Receptors, Ion Channels, and Signaling Mechanisms Underlying Microglial Dynamics
Open accessAbstract
Microglia, the innate immune cells of the CNS, play a pivotal role in brain injury and disease. Microglia are extremely motile; their highly ramified processes constantly survey the brain parenchyma, and they respond promptly to brain damage with targeted process movement toward the injury site. Microglia play a key role in brain development and function by pruning synapses during development, phagocytosing apoptotic newborn neurons, and regulating neuronal activity by direct microglia-neuron or indirect microglia-astrocyte-neuron interactions, which all depend on their process motility. This review highlights recent discoveries about microglial dynamics, focusing on the receptors, ion channels, and signaling pathways involved.
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Striatal microglia are enriched in mRNAs encoding mature microglia-specific homeostatic surveillance proteins, including those mediating G-protein-coupled chemosensing, chemotaxis, GTP signaling, and actin polymerization.
“In contrast, stMg are enriched in mRNAs encoding mature microglia-specific homeostatic surveillance proteins14,15, including those that mediate G-protein-coupled chemosensing, chemotaxis, GTP signaling, and actin polymerization20 (Fig. 1d,e, Supplementary Fig. 5a,b, Supplementary Table 3).”
From Epigenetic regulation of brain region-specific microglia clearance activity (2018) · cites this paper as [20]
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“Other substances that induce microglial chemotaxis in vivo are NO (in the white matter (24)) and fibrinogen (25), which can leak from damaged blood vessels.”
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“Increases in neuronal activity evoked by glutamate (or analogues like NMDA, AMPA, or kainate), or by blocking GABAergic inhibition, led to microglial process extension and enhanced baseline motility, whereas block of AMPA receptors had the opposite effect (5, 37, 50, 75).”
BackgroundInfluentialAge-related alterations in the dynamic behavior of microglia
Damani, M. R., Zhao, L., Fontainhas, A. M., Amaral, J., Fariss, R. N., & Wong, W. T. (2011) · Aging Cell · doi:10.1111/j.1474-9726.2010.00660.x · Cited by 504 · see citing works
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“In line with astrocyte-microglia communication via ATP, blockade of gap junction hemichannels, which may mediate astrocytic ATP release (53, 56, 57), led to microglia adopting shorter process lengths, as well as a reduced baseline process velocity (Fig.”
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“Astrocytes can amplify a local rise in extracellular [ATP] through this ATP-induced ATP release (53, 54), facilitating microglial chemotaxis after focal brain damage (4) and enhancing excitatory neurotransmission following microglia activation by LPS (10).”
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“Fractalkine receptor deficiency leads to a transient reduction of microglial number during early postnatal development (12, 13), microglia-mediated neurotoxicity (65– 67), and impaired phagocytosis of apoptotic newborn neurons, thus causing reduced neurogenesis and deficits in synaptic pruning associated with weaker s…”
BackgroundFractalkine and CX3CR1 regulate hippocampal neurogenesis in adult and aged rats
Bachstetter, A. D., Morganti, J. M., Jernberg, J., Schlunk, A., Mitchell, S. H., Brewster, K. W., Hudson, C. E., Cole, M. J., Harrison, J. K., Bickford, P. C., et al. (2011) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2009.11.022 · Cited by 364 · see citing works
Adenosine A2A receptor mediates microglial process retraction
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“Further work is needed to reveal which other mechanisms exist to evoke a targeted response of microglial processes under pathological conditions when activated microglia have substantially down-regulated their P2Y12 receptor expression (29, 45).”
BackgroundInfluentialThe regulation of cell motility and chemotaxis by phospholipid signaling
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“Because ATP functions in many cell types as an auto- or paracrine signaling molecule acting in the direct vicinity of its release site (74), a similar scenario may hold for microglia (during either baseline surveillance or chemotaxis).”
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“Increases in neuronal activity evoked by glutamate (or analogues like NMDA, AMPA, or kainate), or by blocking GABAergic inhibition, led to microglial process extension and enhanced baseline motility, whereas block of AMPA receptors had the opposite effect (5, 37, 50, 75).”
BackgroundResultInfluentialVesicular release of ATP at central synapses
Pankratov, Y. V., Lalo, U., Verkhratsky, A., & North, R. A. (2006) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-006-0061-x · Cited by 326 · cited 1× · see citing works
“This may reflect co-release of ATP with principal neurotransmitters from neurons (63) or secondary neuronal ATP release following NMDA receptor activation (37, 75), or may involve communication to astrocytes, which release ATP in response to neuronal activity (52).”
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Involvement of P2X 4 and P2Y 12 receptors in ATP‐induced microglial chemotaxis
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“Consistent with this signaling contributing to chemotaxis, blockade of PLC or PI3K or chelation of intracellular Ca(2) with 1,2-bis(o-aminophenoxy)ethane-N,N,N ,N -tetraacetic acid, acetoxymethyl ester (BAPTA-AM) suppresses ATP/ADP-induced chemotaxis in vitro (30, 38).”
BackgroundActivation of Neuronal NMDA Receptors Triggers Transient ATP-Mediated Microglial Process Outgrowth
Dissing-Olesen, L., LeDue, J. M., Rungta, R. L., Hefendehl, J. K., Choi, H. B., & MacVicar, B. A. (2014) · Journal of Neuroscience · doi:10.1523/jneurosci.0405-14.2014 · Cited by 286 · cited 13× · see citing works
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“Indeed, in microglia in situ, only extracellular nucleotides such as ATP, ADP, and UDP evoke inward membrane currents through ionotropic P2X (presumably P2X4 and P2X7) receptors and outward K currents via G protein-coupled (P2Y) purinergic receptors (23, 31–33, 35, 50), whereas other neurotransmitters (glutamate, GABA…”
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“Astrocyte Ca(2) waves can be sensed by some microglia via purinergic receptors that generate an outward membrane current (55).”
BackgroundATP‐induced ATP release from astrocytes
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“In line with astrocyte-microglia communication via ATP, blockade of gap junction hemichannels, which may mediate astrocytic ATP release (53, 56, 57), led to microglia adopting shorter process lengths, as well as a reduced baseline process velocity (Fig.”
BackgroundA release mechanism for stored ATP in ocular ciliary epithelial cells
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“Volume-sensitive Cl channels (and channels with similar pharmacology, like pannexins (46)) also mediate ATP release from cells (47) and, if ATP-induced ATP release from astrocytes promotes microglial chemotaxis by amplifying local ATP signals (4, 10), Cl channel blockers may inhibit chemotaxis by reducing ATP release.”
BackgroundThe actin cytoskeleton in normal and pathological cell motility
Lambrechts, A., Troys, M. V., & Ampè, C. (2004) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2004.01.024 · Cited by 228 · cited 1× · see citing works
“First, both of these modes depend on cytoskeletal changes arising from highly motile bundles of actin filaments (17).”
BackgroundEx Vivo Dynamic Imaging of Retinal Microglia Using Time-Lapse Confocal Microscopy
Lee, J. E., Liang, K. J., Fariss, R. N., & Wong, W. T. (2008) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.08-2076 · Cited by 212 · cited 1× · see citing works
“5 m/min (4, 5, 9, 23, 48), whereas thicker processes closer to the soma are less motile.”
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“Noradrenaline also abolished ATP-induced process outgrowth, suggesting a regulation of purinergic signaling by adrenergic signaling in microglia (58).”
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“Indeed, in microglia in situ, only extracellular nucleotides such as ATP, ADP, and UDP evoke inward membrane currents through ionotropic P2X (presumably P2X4 and P2X7) receptors and outward K currents via G protein-coupled (P2Y) purinergic receptors (23, 31–33, 35, 50), whereas other neurotransmitters (glutamate, GABA…”
BackgroundRegulation of Dynamic Behavior of Retinal Microglia by CX3CR1 Signaling
Liang, K. J., Lee, J. E., Wang, Y. D., Ma, W., Fontainhas, A. M., Fariss, R. N., & Wong, W. T. (2009) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.08-3357 · Cited by 202 · cited 1× · see citing works
“Although process velocity was reduced by 30% for baseline surveillance and in response to tissue damage, microglial morphology and tissue density were unaltered (71).”
BackgroundMicroglia processes block the spread of damage in the brain and require functional chloride channels
Hines, D. J., Hines, R. M., Mulligan, S. J., & MacVicar, B. A. (2009) · Glia · doi:10.1002/glia.20874 · Cited by 202 · see citing works
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Vascular endothelial growth factor induces chemotaxis and proliferation of microglial cells
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“Another indication that extracellular nucleotides regulate microglial process ramification came from mice lacking the ectonucleotidase CD39 (51), the hippocampal microglia of which had a less ramified morphology, with shorter processes covering a smaller cortical area than for wild-type mice, whereas their tissue dens…”
BackgroundInfluentialP2Y12receptor‐mediated integrin‐β1 activation regulates microglial process extension induced by ATP
Ohsawa, K., Irino, Y., Sanagi, T., Nakamura, Y., Suzuki, E., Inoue, K., & Kohsaka, S. (2010) · Glia · doi:10.1002/glia.20963 · Cited by 157 · cited 1× · see citing works
“In vitro, P2Y12 receptor activation also increases expression and activation of integrin M 1 (CD11b/CD29), a cell adhesion molecule that mediates interactions with the extracellular matrix (39, 40).”
BackgroundWu, L., Vadakkan, K. I., & Zhuo, M. (2007) · Glia · doi:10.1002/glia.20500 · Cited by 156 · cited 4× · see citing works
“5 m/min (4, 5, 9, 23, 48), whereas thicker processes closer to the soma are less motile.”
BackgroundInfluentialNO mediates microglial response to acute spinal cord injury under ATP control in vivo
Dibaj, P., Nadrigny, F., Steffens, H., Scheller, A., Hirrlinger, J., Schomburg, E. D., Neusch, C., & Kirchhoff, F. (2010) · Glia · doi:10.1002/glia.20993 · Cited by 144 · cited 3× · see citing works
“Other substances that induce microglial chemotaxis in vivo are NO (in the white matter (24)) and fibrinogen (25), which can leak from damaged blood vessels.”
BackgroundGlutamate release from microglia via glutamate transporter is enhanced by amyloid-beta peptide
Noda, M., Nakanishi, H., & Akaike, N. (1999) · Neuroscience · doi:10.1016/s0306-4522(99)00036-6 · Cited by 143 · see citing works
The bizarre pharmacology of the ATP release channel pannexin1
Dahl, G., Qiu, F., & Wang, J. (2013) · Neuropharmacology · doi:10.1016/j.neuropharm.2013.02.019 · Cited by 128 · cited 1× · see citing works
“Volume-sensitive Cl channels (and channels with similar pharmacology, like pannexins (46)) also mediate ATP release from cells (47) and, if ATP-induced ATP release from astrocytes promotes microglial chemotaxis by amplifying local ATP signals (4, 10), Cl channel blockers may inhibit chemotaxis by reducing ATP release.”
BackgroundSystemic inflammation regulates microglial responses to tissue damage in vivo
Gyoneva, S., Davalos, D., Biswas, D., Swanger, S. A., Garnier‐Amblard, E. C., Loth, F., Akassoglou, K., & Traynelis, S. F. (2014) · Glia · doi:10.1002/glia.22686 · Cited by 126 · see citing works
The brain’s best friend: microglial neurotoxicity revisited
Hellwig, S., Heinrich, A., & Biber, K. (2013) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2013.00071 · Cited by 126 · see citing works
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Involvement of P2X4 receptors in hippocampal microglial activation afterstatus epilepticus
Ulmann, L., Levavasseur, F., Avignone, E., Peyroutou, R., Hirbec, H., Audinat, É., & Rassendren, F. (2013) · Glia · doi:10.1002/glia.22516 · Cited by 110 · cited 1× · see citing works
“In addition to P2Y12, P2X4 receptors might contribute to ATP-evoked chemotaxis of microglia in vitro (30), but expression of P2X4 in situ only occurs after microglial activation, not in quiescent, ramified microglia (35).”
BackgroundAkt activation is involved in P2Y12 receptor‐mediated chemotaxis of microglia
Irino, Y., Nakamura, Y., Inoue, K., Kohsaka, S., & Ohsawa, K. (2008) · Journal of Neuroscience Research · doi:10.1002/jnr.21610 · Cited by 110 · cited 1× · see citing works
“Consistent with this signaling contributing to chemotaxis, blockade of PLC or PI3K or chelation of intracellular Ca(2) with 1,2-bis(o-aminophenoxy)ethane-N,N,N ,N -tetraacetic acid, acetoxymethyl ester (BAPTA-AM) suppresses ATP/ADP-induced chemotaxis in vitro (30, 38).”
BackgroundSmall Rho GTPases in the control of cell shape and mobility
Murali, A., & Rajalingam, K. (2013) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-013-1519-6 · Cited by 105 · cited 1× · see citing works
“Furthermore, the small Rho-GTPase Rac, a key regulator of actin dynamics (20), is highly enriched in the motile endings of microglial processes, and Rac down-regulation prevents directed process movement in response to neuronal activity (9).”
BackgroundZujovic, V., Schussler, N., Jourdain, D., Duverger, D., & Taupin, V. (2001) · Journal of Neuroimmunology · doi:10.1016/s0165-5728(01)00259-4 · Cited by 102 · see citing works
The ectonucleotidase cd39/ENTPDase1 modulates purinergic‐mediated microglial migration
Färber, K., Markworth, S., Pannasch, U., Nolte, C., Prinz, V., Kronenberg, G., Gertz, K. R., Endres, M., Bechmann, I., Enjyoji, K., et al. (2007) · Glia · doi:10.1002/glia.20606 · Cited by 102 · cited 1× · see citing works
“In cultured microglia, although chemotactic migration was not induced by adenosine alone, it was reduced with adenosine A1 receptors blocked or knocked out, or with the ectonucleotidase CD39 deleted (43), which seems at variance with a role only for P2Y12 receptors in regulating chemotaxis (34).”
BackgroundArnoux, I., Hoshiko, M., Mandavy, L., Avignone, E., Yamamoto, N., & Audinat, É. (2013) · Glia · doi:10.1002/glia.22503 · Cited by 96 · see citing works
Kurpius, D., Nolley, E. P., & Dailey, M. E. (2007) · Glia · doi:10.1002/glia.20509 · Cited by 83 · see citing works
Resting Microglial Motility Is Independent of Synaptic Plasticity in Mammalian Brain
Wu, L., & Zhuo, M. (2008) · Journal of Neurophysiology · doi:10.1152/jn.01210.2007 · Cited by 81 · cited 2× · see citing works
“Furthermore, contradicting the idea that process motility correlates with neuronal activity, highfrequency stimulation inducing long-term potentiation in hippocampal slices did not change microglial baseline surveillance (59).”
BackgroundAdenosine A3 receptor is involved in ADP‐induced microglial process extension and migration
Ohsawa, K., Sanagi, T., Nakamura, Y., Suzuki, E., Inoue, K., & Kohsaka, S. (2012) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2012.07693.x · Cited by 79 · cited 1× · see citing works
“In another study, selective P2Y12 receptor activation by 2-methylthioADP led to microglial process outgrowth and migration only on co-stimulation with adenosine, which, in contrast to the aforementioned study, was attributed to adenosine acting via A3 adenosine receptors (44).”
ResultDhuill, C. N., Fox, G. B., Pittock, S. J., O’Connell, A. W., Murphy, K. J., & Regan, C. M. (1999) · Journal of Neuroscience Research · doi:10.1002/(sici)1097-4547(19990101)55:1 · Cited by 73 · see citing works
Isfort, K., Ebert, F., Bornhorst, J., Sargin, S., Kardakaris, R., Pasparakis, M., Bähler, M., Schwerdtle, T., Schwab, A., & Hanley, P. J. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.289793 · Cited by 51 · see citing works
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“High amounts of filamentous actin are present in microglial cells (18), and agents blocking actin polymerization such as cytochalasin B or latrunculin B inhibit both microglial baseline surveillance and chemotaxis in situ (19).”
BackgroundSimoni, A. D., Allen, N. J., & Attwell, D. (2008) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2008.06417.x · Cited by 27 · cited 1× · see citing works
“Indeed, in microglia in situ, only extracellular nucleotides such as ATP, ADP, and UDP evoke inward membrane currents through ionotropic P2X (presumably P2X4 and P2X7) receptors and outward K currents via G protein-coupled (P2Y) purinergic receptors (23, 31–33, 35, 50), whereas other neurotransmitters (glutamate, GABA…”
BackgroundSelf-citationMcIlvain, H. B., Ma, L., Ludwig, B., Manners, M. T., Martone, R. L., Dunlop, J., Kaftan, E. J., Kennedy, J. D., & Whiteside, G. T. (2010) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2010.06.046 · Cited by 17 · cited 1× · see citing works
“In vitro, P2Y12 receptor activation also increases expression and activation of integrin M 1 (CD11b/CD29), a cell adhesion molecule that mediates interactions with the extracellular matrix (39, 40).”
BackgroundZujovic (2000) · doi:10.1002/(sici)1098-1136(20000215)29:4
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Inflammation as a central mechanism in Alzheimer's disease
Kinney, J. W., Bemiller, S. M., Murtishaw, A. S., Leisgang, A. M., Salazar, A. M., & Lamb, B. T. (2018) · Alzheimer's & Dementia: Translational Research & Clinical Interventions · doi:10.1016/j.trci.2018.06.014 · Cited by 2,253 · see citing works
“Overall surveillance of the surrounding neuronal environment is accomplished via a large number of signaling mechanisms [99,102].”
BackgroundAmyloid β-based therapy for Alzheimer’s disease: Challenges, successes and future
Zhang, Y., Chen, H., Li, R., Sterling, K., & Song, W. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01484-7 · Cited by 988 · see citing works
“These cells communicate with surrounding environments including neurons, astrocytes and blood vessels to maintain the development and homeostasis of the CNS.(163,164) When microglia recognize the insults of the CNS, they respond to the injury or invasion by a morphological change, resulting in cell enlargement and mig…”
BackgroundEpigenetic regulation of brain region-specific microglia clearance activity
Ayata, P., Badimon, A., Strasburger, H. J., Duff, M. K., Montgomery, S. E., Loh, Y.-H. E., Ebert, A., Pimenova, A. A., Ramirez, B. R., Chan, A. T., et al. (2018) · Nature Neuroscience · doi:10.1038/s41593-018-0192-3 · Cited by 460 · see citing works
CLC Chloride Channels and Transporters: Structure, Function, Physiology, and Disease
Jentsch, T. J., & Pusch, M. (2018) · Physiological Reviews · doi:10.1152/physrev.00047.2017 · Cited by 452 · see citing works
GABA-Receptive Microglia Selectively Sculpt Developing Inhibitory Circuits
Favuzzi, E., Huang, S., Saldi, G.-A., Binan, L., Ibrahim, L. A., Fernández-Otero, M., Cao, Y., Zeine, A., Sefah, A., Zheng, K., et al. (2020) · Cell · doi:10.1016/j.cell.2021.06.018 · Cited by 321 · see citing works
“In response to various chemotactic signals, microglia are attracted to and interact with neurons and synapses (Badimon et al., 2020; Cserép et al., 2020; Madry and Attwell, 2015).”
Mast cells in neuroinflammation and brain disorders
Hendriksen, E., van Bergeijk, D. A., Oosting, R. S., & Redegeld, F. A. (2017) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2017.05.001 · Cited by 240 · see citing works
“P2Y receptors, cytokine receptors, integrins), which enable them to interact with neighbouring cells including neurons, astrocytes and immune cells [11-13].”
How microglia sense and regulate neuronal activity
Umpierre, A. D., & Wu, L. (2021) · Glia · doi:10.1002/glia.23961 · Cited by 237 · see citing works
“However, there are additional mechanisms that also influence microglial motility (Madry & Attwell, 2015).”
BackgroundOxidative Stress‐Related Mechanisms in Schizophrenia Pathogenesis and New Treatment Perspectives
Ermakov, E. A., Dmitrieva, E. M., Parshukova, D. A., Kazantseva, D. V., Vasilieva, A. R., & Smirnova, L. P. (2021) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2021/8881770 · Cited by 252 · see citing works
“Ionotropic P2X and metabotropic P2Y purinergic receptors are important for the regulation of the microglial actin cytoskeleton [262].”
BackgroundHaslund‐Vinding, J., McBean, G., Jaquet, V, & Vilhardt, F. (2017) · British Journal of Pharmacology · doi:10.1111/bph.13425 · Cited by 169 · see citing works
Molecular Mechanisms of Microglial Motility: Changes in Ageing and Alzheimer’s Disease
Franco-Bocanegra, D. K., McAuley, C., Nicoll, J. A. R., & Boche, D. (2019) · Cells · doi:10.3390/cells8060639 · Cited by 147 · see citing works
“Studies have shown that surveillance motility is highly dependent of morphological factors such as the number, the length, and the degree of ramification of the microglial processes [19].”
BackgroundInfluentialLiu, C.-C., Wang, N., Chen, Y., Inoue, Y., Shue, F., Ren, Y., Wang, M., Qiao, W., Ikezu, T. C., Li, Z., et al. (2023) · Nature Immunology · doi:10.1038/s41590-023-01640-9 · Cited by 146 · see citing works
“The morphology of microglia is correlated with their activation status in different pathological states 44,45 ; thus, we investigated the effects of apoE isoforms on microglial morphology.”
BackgroundLannes, N., Eppler, E., Etemad, S., Yotovski, P., & Filgueira, L. (2017) · Oncotarget · doi:10.18632/oncotarget.23106 · Cited by 139 · see citing works
“Microglia build a 3-dimensional network in the CNS and they communicate also through hemichannels and gap junctions [161, 162].”
BackgroundPuntambekar, S. S., Moutinho, M., Lin, P. B.-C., Jadhav, V., Tumbleson-Brink, D., Balaji, A., Benito, M. A., Xu, G., Oblak, A., Lasagna-Reeves, C. A., et al. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00545-9 · Cited by 113 · see citing works
“Signaling via CX3CR1 and its neuronal ligand CX3CL1 represents one of multiple important neuro-glial communication axes that maintain microglial homeostasis [9, 10].”
BackgroundMicroglial Dysregulation in OCD, Tourette Syndrome, and PANDAS
Frick, L. R., & Pittenger, C. (2016) · Journal of Immunology Research · doi:10.1155/2016/8606057 · Cited by 111 · see citing works
“This may lead to impairments in their surveillance ability [63, 64].”
Ion Channels and Receptors as Determinants of Microglial Function
Izquierdo, P., Attwell, D., & Madry, C. (2019) · Trends in Neurosciences · doi:10.1016/j.tins.2018.12.007 · Cited by 102 · see citing works
Self-citationAlexaki, V. I., Fodelianaki, G., Neuwirth, A., Mund, C., Kourgiantaki, A., Ieronimaki, E., Lyroni, K., Troullinaki, M., Fujii, C., Kanczkowski, W., et al. (2017) · Molecular Psychiatry · doi:10.1038/mp.2017.167 · Cited by 99 · see citing works
Purinergic signaling orchestrating neuron-glia communication
Agostinho, P. M., Madeira, D., Dias, L., Simões, A. P., Cunha, R. A., & Canas, P. M. (2020) · Pharmacological Research · doi:10.1016/j.phrs.2020.105253 · Cited by 91 · see citing works
Microglial morphology in Alzheimer’s disease and after Aβ immunotherapy
Franco-Bocanegra, D., Gourari, Y., McAuley, C., Chatelet, D. S., Johnston, D. A., Nicoll, J. A. R., & Boche, D. (2021) · Scientific Reports · doi:10.1038/s41598-021-95535-0 · Cited by 85 · see citing works
Altered morphological dynamics of activated microglia after induction of status epilepticus
Avignone, E., Lepleux, M., Angibaud, J., & Nägerl, U. V. (2015) · Journal of Neuroinflammation · doi:10.1186/s12974-015-0421-6 · Cited by 88 · see citing works
“However, purinergic signaling seems to play a major role [6, 11].”
BackgroundMorrison, H. W., & Filosa, J. A. (2016) · Neuroscience · doi:10.1016/j.neuroscience.2016.09.047 · Cited by 82 · see citing works
“fractalkine and S100β respectively) (Bianchi et al., 2010; Madry and Attwell, 2015).”
BackgroundGhosh, M. K., Chakraborty, D., Sarkar, S., Bhowmik, A., & Basu, M. (2019) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-019-0075-4 · Cited by 69 · see citing works
Glial and neuroimmune cell choreography in sexually dimorphic pain signaling
Midavaine, É., Côté, J., Marchand, S., & Sarret, P. (2021) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2021.01.023 · Cited by 67 · see citing works
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“With the focus of this review on astrocytes, researches on cell motility in oligodendrocytes and microglia have been reviewed in other recent publications [18, 19].”
BackgroundMicroglia Purinoceptor P2Y6: An Emerging Therapeutic Target in CNS Diseases
Anwar, S., Pons, V., & Rivest, S. (2020) · Cells · doi:10.3390/cells9071595 · Cited by 61 · see citing works
“ATP is a potent inducer of microglia motility [48].”
BackgroundHow microglia contribute to the induction and maintenance of neuropathic pain
Malcangio, M., & Sideris-Lampretsas, G. (2025) · Nature reviews. Neuroscience · doi:10.1038/s41583-025-00914-5 · Cited by 66 · see citing works
“In homeostatic conditions, ATP is rapidly hydrolysed to ADP and further converted to AMP and adenosine 44 .”
Jairaman, A., McQuade, A., Granzotto, A., Kang, Y. J., Chadarevian, J. P., Gandhi, S., Parker, I., Smith, I., Cho, H., Sensi, S. L., et al. (2022) · eLife · doi:10.7554/elife.73021 · Cited by 61 · see citing works
“ATP released from both homeostatic and damaged cells is hydrolyzed locally by nucleosidases such as the ectonucleotidase NTPDase1 (CD39) or pyrophosphatase NPP1 to produce ADP ( Dissing-Olesen et al., 2014 ; Madry and Attwell, 2015 ; Zhang et al., 2014 ).”
Madry, C., Arancibia‐Cárcamo, I. L., Kyrargyri, V., Chan, V. T. T., Hamilton, N. B., & Attwell, D. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1715354115 · Cited by 58 · see citing works
“A signaling is present in many tissues, but is particularly important for microglia, the brain’s innate immune cells (1).”
BackgroundSelf-citationThermosensitive TRPV4 channels mediate temperature-dependent microglia movement
Nishimoto, R., Derouiche, S., Eto, K., Deveci, A., Kashio, M., Kimori, Y., MATSUOKA, Y., Morimatsu, H., Nabekura, J., & Tominaga, M. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2012894118 · Cited by 59 · see citing works
In vivo characterization of functional states of cortical microglia during peripheral inflammation
Riester, K., Brawek, B., Savitska, D., Fröhlich, N. T., Zirdum, E., Mojtahedi, N., Heneka, M. T., & Garaschuk, O. (2019) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2019.12.007 · Cited by 59 · see citing works
In Vivo Imaging of Microglial Calcium Signaling in Brain Inflammation and Injury
Tvrdík, P., & Kalani, M. Y. S. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18112366 · Cited by 51 · see citing works
“This signaling pathway eventually leads to activation of protein kinase B (PKB) and reorganization of the actin cytoskeleton, leading to cell growth and chemotaxis [18].”
BackgroundEffect of Caloric Restriction on the in vivo Functional Properties of Aging Microglia
Olmedillas, M., Fröhlich, N. T., Figarella, K., Mojtahedi, N., & Garaschuk, O. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.00750 · Cited by 45 · see citing works
“The latter include gene expression (41) proliferation (42), phagocytosis (43), IL-1β production, strongly associated with the activation of the NLRP3 inflammasome (44, 45), and cytoskeletal rearrangements necessary for process extension (46, 47).”
BackgroundSáez-Orellana, F., Fuentes-Fuentes, M. C., Godoy, P. A., Silva-Grecchi, T., Panes-Fernández, J., Guzmán, L., Yévenes, G. E., Gavilán, J., Egan, T. M., Aguayo, L. G., et al. (2017) · Neuropharmacology · doi:10.1016/j.neuropharm.2017.10.027 · Cited by 43 · see citing works
“Thus, it is entirely possible that eATP contributes to neuroinflammation in AD patients (Di Virgilio et al., 2009) by gating P2X7Rs and activating microglia (Choi et al., 2007; Madry and Attwell, 2015; Parvathenani et al., 2003).”
Ivan, D. C., Berve, K., Walthert, S., Monaco, G., Borst, K., Bouillet, E., Ferreira, F. M., Lee, H., Steudler, J., Buch, T., et al. (2023) · Acta Neuropathologica Communications · doi:10.1186/s40478-023-01535-8 · Cited by 41 · see citing works
“While the correlation between morphological changes and functional alterations in BAMs remains unclear, highly ramified microglia are normally associated with increased homeostatic surveillance and neuroprotective functions [81], with the complexity of microglia ramification regulated by the sensing of neuronal activi…”
BackgroundMicroglia as therapeutic targets after neurological injury: strategy for cell therapy
Scott, M. C., Bedi, S. S., Olson, S. D., Sears, C. M., & Cox, C. S. (2021) · Expert Opinion on Therapeutic Targets · doi:10.1080/14728222.2021.1934447 · Cited by 42 · see citing works
“membrane voltage, intracellular calcium concentration, and activation of G-protein coupled receptors [58].”
BackgroundEyo, U. B., Miner, S. A., Weiner, J. A., & Dailey, M. E. (2015) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2015.11.009 · Cited by 39 · see citing works
“Because purines have been shown to strongly regulate microglial motility and migration (Madry and Attwell, 2015; Ohsawa and Kohsaka, 2011) these molecules are good candidates for regulating developmental changes in microglial behavior.”
Barkaway, A., Attwell, D., & Korte, N. (2022) · Neurophotonics · doi:10.1117/1.nph.9.3.031914 · Cited by 37 · see citing works
“FKN is predominantly present in neurons (membrane-bound or released in a soluble form) and binds to CX3CR1 selectively expressed in microglia orMΦ.(234) In the healthy brain, FKN promotes synaptic strength, neurogenesis, and memory formation and may act as a “find me” signal for microglia to clear neuronal debris,(201…”
BackgroundSelf-citationPan, K., & Garaschuk, O. (2022) · The Journal of Physiology · doi:10.1113/jp279521 · Cited by 35 · see citing works
“…a negative resting membrane potential, essential for normal micro-glial ramification and surveillance, the activation of P2Y12 receptors causes the phosphorylation of the serine/threonine kinase Akt via phosphatidylinositol 3-kinase, PLC-, and Ca 2 + -mediated mechanisms (Madry & Attwell, 2015).”
Gullo, F., Ceriani, M., D’Aloia, A., Wanke, E., Constanti, A., Costa, B., & Lecchi, M. (2017) · Frontiers in Neuroscience · doi:10.3389/fnins.2017.00500 · Cited by 35 · see citing works
“Only recently, ion channels have also been described to be functionally expressed in microglia (for a minireview, see Madry and Attwell, 2015).”
BackgroundZahiri, D., Burow, P., Großmann, C., Müller, C. E., Klapperstück, M., & Markwárdt, F. (2020) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2020.118915 · Cited by 31 · see citing works
Modulation of Microglial Function by ATP-Gated P2X7 Receptors: Studies in Rat, Mice and Human
Tewari, M., Michalski, S. A., & Egan, T. M. (2024) · Cells · doi:10.3390/cells13020161 · Cited by 33 · see citing works
“The first-order branches, which can reach a length of 50 µ m, are highly motile, extending and retracting at a rate of 1.5 µ m/min and capable of surveying the entire brain environment once every few hours [141,143].”
BackgroundInfluentialNeuronal brain‐derived neurotrophic factor manipulates microglial dynamics
Onodera, J., Nagata, H., Nakashima, A., Ikegaya, Y., & Koyama, R. (2021) · Glia · doi:10.1002/glia.23934 · Cited by 42 · see citing works
“Microglia phagocytose or trogocytose axonal compartments to refine neuronal circuits (Schafer et al., 2012; Weinhard et al., 2018); these functions of microglia crucially depend on the surveillance and detection of neuronal components mediated by extracellular molecules (Madry & Attwell, 2015).”
BackgroundMartín‐Estebané, M., Navascués, J., Sierra, A., Martín‐Guerrero, S. M., Cuadros, M. Á., Carrasco, M., & Marín‐Teva, J. L. (2017) · PLoS ONE · doi:10.1371/journal.pone.0182450 · Cited by 27 · see citing works
Roles of Microglial Ion Channel in Neurodegenerative Diseases
Cojocaru, A., Burada, E., Bălșeanu, A.-T., Deftu, A., Cătălin, B., Popa‐Wagner, A., & Osiac, E. (2021) · Journal of Clinical Medicine · doi:10.3390/jcm10061239 · Cited by 28 · see citing works
“Another class of channels expressed in microglia cells that are of particular interest for neurodegeneration is represented by the potential transient receptor (TRP) channels [22,82].”
BackgroundMaking tracks: microglia and the extracellular matrix
Wareham, L. K., & Calkins, D. J. (2025) · Molecular Neurodegeneration · doi:10.1186/s13024-025-00898-x · Cited by 31 · see citing works
“The changes exerted by and influencing the motility of individual microglial processes, by comparison, are extraordinarily focal, just a fraction of the small diameter of the diameter of the cell body (typically, 3–6 μm; [75]).”
The role of microglia membrane potential in chemotaxis
Laprell, L., Schulze, C., Brehme, M.-L., & Oertner, T. G. (2021) · Journal of Neuroinflammation · doi:10.1186/s12974-020-02048-0 · Cited by 25 · see citing works
Microglial TNFα controls daily changes in synaptic GABAARs and sleep slow waves
Pinto, M. J., Bizien, L., Fabre, J. M., Ðukanović, N., Lepetz, V., Henderson, F., Pujol, M., Sala, R. W., Tarpin, T., Popa, D., et al. (2024) · The Journal of Cell Biology · doi:10.1083/jcb.202401041 · Cited by 28 · see citing works
“Microglia behavior is finely tuned by ATP via an array of purinergic receptors (Madry and Attwell, 2015).”
Beeken, J., Mertens, M., Stas, N., Kessels, S., Aerts, L., Janssen, B., Mussen, F., Pinto, S., Vennekens, R., Rigo, J., et al. (2022) · Glia · doi:10.1002/glia.24243 · Cited by 24 · see citing works
Xie, X., Hao, J.-J., Shi, J.-Z., Zhou, Y., Liu, P., Wang, F., Zheng, X.-M., Yu, X., Wang, C., Yan, Y., et al. (2023) · International Immunopharmacology · doi:10.1016/j.intimp.2023.109994 · Cited by 22 · see citing works
Tian, Y., Milić, J., Monasor, L. S., Chakraborty, R., Wang, S., Yuan, Y., Asare, Y., Behrends, C., Tahirovic, S., & Bernhagen, J. (2023) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-023-04911-8 · Cited by 21 · see citing works
“Interestingly, Akt signaling is a key pathway associated with microglia cell motility [62, 63].”
BackgroundMercury neurotoxicity in gold miners
Lopez, M. E. C., Augusto‐Oliveira, M., Lopes-Araújo, A., Santos-Sacramento, L., Monteiro, J. R. S., da Rocha, F. F., & Arrifano, G. D. P. (2022) · Advances in neurotoxicology · doi:10.1016/bs.ant.2022.04.003 · Cited by 20 · see citing works
Marin, I. A., Gutman-Wei, A. Y., Chew, K. S., Raissi, A. J., Djurisic, M. R., & Shatz, C. J. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2203965119 · Cited by 16 · see citing works
Bace1 Deletion in the Adult Reverses Epileptiform Activity and Sleep–wake Disturbances in AD Mice
Yao, A. Y., Halloran, P. J., Ge, Y., Singh, N., Zhou, J., Galske, J., He, W., Yan, R., & Hu, X. (2023) · Journal of Neuroscience · doi:10.1523/jneurosci.2124-22.2023 · Cited by 21 · see citing works
“Morphologic variation in microglial processes may lead to differences in motility and ultimately impacts microglial function (Nimmerjahn et al., 2005; Madry and Attwell, 2015).”
Quantitative modeling of regular retinal microglia distribution
Endo, Y., Asanuma, D., Namiki, S., Sugihara, K., Hirose, K., Uemura, A., Kubota, Y., & Miura, T. (2021) · Scientific Reports · doi:10.1038/s41598-021-01820-3 · Cited by 16 · see citing works
Guzmán‐Ruiz, M. A., Vargas, N. N. G., Carreto, R. J. R., González-Orozco, J. C., Torres-Hernández, B. A., Valle-Rodríguez, M., Guevara‐Guzmán, R., & Chavarría, A. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1392077 · Cited by 16 · see citing works
Shirakawa, H., & Kaneko, S. (2018) · Biological and Pharmaceutical Bulletin · doi:10.1248/bpb.b18-00319 · Cited by 15 · see citing works
Richard, S. A. (2022) · Journal of Oncology · doi:10.1155/2022/8903482 · Cited by 14 · see citing works
Dynamic changes in mitochondria support phenotypic flexibility of microglia
Espinoza, K., Schaler, A. W., Gray, D. T., Sass, A. R., Escobar, A., Moore, K., Yu, M. A., Chamorro, C. G., & Biase, L. M. D. (2025) · Nature Communications · doi:10.1038/s41467-025-66709-5 · Cited by 14 · see citing works
Maturation of the microglial population varies across mesolimbic nuclei
Hope, K. T., Hawes, I. A., Moca, E. N., Bonci, A., & Biase, L. M. D. (2020) · European Journal of Neuroscience · doi:10.1111/ejn.14740 · Cited by 14 · see citing works
“The highly ramified processes of adult microglia have been associated with tissue surveillance, synapse formation, synapse elimination, and changes in synaptic receptor expression (Madry & Attwell, 2015; Wu, Dissing-Olesen, MacVicar, & Stevens, 2015).”
BackgroundDyne, E. D., Cawood, M., Suzelis, M., Russell, R., & Kim, M. (2021) · The Journal of Comparative Neurology · doi:10.1002/cne.25274 · Cited by 13 · see citing works
“Microglia can undergo directed motility while surveilling for cues, where the cell body remains relatively stationary while the processes extend toward biochemical cues (Khurana, 2002; Madry & Attwell, 2015).”
BackgroundMicroglia and status epilepticus in the immature brain
López‐Meraz, M. L., & Álvarez‐Croda, D. (2022) · Epilepsia Open · doi:10.1002/epi4.12610 · Cited by 11 · see citing works
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“This process was driven by ATP/ADP-induced P2Y12 receptor signaling, activation of phospholipase C and Ca2+-dependent phosphorylation of serine/threonine kinase (Akt) as well as phosphoinositide-3-kinase (PI3K)-mediated Akt phosphorylation (Eichhoff et al., 2011; Madry & Attwell, 2015).”
BackgroundControl of microglial dynamics by Arp2/3 and the autism and schizophrenia-associated protein Cyfip1
Drew, J., Arancibia-Carcamo, I. L., Jolivet, R., Lopez-Domenech, G., Attwell, D., & Kittler, J. T. (2020) · doi:10.1101/2020.05.31.124941 · Cited by 12 · see citing works
“The ramified shape of surveying microglia forms dynamically from the extension and retraction of processes (Arcuri et al., 2017; Madry and Attwell, 2015).”
BackgroundSelf-citationOpen chromatin landscape of rat microglia upon proinvasive or inflammatory polarization
Przanowski, P., Mondal, S. S., Cabaj, A., Dębski, K. J., Wojtaś, B., Gielniewski, B., Kaza, B., Kaminska, B., & Dąbrowski, M. (2019) · Glia · doi:10.1002/glia.23686 · Cited by 9 · see citing works
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“Microglia appearance can range from ramified to amoeboid-like cells dependent on their microenvironment [4,5], however this two state model does not capture the full range of microglia heterogenity [6].”
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Self-citationA Comprehensive Review of Herbal Medicines for the Treatment of Alzheimer's Disease
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Calcium Signalling in Microglia
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Effects of diet on immune cells within the central nervous system
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Protective effect of acute splenic irradiation in rats with traumatic brain injury
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“These receptors activate signaling pathways involving Akt, which in turn promote actin cytoskeleton reorganization and the expression and activation of integrins, key regulators of structural and morphological dynamics in microglia (Madry and Attwell 2015; Ohsawa et al. 2010).”
p27kip1 Modulates the Morphology and Phagocytic Activity of Microglia
Beeken, J., Kessels, S., Rigo, J., Alpizar, Y. A., Nguyen, L., & Brône, B. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms231810432 · Cited by 5 · see citing works
“Moreover, brain surveillance is also regulated by the density of microglia, the velocity of process movement, the extension and retraction frequency, as well as the morphological complexity [17,41].”
BackgroundInfluentialEppur si muove: the dynamic brain pericyte
Wilhelm, I., Győri, F., Dudás, T., Nagy, V., Shreeya, T., Krecsmarik, M., Farkas, A. E., Fazakas, C., & Krizbai, I. A. (2025) · Fluids and Barriers of the CNS · doi:10.1186/s12987-025-00706-0 · Cited by 4 · see citing works
“This phenomenon occurs much more slowly than the 0.6–2.5 μm/min velocity of microglia processes [115, 116] and becomes even slower with ageing, significantly contributing to increased variability in blood flow [110].”
InfluentialMathematical Modeling of PI3K/Akt Pathway in Microglia
Poshtkohi, A., Wade, J. J., Mcdaid, L. J., Liu, J., Dallas, M. L., & Bithell, A. (2024) · Neural Computation · doi:10.1162/neco_a_01643 · Cited by 4 · see citing works
“P2Y 12 is an important receptor that is reported to be actively responsible for directed motility and chemotaxis (Madry & Attwell, 2015).”
BackgroundInfluentialSun, X. (2022) · Brain Science Advances · doi:10.26599/bsa.2023.9050001 · Cited by 4 · see citing works
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Phytochemicals Effects on Neurodegenerative Diseases
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“The ramified shape of surveying microglia forms dynamically from the extension and retraction of processes (58, 59).”
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“Instead, FL2 knockdown microglia displayed characteristics associated with active growth and surveillance [3, 41].”
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Microglial TNFα controls synaptic GABAARs, sleep slow waves and memory consolidationPreprint
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The Arp2/3 complex controls the development of homeostatic microglia
Safaiyan, S., Frosch, M., Bickel, T., Monaco, G., Dvir, R., Madry, C., Bosch, L. F. P., Kierdorf, K., Innocenti, M., Priller, J., et al. (2026) · EMBO Reports · doi:10.1038/s44319-026-00721-8 · Cited by 1 · see citing works
“In the presence of a tissue injury, microglia switch from random to directed chemotactic motility (Hines et al, 2009; Madry and Attwell, 2015), which is mediated by morphological remodeling and microglial sensome (Das and Chinnathambi, 2020; Hickman and El Khoury, 2019).”
Self-citationMicroglia in Epilepsy: From Molecular Mechanism to Therapeutic Strategy
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“Microglial activation is characterized by changes in cell morphology and biochemistry [41].”
The role of microglia membrane potential in chemotaxisPreprint
Laprell, L., Schulze, C., Brehme, M.-L., & Oertner, T. G. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.05.19.104109 · Cited by 1 · see citing works
“In particular, potassium channel expression plays an important role in the regulation of the hyperpolarized membrane potential (for review see (Madry and Attwell, 2015; Nguyen et al., 2017b; Thei et al., 2018)).”
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“, 2016), as well as their expression of ion channels (Madry and Attwell, 2015; Echeverry et al., 2016; Pappalardo et al., 2016).”
Investigating adrenoceptor regulation of the astroglial glycogen reserve
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“The highly ramified processes of adult microglia have been associated with a tissue surveillance phenotype (Madry & Attwell, 2015).”
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Myelin pruning by microglia during development
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Additional file 3 of The role of microglia membrane potential in chemotaxis
Laprell, L., Schulze, C., Brehme, M.-L., & Oertner, T. G. (2021) · Figshare · doi:10.6084/m9.figshare.13551889
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Additional file 1 of The role of microglia membrane potential in chemotaxis
Laprell, L., Schulze, C., Brehme, M.-L., & Oertner, T. G. (2021) · Figshare · doi:10.6084/m9.figshare.13551883
Ivan, D. C., Berve, K., Walthert, S., Monaco, G., Borst, K., Bouillet, E., Ferreira, F. M., Lee, H., Steudler, J., Buch, T., et al. (2023) · Figshare · doi:10.6084/m9.figshare.22624237
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Additional file 2 of The role of microglia membrane potential in chemotaxis
Laprell, L., Schulze, C., Brehme, M.-L., & Oertner, T. G. (2021) · Figshare · doi:10.6084/m9.figshare.13551886
Additional file 5 of The role of microglia membrane potential in chemotaxis
Laprell, L., Schulze, C., Brehme, M.-L., & Oertner, T. G. (2021) · Figshare · doi:10.6084/m9.figshare.13551895
Additional file 4 of The role of microglia membrane potential in chemotaxis
Laprell, L., Schulze, C., Brehme, M.-L., & Oertner, T. G. (2021) · Figshare · doi:10.6084/m9.figshare.13551892
Additional file 6 of The role of microglia membrane potential in chemotaxis
Laprell, L., Schulze, C., Brehme, M.-L., & Oertner, T. G. (2021) · Figshare · doi:10.6084/m9.figshare.13551898
Puntambekar, S. S., Moutinho, M., Lin, P. B., Jadhav, V., Tumbleson, D. M., Balaji, A., Benito, M. A., Xu, G., Oblak, A. L., Lasagna‐Reeves, C. A., et al. (2022) · Figshare · doi:10.6084/m9.figshare.20175603
- Authors
- Madry, C., & Attwell, D.
- Affiliations
- University College London (GB)
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2015-05
- Volume
- 290
- Issue
- 20
- Pages
- 12443-12450
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC4432265
- OpenAlex
- W2081351019
- Cited by
- 109
- References
- 76
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 8 · 2023: 10 · 2022: 15 · 2021: 21 · 2020: 11 · 2019: 10 · 2018: 6 · 2017: 9 · 2016: 5 · 2015: 2
- FWCI
- 0.58
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Wellcome Trust (099222/Z/12/Z, 99222)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
- Keywords
- microglia, microglial motility, microglial receptors, ion channels, signaling pathways, brain injury, synaptic pruning, microglia-neuron interaction
- MeSH terms
- Animals, Astrocytes, Brain Injuries, Cell Communication, Cell Movement, Humans, Ion Channels, Neurons, Phagocytosis, Receptors, Cell Surface, Synapses, Apoptosis, Microglia
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