) mice in brain slices and during startle responses in vivo . Nat. Neurosci. 18 , 708 – 717 Google Scholar CrossRef Search ADS PubMed 30 Ding F. , O’Donnell J. , Thrane A.S. , Zeppenfeld D. , Kang H. , Xie L. , Wang F. , Nedergaard M. ( 2013 ) alpha1-Adrenergic receptors mediate coordinated Ca2+ signaling of cortical astrocytes in awake, behaving mice . Cell Calcium 54 , 387 – 394 Google Scholar CrossRef Search ADS PubMed 31 Farber K. , Pannasch U. , Kettenmann H. ( 2005 ) Dopamine and noradrenaline control distinct functions in rodent microglial cells . Mol. Cell. Neurosci . 29 , 128 – 138 Google Scholar CrossRef Search ADS PubMed 32 Kirchhoff F. , Mulhardt C. , Pastor A. , Becker C.M. , Kettenmann H. ( 1996 ) Expression of glycine receptor subunits in glial cells of the rat spinal cord . J. Neurochem. 66 , 1383 – 1390 Google Scholar CrossRef Search ADS PubMed 33 Dani J.W. , Chernjavsky A. , Smith S.J. ( 1992 ) Neuronal activity triggers calcium waves in hippocampal astrocyte networks . Neuron 8 , 429 – 440 Google Scholar CrossRef Search ADS PubMed 34 Cornell-Bell A.H. , Finkbeiner S.M. , Cooper M.S. , Smith S.J. ( 1990 ) Glutamate induces calcium waves in cultured astrocytes: long-range glial signaling . Science 247 , 470 – 473 Google Scholar CrossRef Search ADS PubMed 35 Bezzi P. , Carmignoto G. , Pasti L. , Vesce S. , Rossi D. , Rizzini B.L. , Pozzan T. , Volterra A. ( 1998 ) Prostaglandins stimulate calcium-dependent glutamate release in astrocytes . Nature 391 , 281 – 285 Google Scholar CrossRef Search ADS PubMed 36 Parpura V. , Basarsky T.A. , Liu F. , Jeftinija K. , Jeftinija S. , Haydon P.G. ( 1994 ) Glutamate-mediated astrocyte-neuron signalling . Nature 369 , 744 – 747 Google Scholar CrossRef Search ADS PubMed 37 Panatier A. , Vallee J. , Haber M. , Murai K.K. , Lacaille J.C. , Robitaille R. ( 2011 ) Astrocytes are endogenous regulators of basal transmission at central synapses . Cell 146 , 785 – 798 Google Scholar CrossRef Search ADS PubMed 38 Hirase H. , Qian L. , Bartho P. , Buzsaki G. ( 2004 ) Calcium dynamics of cortical astrocytic networks in vivo . PLoS Biol. 2 , E96 Google Scholar CrossRef Search ADS PubMed 39 Wang X. , Lou N. , Xu Q. , Tian G.F. , Peng W.G. , Han X. , Kang J. , Takano T. , Nedergaard M. ( 2006 ) Astrocytic Ca2+ signaling evoked by sensory stimulation in vivo . Nat. Neurosci. 9 , 816 – 823 Google Scholar CrossRef Search ADS PubMed 40 Winship I.R. , Plaa N. , Murphy T.H. ( 2007 ) Rapid astrocyte calcium signals correlate with neuronal activity and onset of the hemodynamic response in vivo . J. Neurosci . 27 , 6268 – 6272 Google Scholar CrossRef Search ADS PubMed 41 Schummers J. , Yu H. , Sur M. ( 2008 ) Tuned responses of astrocytes and their influence on hemodynamic signals in the visual cortex . Science 320 , 1638 – 1643 Google Scholar CrossRef Search ADS PubMed 42 Petzold G.C. , Albeanu D.F. , Sato T.F. , Murthy V.N. ( 2008 ) Coupling of neural activity to blood flow in olfactory glomeruli is mediated by astrocytic pathways . Neuron 58 , 897 – 910 Google Scholar CrossRef Search ADS PubMed 43 Nimmerjahn A. , Mukamel E.A. , Schnitzer M.J. ( 2009 ) Motor behavior activates Bergmann glial networks . Neuron 62 , 400 – 412 Google Scholar CrossRef Search ADS PubMed 44 Hamilton N.B. , Attwell D. ( 2010 ) Do astrocytes really exocytose neurotransmitters? Nat. Rev. Neurosci. 11 , 227 – 238 Google Scholar CrossRef Search ADS PubMed 45 Araque A. , Carmignoto G. , Haydon P.G. , Oliet S.H. , Robitaille R. , Volterra A. ( 2014 ) Gliotransmitters travel in time and space . Neuron 81 , 728 – 739 Google Scholar CrossRef Search ADS PubMed 46 Shigetomi E. , Kracun S. , Sofroniew M.V. , Khakh B.S. ( 2010 ) A genetically targeted optical sensor to monitor calcium signals in astrocyte processes . Nat. Neurosci. 13 , 759 – 766 Google Scholar CrossRef Search ADS PubMed 47 Shigetomi E. , Tong X. , Kwan K.Y. , Corey D.P. , Khakh B.S. ( 2012 ) TRPA1 channels regulate astrocyte resting calcium and inhibitory synapse efficacy through GAT-3 . Nat. Neurosci. 15 , 70 – 80 Google Scholar CrossRef Search ADS 48 Zonta M. , Angulo M.C. , Gobbo S. , Rosengarten B. , Hossmann K.A. , Pozzan T. , Carmignoto G. ( 2003 ) Neuron-to-astrocyte signaling is central to the dynamic control of brain microcirculation . Nat. Neurosci. 6 , 43 – 50 Google Scholar CrossRef Search ADS PubMed 49 Cunningham C. ( 2013 ) Microglia and neurodegeneration: the role of systemic inflammation . Glia 61 , 71 – 90 Google Scholar CrossRef Search ADS PubMed 50 Kettenmann H. , Hanisch U.K. , Noda M. , Verkhratsky A. ( 2011 ) Physiology of microglia . Physiol. Rev. 91 , 461 – 553 Google Scholar CrossRef Search ADS PubMed 51 Blinzinger K. , Kreutzberg G. ( 1968 ) Displacement of synaptic terminals from regenerating motoneurons by microglial cells . Z. Zellforsch. Mikrosk. Anat . 85 , 145 – 157 Google Scholar CrossRef Search ADS PubMed 52 Trapp B.D. , Wujek J.R. , Criste G.A. , Jalabi W. , Yin X. , Kidd G.J. , Stohlman S. , Ransohoff R. ( 2007 ) Evidence for synaptic stripping by cortical microglia . Glia 55 , 360 – 368 Google Scholar CrossRef Search ADS PubMed 53 Nimmerjahn A. , Kirchhoff F. , Helmchen F. ( 2005 ) Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo . Science 308 , 1314 – 1318 Google Scholar CrossRef Search ADS PubMed 54 Davalos D. , Grutzendler J. , Yang G. , Kim J.V. , Zuo Y. , Jung S. , Littman D.R. , Dustin M.L. , Gan W.B. ( 2005 ) ATP mediates rapid microglial response to local brain injury in vivo . Nat. Neurosci. 8 , 752 – 758 Google Scholar CrossRef Search ADS PubMed 55 Haynes S.E. , Hollopeter G. , Yang G. , Kurpius D. , Dailey M.E. , Gan W.B. , Julius D. ( 2006 ) The P2Y12 receptor regulates microglial activation by extracellular nucleotides . Nat. Neurosci. 9 , 1512 – 1519 Google Scholar CrossRef Search ADS PubMed 56 Eyo U.B. , Peng J. , Swiatkowski P. , Mukherjee A. , Bispo A. , Wu L.J. ( 2014 ) Neuronal hyperactivity recruits microglial processes via neuronal NMDA receptors and microglial P2Y12 receptors after status epilepticus . J. Neurosci . 34 , 10528 – 10540 Google Scholar CrossRef Search ADS PubMed 57 Wake H. , Moorhouse A.J. , Jinno S. , Kohsaka S. , Nabekura J. ( 2009 ) Resting microglia directly monitor the functional state of synapses in vivo and determine the fate of ischemic terminals . J. Neurosci . 29 , 3974 – 3980 Google Scholar CrossRef Search ADS PubMed 58 Tremblay M.E. , Lowery R.L. , Majewska A.K. ( 2010 ) Microglial interactions with synapses are modulated by visual experience . PLoS Biol. 8 , e1000527 Google Scholar CrossRef Search ADS PubMed 59 Stevens B. , Allen N.J. , Vazquez L.E. , Howell G.R. , Christopherson K.S. , Nouri N. , Micheva K.D. , Mehalow A.K. , Huberman A.D. , Stafford B. , Sher A. , Litke A.M. , Lambris J.D. , Smith S.J. , John S.W. , Barres B.A. ( 2007 ) The classical complement cascade mediates CNS synapse elimination . Cell 131 , 1164 – 1178 Google Scholar CrossRef Search ADS PubMed 60 Schafer D.P. , Lehrman E.K. , Kautzman A.G. , Koyama R. , Mardinly A.R. , Yamasaki R. , Ransohoff R.M. , Greenberg M.E. , Barres B.A. , Stevens B. ( 2012 ) Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner . Neuron 74 , 691 – 705 Google Scholar CrossRef Search ADS PubMed 61 Paolicelli R.C. , Bolasco G. , Pagani F. , Maggi L. , Scianni M. , Panzanelli P. , Giustetto M. , Ferreira T.A. , Guiducci E. , Dumas L. , Ragozzino D. , Gross C.T. ( 2011 ) Synaptic pruning by microglia is necessary for normal brain development . Science 333 , 1456 – 1458 Google Scholar CrossRef Search ADS PubMed 62 Wake H. , Moorhouse A.J. , Miyamoto A. , Nabekura J. ( 2013 ) Microglia: actively surveying and shaping neuronal circuit structure and function . Trends Neurosci . 36 , 209 – 217 Google Scholar CrossRef Search ADS PubMed 63 Li Y. , Du X.F. , Liu C.S. , Wen Z.L. , Du J.L. ( 2012 ) Reciprocal regulation between resting microglial dynamics and neuronal activity in vivo . Dev. Cell 23 , 1189 – 1202 Google Scholar CrossRef Search ADS PubMed 64 Parkhurst C.N. , Yang G. , Ninan I. , Savas J.N. , Yates J.R. 3rd , Lafaille J.J. , Hempstead B.L. , Littman D.R. , Gan W.B. ( 2013 ) Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor . Cell 155 , 1596 – 1609 Google Scholar CrossRef Search ADS PubMed 65 Beggs S. , Trang T. , Salter M.W. ( 2012 ) P2X4R+ microglia drive neuropathic pain . Nat. Neurosci. 15 , 1068 – 1073 Google Scholar CrossRef Search ADS PubMed 66 Coull J.A. , Beggs S. , Boudreau D. , Boivin D. , Tsuda M. , Inoue K. , Gravel C. , Salter M.W. , De Koninck Y. ( 2005 ) BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain . Nature 438 , 1017 – 1021 Google Scholar CrossRef Search ADS PubMed 67 Farber K. , Kettenmann H. ( 2006 ) Functional role of calcium signals for microglial function . Glia 54 , 656 – 665 Google Scholar CrossRef Search ADS PubMed 68 Pozner A. , Xu B. , Palumbos S. , Gee J.M. , Tvrdik P. , Capecchi M.R. ( 2015 ) Intracellular calcium dynamics in cortical microglia responding to focal laser injury in the PC:: G 5-tdT reporter mouse . Front. Mol. Neurosci . 8 , 12 Google Scholar CrossRef Search ADS PubMed 69 Barres B.A. , Raff M.C. ( 1993 ) Proliferation of oligodendrocyte precursor cells depends on electrical activity in axons . Nature 361 , 258 – 260 Google Scholar CrossRef Search ADS PubMed 70 Li Q. , Brus-Ramer M. , Martin J.H. , McDonald J.W. ( 2010 ) Electrical stimulation of the medullary pyramid promotes proliferation and differentiation of oligodendrocyte progenitor cells in the corticospinal tract of the adult rat . Neurosci. Lett . 479 , 128 – 133 Google Scholar CrossRef Search ADS PubMed 71 Simon C. , Gotz M. , Dimou L. ( 2011 ) Progenitors in the adult cerebral cortex: cell cycle properties and regulation by physiological stimuli and injury . Glia 59 , 869 – 881 Google Scholar CrossRef Search ADS PubMed 72 Mangin J.M. , Li P. , Scafidi J. , Gallo V. ( 2012 ) Experience-dependent regulation of NG2 progenitors in the developing barrel cortex . Nat. Neurosci. 15 , 1192 – 1194 Google Scholar CrossRef Search ADS PubMed 73 Gibson E.M. , Purger D. , Mount C.W. , Goldstein A.K. , Lin G.L. , Wood L.S. , Inema I. , Miller S.E. , Bieri G. , Zuchero J.B. , Barres B.A. , Woo P.J. , Vogel H. , Monje M. ( 2014 ) Neuronal activity promotes oligodendrogenesis and adaptive myelination in the mammalian brain . Science 344 , 1252304 Google Scholar CrossRef Search ADS PubMed 74 Chittajallu R. , Aguirre A. , Gallo V. ( 2004 ) NG2-positive cells in the mouse white and grey matter display distinct physiological properties . J. Physiol . 561 , 109 – 122 Google Scholar CrossRef Search ADS PubMed 75 Lin S.C. , Huck J.H. , Roberts J.D. , Macklin W.B. , Somogyi P. , Bergles D.E. ( 2005 ) Climbing fiber innervation of NG2-expressing glia in the mammalian cerebellum . Neuron 46 , 773 – 785 Google Scholar CrossRef Search ADS PubMed 76 Ziskin J.L. , Nishiyama A. , Rubio M. , Fukaya M. , Bergles D.E. ( 2007 ) Vesicular release of glutamate from unmyelinated axons in white matter . Nat. Neurosci. 10 , 321 – 330 Google Scholar CrossRef Search ADS PubMed 77 Zonouzi M. , Scafidi J. , Li P. , McEllin B. , Edwards J. , Dupree J.L. , Harvey L. , Sun D. , Hubner C.A. , Cull-Candy S.G. , Farrant M. , Gallo V. ( 2015 ) GABAergic regulation of cerebellar NG2 cell development is altered in perinatal white matter injury . Nat. Neurosci. 18 , 674 – 682 Google Scholar CrossRef Search ADS PubMed 78 Rivers L.E. , Young K.M. , Rizzi M. , Jamen F. , Psachoulia K. , Wade A. , Kessaris N. , Richardson W.D. ( 2008 ) PDGFRA/NG2 glia generate myelinating oligodendrocytes and piriform projection neurons in adult mice . Nat. Neurosci. 11 , 1392 – 1401 Google Scholar CrossRef Search ADS PubMed 79 McKenzie I.A. , Ohayon D. , Li H. , de Faria J.P. , Emery B. , Tohyama K. , Richardson W.D. ( 2014 ) Motor skill learning requires active central myelination . Science 346 , 318 – 322 Google Scholar CrossRef Search ADS PubMed 80 Xiao L. , Ohayon D. , McKenzie I.A. , Sinclair-Wilson A. , Wright J.L. , Fudge A.D. , Emery B. , Li H. , Richardson W.D. ( 2016 ) Rapid production of new oligodendrocytes is required in the earliest stages of motor-skill learning . Nat. Neurosci. 19 , 1210 – 1217 Google Scholar CrossRef Search ADS PubMed 81 Yeung M.S. , Zdunek S. , Bergmann O. , Bernard S. , Salehpour M. , Alkass K. , Perl S. , Tisdale J. , Possnert G. , Brundin L. , Druid H. , Frisen J. ( 2014 ) Dynamics of oligodendrocyte generation and myelination in the human brain . Cell 159 , 766 – 774 Google Scholar CrossRef Search ADS PubMed 82 Grubb M.S. , Burrone J. ( 2010 ) Activity-dependent relocation of the axon initial segment fine-tunes neuronal excitability . Nature 465 , 1070 – 1074 Google Scholar CrossRef Search ADS PubMed 83 Demerens C. , Stankoff B. , Logak M. , Anglade P. , Allinquant B. , Couraud F. , Zalc B. , Lubetzki C. ( 1996 ) Induction of myelination in the central nervous system by electrical activity . Proc. Natl. Acad. Sci. U.S.A. 93 , 9887 – 9892 Google Scholar CrossRef Search ADS PubMed 84 Wurtz C.C. , Ellisman M.H. ( 1986 ) Alterations in the ultrastructure of peripheral nodes of Ranvier associated with repetitive action potential propagation . J. Neurosci . 6 , 3133 – 3143 Google Scholar CrossRef Search ADS PubMed 85 Hines J.H. , Ravanelli A.M. , Schwindt R. , Scott E.K. , Appel B. ( 2015 ) Neuronal activity biases axon selection for myelination in vivo . Nat. Neurosci. 18 , 683 – 689 Google Scholar CrossRef Search ADS PubMed 86 Scholz J. , Klein M.C. , Behrens T.E. , Johansen-Berg H. ( 2009 ) Training induces changes in white-matter architecture . Nat. Neurosci. 12 , 1370 – 1371 Google Scholar CrossRef Search ADS PubMed 87 Carreiras M. , Seghier M.L. , Baquero S. , Estevez A. , Lozano A. , Devlin J.T. , Price C.J. ( 2009 ) An anatomical signature for literacy . Nature 461 , 983 – 986 Google Scholar CrossRef Search ADS PubMed 88 Bengtsson S.L. , Nagy Z. , Skare S. , Forsman L. , Forssberg H. , Ullen F. ( 2005 ) Extensive piano practicing has regionally specific effects on white matter development . Nat. Neurosci. 8 , 1148 – 1150 Google Scholar CrossRef Search ADS PubMed 89 Fields R.D. ( 2011 ) Imaging learning: the search for a memory trace . Neuroscientist 17 , 185 – 196 Google Scholar CrossRef Search ADS PubMed 90 Stevens B. , Porta S. , Haak L.L. , Gallo V. , Fields R.D. ( 2002 ) Adenosine: a neuron-glial transmitter promoting myelination in the CNS in response to action potentials . Neuron 36 , 855 – 868 Google Scholar CrossRef Search ADS PubMed 91 Wake H. , Lee P.R. , Fields R.D. ( 2011 ) Control of local protein synthesis and initial events in myelination by action potentials . Science 333 , 1647 – 1651 Google Scholar CrossRef Search ADS PubMed 92 Wake H. , Ortiz F.C. , Woo D.H. , Lee P.R. , Angulo M.C. , Fields R.D. ( 2015 ) Nonsynaptic junctions on myelinating glia promote preferential myelination of electrically active axons . Nat. Commun . 6 , 7844 Google Scholar CrossRef Search ADS PubMed 93 Lundgaard I. , Luzhynskaya A. , Stockley J.H. , Wang Z. , Evans K.A. , Swire M. , Volbracht K. , Gautier H.O.B. , Franklin R.J.M. , ffrench-Constant C. , Attwell D. , Káradóttir R.T. ( 2013 ) Neuregulin and BDNF induce a switch to NMDA receptor-dependent myelination by oligodendrocytes . PLoS Biol. 11 , e1001743 Google Scholar CrossRef Search ADS PubMed 94 Liu J. , Dietz K. , DeLoyht J.M. , Pedre X. , Kelkar D. , Kaur J. , Vialou V. , Lobo M.K. , Dietz D.M. , Nestler E.J. , Dupree J. , Casaccia P. ( 2012 ) Impaired adult myelination in the prefrontal cortex of socially isolated mice . Nat. Neurosci. 15 , 1621 – 1623 Google Scholar CrossRef Search ADS PubMed 95 Makinodan M. , Rosen K.M. , Ito S. , Corfas G. ( 2012 ) A critical period for social experience-dependent oligodendrocyte maturation and myelination . Science 337 , 1357 – 1360 Google Scholar CrossRef Search ADS PubMed 96 Sampaio-Baptista C. , Khrapitchev A.A. , Foxley S. , Schlagheck T. , Scholz J. , Jbabdi S. , DeLuca G.C. , Miller K.L. , Taylor A. , Thomas N. , Kleim J. , Sibson N.R. , Bannerman D. , Johansen-Berg H. ( 2013 ) Motor skill learning induces changes in white matter microstructure and myelination . J. Neurosci . 33 , 19499 – 19503 Google Scholar CrossRef Search ADS PubMed 97 Dubois-Dalcq M. , Behar T. , Hudson L. , Lazzarini R.A. ( 1986 ) Emergence of three myelin proteins in oligodendrocytes cultured without neurons . J. Cell Biol . 102 , 384 – 392 Google Scholar CrossRef Search ADS PubMed 98 Rosenberg S.S. , Kelland E.E. , Tokar E. , De la Torre A.R. , Chan J.R. ( 2008 ) The geometric and spatial constraints of the microenvironment induce oligodendrocyte differentiation . Proc. Natl. Acad. Sci. U.S.A . 105 , 14662 – 14667 Google Scholar CrossRef Search ADS PubMed 99 Lee S. , Leach M.K. , Redmond S.A. , Chong S.Y. , Mellon S.H. , Tuck S.J. , Feng Z.Q. , Corey J.M. , Chan J.R. ( 2012 ) A culture system to study oligodendrocyte myelination processes using engineered nanofibers . Nat. Methods 9 , 917 – 922 Google Scholar CrossRef Search ADS PubMed 100 Nave K.A. , Ehrenreich H. ( 2014 ) Myelination and oligodendrocyte functions in psychiatric diseases . JAMA Psychiatry 71 , 582 – 584 Google Scholar CrossRef Search ADS PubMed 101 Hakak Y. , Walker J.R. , Li C. , Wong W.H. , Davis K.L. , Buxbaum J.D. , Haroutunian V. , Fienberg A.A. ( 2001 ) Genome-wide expression analysis reveals dysregulation of myelination-related genes in chronic schizophrenia . Proc. Natl. Acad. Sci. U.S.A . 98 , 4746 – 4751 Google Scholar CrossRef Search ADS PubMed 102 Bennett I.J. , Madden D.J. ( 2014 ) Disconnected aging: cerebral white matter integrity and age-related differences in cognition . Neuroscience 276 , 187 – 205 Google Scholar CrossRef Search ADS PubMed Abbreviations Abbreviations AIS axonal initial segment AMPAR alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor ATP adenosine triphosphate BBB blood−brain barrier BDNF brain-derived neurotrophic factor CNS central nervous system CX3CR1 fractalkine receptor DRG dorsal root ganglion DTI diffusion tensor imaging FA fractional anisotropy GABAR gamma-aminobutyric acid receptor GFP green fluorescent protein MBP myelin basic protein mGluR metabotropic glutamate receptor MRI magnetic resonance imaging NG2 nerve/glia antigen 2 NMDAR N-methyl-d-aspartate receptor OPCs oligodendrocyte progenitor cells Pdgfra alpha receptor for platelet-derived growth factor TRPA1 transient receptor potential A1 TTX tetrodotoxin © The Author(s) 2018. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)
The Journal of Biochemistry – Oxford University Press
Published: Feb 13, 2018
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