Activity-dependent functions of non-electrical glial cells

Activity-dependent functions of non-electrical glial cells 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. 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( 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) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png The Journal of Biochemistry Oxford University Press

Activity-dependent functions of non-electrical glial cells

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Oxford University Press
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© The Author(s) 2018. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved
ISSN
0021-924X
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1756-2651
D.O.I.
10.1093/jb/mvy023
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Abstract

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. 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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)

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The Journal of BiochemistryOxford University Press

Published: Feb 13, 2018

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