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Deficiency of the Microglial Receptor CX3CR1 Impairs Postnatal Functional Development of Thalamocortical Synapses in the Barrel Cortex
Open accessAbstract
Accumulative evidence indicates that microglial cells influence the normal development of brain synapses. Yet, the mechanisms by which these immune cells target maturating synapses and influence their functional development at early postnatal stages remain poorly understood. Here, we analyzed the role of CX3CR1, a microglial receptor activated by the neuronal chemokine CX3CL1 (or fractalkine) which controls key functions of microglial cells. In the whisker-related barrel field of the mouse somatosensory cortex, we show that the recruitment of microglia to the sites where developing thalamocortical synapses are concentrated (i.e., the barrel centers) occurs only after postnatal day 5 and is controlled by the fractalkine/CX3CR1 signaling pathway. Indeed, at this developmental stage fractalkine is overexpressed within the barrels and CX3CR1 deficiency delays microglial cell recruitment into the barrel centers. Functional analysis of thalamocortical synapses shows that CX3CR1 deficiency also delays the functional maturation of postsynaptic glutamate receptors which normally occurs at these synapses between the first and second postnatal week. These results show that reciprocal interactions between neurons and microglial cells control the functional maturation of cortical synapses.
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“KO mice lacking fractalkine receptor show transient excitatory hyperconnectivity followed by weak synaptic multiplicity and reduced functional brain connectivity in adulthood11,12, suggesting that a failure to eliminate synapses at the correct developmental time prevents the normal strengthening of synaptic connections.”
From Microglia remodel synapses by presynaptic trogocytosis and spine head filopodia induction (2018) · cites this paper as [12]
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Synaptic Pruning by Microglia Is Necessary for Normal Brain Development
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“…be that MGCs, once inside TCA clusters, could contribute to the selection of synapses with a mature signature of their glutamate receptors (Yashiro and Philpot, 2008) by pruning immature synapses through phagocytosis (Paolicelli et al., 2011) in a complement-dependent manner (Schafer et al., 2012).”
BackgroundMicroglia: Active sensor and versatile effector cells in the normal and pathologic brain
Hanisch, U.-K., & Kettenmann, H. (2007) · Nature Neuroscience · doi:10.1038/nn1997 · Cited by 3,676 · cited 1×
“In the diseased adult CNS, several signaling pathways control the recruitment of microglia at sites of compromised homeostasis (Hanisch and Kettenmann, 2007; Ransohoff and Perry, 2009).”
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“In few experiments heterozygous CX3CR1 /eGFP mice of either sex were obtained by crossing CX3CR1 eGFP/eGFP (Jung et al., 2000) with wild-type C57BL/6J mice (Janvier).”
BackgroundMethodInfluentialNeurotrophins and their receptors: A convergence point for many signalling pathways
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Microglial physiology: unique stimuli, specialized responses
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BackgroundControl of microglial neurotoxicity by the fractalkine receptor
Cardona, A. E., Pioro, E. P., Sasse, M. E., Kostenko, V., Cardona, S. M., Dijkstra, I. M., Huang, D., Kidd, G., Dombrowski, S., Dutta, R., et al. (2006) · Nature Neuroscience · doi:10.1038/nn1715 · Cited by 1,531 · cited 1×
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“…local role of fractalkine in which cellular elements localized within the barrel hollows, possibly thalamic fibers, overexpress the chemokine at P5–P7 and thus favor directed migration of microglia (Harrison et al., 1998; Maciejewski-Lenoir et al., 1999) toward maturating thalamocortical synapses.”
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Tremblay, M.-È., Stevens, B., Sierra, A., Wake, H., Bessis, A., & Nimmerjahn, A. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.4158-11.2011 · Cited by 992 · cited 1×
“In rodents, experimental evidence shows that MGCs contribute to developmentally regulated neuronal apoptosis but also to synapse pruning (Mallat et al., 2005; Pont-Lezica et al., 2011; Schlegelmilch et al., 2011; Tremblay et al., 2011).”
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Pathologic role of glial nitric oxide in adult and pediatric neuroinflammatory diseases
Ghasemi, M., & Fatemi, A. S. (2014) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2014.06.002 · Cited by 103
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“…of synaptic elements during the entire lifespan, and the formation of learning-dependent synapses in the mature brain, as well as maturation and plasticity of excitatory synapses (Tremblay et al., 2010; Paolicelli et al., 2011; Hoshiko et al., 2012; Schafer et al., 2012; Parkhurst et al., 2013).”
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BackgroundThe emerging tale of microglia in psychiatric disorders
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“In the healthy CNS, they continuously survey their microenvironment, and their activation is a 2-step process, requiring loss of inhibitory signals such as CD200 and CX3CL1 from neurons and the triggering of receptors by a range of stimuli (5).”
Neuronal and microglial regulators of cortical wiring: usual and novel guideposts
Squarzoni, P. (2015) · Frontiers in Neuroscience · doi:10.3389/fnins.2015.00248 · Cited by 91
“While the origin of these repopulating cells is still debated, it has been shown for the adult repopulation that a local brain pool of nestin-positive cells differentiates into microglia thereby restoring their usual number (Elmore et al., 2014).”
BackgroundHuman neuronal maturation comes of age: cellular mechanisms and species differences
Wallace, J. L., & Pollen, A. A. (2024) · Nature Reviews Neuroscience · doi:10.1038/s41583-023-00760-3 · Cited by 82
“of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) to NMDARs via fractalkine signalling 168,169 and in promoting spine growth and plasticity via IL-33-mediated remodelling of the local ECM 170 .”
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BackgroundVanRyzin, J. W., Yu, S. J., Perez‐Pouchoulen, M., & McCarthy, M. M. (2016) · eNeuro · doi:10.1523/eneuro.0297-16.2016 · Cited by 83
“, 2013), aid in synaptic maturation and function (Tremblay et al., 2010; Paolicelli et al., 2011; Hoshiko et al., 2012; Squarzoni et al., 2014), and mediate the development of sexspecific circuitry (Lenz et al.”
BackgroundThe molecular and cell biology of pediatric low-grade gliomas
Chen, Y.-H., & Gutmann, D. H. (2013) · Oncogene · doi:10.1038/onc.2013.148 · Cited by 80
Shook, L. L., Kışlal, S., & Edlow, A. G. (2020) · Prenatal Diagnosis · doi:10.1002/pd.5724 · Cited by 88
“function during a critical developmental period could result in defective maturation of synaptic circuits, impaired synaptic pruning, and an increase in redundant or unnecessary synapses.(107,108) A better under-”
BackgroundMicroglia-astrocyte crosstalk regulates synapse remodeling via Wnt signaling
Faust, T. E., Lee, Y., O’Connor, C. D., Boyle, M. A., Gunner, G., Durán‐Laforet, V., Ferrari, L. L., Murphy, R. E., Badimon, A., Sakers, K., et al. (2025) · Cell · doi:10.1016/j.cell.2025.08.023 · Cited by 93
Lowery, R. L., Tremblay, M., Hopkins, B. E., & Majewska, A. K. (2017) · Glia · doi:10.1002/glia.23192 · Cited by 86
“Experiments examining microglial infiltration into thalamocortical axon (TCA) clusters were carried out at p7 and p10 to replicate previously published methods (Hoshiko et al., 2012).”
BackgroundMethodResultInfluentialFractalkine is a “find-me” signal released by neurons undergoing ethanol-induced apoptosis
Sokolowski, J. D., Chabanon-Hicks, C., Han, C. Z., Heffron, D. S., & Mandell, J. W. (2014) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2014.00360 · Cited by 79
Bordeleau, M., Carrier, M., Luheshi, G. N., & Tremblay, M.-È. (2019) · Seminars in Cell & Developmental Biology · doi:10.1016/j.semcdb.2019.06.001 · Cited by 75
Rewiring of Memory Circuits: Connecting Adult Newborn Neurons With the Help of Microglia
Rodríguez-Iglesias, N., Sierra, A., & Valero, J. (2019) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2019.00024 · Cited by 76
The Role of Microglia in Perioperative Neuroinflammation and Neurocognitive Disorders
Saxena, S., Kruys, V., Vamecq, J., & Maze, M. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.671499 · Cited by 73
“In obese mice, microglial activation, through the CX3CR1 pathway can result in cognitive impairment (Cope et al., 2018).”
BackgroundMicroglia mediated neuroinflammation in autism spectrum disorder
Liao, X., Yang, J., Wang, H., & Li, Y. (2020) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2020.07.013 · Cited by 79
Yoshino, Y., Roy, B., & Dwivedi, Y. (2020) · Neuropsychopharmacology · doi:10.1038/s41386-020-00861-y · Cited by 70
Neuroinflammation, Early-Life Adversity, and Brain Development
Andersen, S. L. (2022) · Harvard Review of Psychiatry · doi:10.1097/hrp.0000000000000325 · Cited by 73
O’Keeffe, M., Booker, S. A., Walsh, D. A., Li, M., Henley, C., de Oliveira, L. S., Liu, M., Wang, X., Banqueri, M., Ridley, K., et al. (2025) · Nature Neuroscience · doi:10.1038/s41593-024-01833-x · Cited by 66
“…is that the developmental functions previously attributed to microglia were based on studying mice globally deficient in Cx3cr1 , Cr3 , C3 or C1qa 3,4,6–8, 36– 38 , meaning that A recent study used the Csf1r ∆FIRE/∆FIRE mouse to study aspects of neuronal development, focusing on the HPC 39 .”
Experience-Dependent Synaptic Plasticity in V1 Occurs without Microglial CX3CR1
Schecter, R. W., Maher, E. E., Welsh, C. A., Stevens, B., Erişir, A., & Bear, M. F. (2017) · Journal of Neuroscience · doi:10.1523/jneurosci.2679-16.2017 · Cited by 71
“…is less mature than the age-matched WT cortex, which would parallel data found in the hippocampus (Paolicelli et al., 2011) and the barrel cortex (Hoshiko et al., 2012), suggesting an overall developmental delay in the brains of Cx3cr1 KO mice, but one that does not impact visual cortical…”
BackgroundMicroglia and Synapse: Interactions in Health and Neurodegeneration
Šišková, Z., & Tremblay, M.-È. (2013) · Neural Plasticity · doi:10.1155/2013/425845 · Cited by 80
“Morphological specializations resembling finger-like protrusions wrapping around dendritic spines were described based on electron microscopy with three-dimensional reconstruction (Figure 2).”
Wang, X., & Li, L. (2021) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2021.722028 · Cited by 71
Modulation of adult-born neurons in the inflamed hippocampus
Bélarbi, K., & Rosi, S. (2013) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2013.00145 · Cited by 68
“These results, together with recent data (Rogers et al., 2011; Hoshiko et al., 2012) suggest that CX3CL1/CX3CR1 is an important neuron-microglia signaling pathway necessary for synaptic pruning and maturation (Paolicelli et al., 2011).”
ResultGupta, N., Shyamasundar, S., Patnala, R., Karthikeyan, A., Arumugam, T. V., Ling, E., & Dheen, S. T. (2018) · Expert Opinion on Therapeutic Targets · doi:10.1080/14728222.2018.1515917 · Cited by 67
Microglia Mediate HIV-1 gp120-Induced Synaptic Degeneration in Spinal Pain Neural Circuits
Ru, W., Liu, X., Bae, C., Shi, Y., Walikonis, R. S., Chung, J. M., & Tang, S. (2019) · Journal of Neuroscience · doi:10.1523/jneurosci.2851-18.2019 · Cited by 68
“Previous studies indicate that the FKN/CX3CR1 signaling modulates synapse pruning during development (Paolicelli et al., 2011; Hoshiko et al., 2012).”
BackgroundSingle Cell RNA-Seq Analysis Reveals Compartment-Specific Heterogeneity and Plasticity of Microglia
Zheng, J., Ru, W., Adolacion, J. R. T., Spurgat, M. S., Liu, X., Yuan, S., Liang, R. X., Dong, J., Potter, A. S., Potter, S. S., et al. (2020) · iScience · doi:10.1016/j.isci.2021.102186 · Cited by 64
“During development, microglia participate in neural circuit formation by regulating specific processes such as axon outgrowth and synapse maturation and pruning (Hoshiko et al., 2012; Schafer et al., 2013).”
BackgroundAcharjee, S., Verbeek, M., Gómez, C., Bisht, K., Lee, B., Benoit, L., Sharkey, K. A., Benediktsson, A. M., Tremblay, M., & Pittman, Q. J. (2018) · Journal of Neuroscience · doi:10.1523/jneurosci.0398-18.2018 · Cited by 63
“The AMPAR activation can lead to spine maturation (Fischer et al., 2000; Hoshiko et al., 2012).”
BackgroundCrespo‐Castrillo, A., & Arévalo, M. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21093219 · Cited by 65
“Through this receptor, microglia surveil the state of the neural connections, being able to not only act in case of damage but also modulate and maintain dynamic and constant monitoring of all circuits [44,45].”
BackgroundThe role of immune cells in brain development and neurodevelopmental diseases
Tanabe, S., & Yamashita, T. (2018) · International Immunology · doi:10.1093/intimm/dxy041 · Cited by 66
Thion, M. S., Mosser, C., Férézou, I., Grisel, P., Baptista, S., Low, D., Ginhoux, F., Garel, S., & Audinat, É. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.06.086 · Cited by 64
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Mechanisms of microglia-mediated synapse turnover and synaptogenesis
Ball, J. B., Green‐Fulgham, S. M., & Watkins, L. R. (2022) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2022.102336 · Cited by 64
Glial smog: Interplay between air pollution and astrocyte-microglia interactions
Gómez‐Budia, M., Konttinen, H., Saveleva, L., Korhonen, P., Jalava, P., Kanninen, K. M., & Malm, T. (2020) · Neurochemistry International · doi:10.1016/j.neuint.2020.104715 · Cited by 60
Microglia as the Critical Regulators of Neuroprotection and Functional Recovery in Cerebral Ischemia
Gaire, B. P. (2021) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-021-01145-9 · Cited by 65
The Role of Glial Cells in Synaptic Dysfunction: Insights into Alzheimer's Disease Mechanisms
Yu, Y., Chen, R., Mao, K., Deng, M., & Li, Z. (2023) · Aging and Disease · doi:10.14336/ad.2023.0718 · Cited by 62
“These mediators can disrupt synaptic signaling, perturb synaptic connections, induce neuronal degeneration and apoptosis, and ultimately contribute to cognitive impairment [21–25].”
BackgroundThe GluN2A Subunit Regulates Neuronal NMDA receptor-Induced Microglia-Neuron Physical Interactions
Eyo, U. B., Bispo, A., Liu, J., Sabu, S., Wu, R., DiBona, V. L., Zheng, J., Murugan, M., Zhang, H., Tang, Y., et al. (2018) · Scientific Reports · doi:10.1038/s41598-018-19205-4 · Cited by 57
The ins and outs of microglial cells in brain health and disease
Pallarés-Moratalla, C., & Bergers, G. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1305087 · Cited by 66
Mendiola, A. S., Garza, R., Cardona, S. M., Mythen, S. A., Lira, S. A., Akassoglou, K., & Cardona, A. E. (2017) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2016.00303 · Cited by 57
“During health, FKN/CX3CR1 signaling contributes to prenatal and postnatal brain development (Paolicelli et al., 2011; Hoshiko et al., 2012).”
BackgroundChamera, K., Kotarska, K., Szuster-Głuszczak, M., Trojan, E., Skórkowska, A., Pomierny, B., Krzyżanowska, W., Bryniarska, N., & Basta‐Kaim, A. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-020-01923-0 · Cited by 57
“It has been found that CX3CL1 regulates the distinctive colonization pattern of microglia populations [63], while dysfunction in CX3CL1 signalling impairs this process in the cortex and in the hippocampus [64].”
BackgroundMicroglia as therapeutic target in central nervous system disorders
Fatoba, O., Itokazu, T., & Yamashita, T. (2020) · Journal of Pharmacological Sciences · doi:10.1016/j.jphs.2020.07.004 · Cited by 57
The force awakens: insights into the origin and formation of microglia
Tay, T. L., Hagemeyer, N., & Prinz, M. (2016) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2016.04.003 · Cited by 59
The Role of the Microglial Cx3cr1 Pathway in the Postnatal Maturation of Retinal Photoreceptors
Jobling, A. I., Waugh, M., Vessey, K. A., Phipps, J. A., Trogrlic, L., Greferath, U., Mills, S. A., Tan, Z. L., Ward, M. M., & Fletcher, E. L. (2018) · Journal of Neuroscience · doi:10.1523/jneurosci.2368-17.2018 · Cited by 55
“…undertaken in the retina has indicated that the dynamics of microglial processes are modulated by fractalkine/Cx3cr1 signaling (Liang et al., 2009), while microglial migration is impaired in the somatosensory barrel cortex of Cx3cr1-deficient mice (Hoshiko et al., 2012; Arnoux and Audinat, 2015).”
BackgroundInfluentialLelli, A., Gervais, A., Colin, C., Chéret, C., de Almodóvar, C. R., Carmeliet, P., Krause, K., Boillée, S., & Mallat, M. (2013) · Glia · doi:10.1002/glia.22540 · Cited by 60
“They also contribute to postnatal synaptic pruning or maturation in the optic tectum, the hippocampus or the cerebral cortex (Hoshiko et al., 2012; Paolicelli et al., 2011; Schafer et al., 2012).”
BackgroundO’Sullivan, S. A., Gasparini, F., Mir, A. K., & Dev, K. K. (2016) · Journal of Neuroinflammation · doi:10.1186/s12974-016-0659-7 · Cited by 56
“However, CX3CR1 mice have more synapses, a reduced number of microglia in the hippocampus and delayed maturation of functional glutamate receptors [64, 71].”
BackgroundRecent advances in the understanding of microglial development and homeostasis
Low, D., & Ginhoux, F. (2018) · Cellular Immunology · doi:10.1016/j.cellimm.2018.01.004 · Cited by 57
Wallace, J. L., Lord, J. S., Dissing‐Olesen, L., Stevens, B., & Murthy, V. N. (2020) · eLife · doi:10.7554/elife.50531 · Cited by 53
“, 2017) as well as delays in maturation of the AMPA/NMDA ratio (Hoshiko et al., 2012).”
BackgroundInfluentialMicroglia: Lifelong modulator of neural circuits
Ikegami, A., Haruwaka, K., & Wake, H. (2019) · Neuropathology · doi:10.1111/neup.12560 · Cited by 49
“Many other studies show dysfunctional pruning of synaptic / neuronal components in CX3CR1 KO mice by microglia in the hippocampus and somatosensory cortex.(15,16) Conversely, recent studies in CX3CR1 KO mice claim that the fractalkine-CX3CR1 pathway is not necessary in some brain regions.”
BackgroundUeno, M., & Yamashita, T. (2014) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2014.02.004 · Cited by 56
Hayashi, Y. (2013) · Journal of Neurological Disorders · doi:10.4172/2329-6895.1000120 · Cited by 49
“During the postnatal developmental stage, microglia have an important role in the regulation of synapse maturation with phagocytosis occurring through CX3CR1 signaling in the hippocampus or barrel cortex [4,5].”
BackgroundMicroglia Regulate Pruning of Specialized Synapses in the Auditory Brainstem
Milinkeviciute, G., Henningfield, C. M., Muniak, M. A., Chokr, S. M., Green, K. N., & Cramer, K. S. (2019) · Frontiers in Neural Circuits · doi:10.3389/fncir.2019.00055 · Cited by 52
Step by step: cells with multiple functions in cortical circuit assembly
Cossart, R., & Garel, S. (2022) · Nature reviews. Neuroscience · doi:10.1038/s41583-022-00585-6 · Cited by 54
Cong, Q., Soteros, B. M., Huo, A., Li, Y., Tenner, A. J., & Sia, G.-M. (2021) · Glia · doi:10.1002/glia.24114 · Cited by 49
“…2007); CD47, SRPX2 mediated “don't eat me” signaling (Cong et al., 2020; Lehrman et al., 2018; Soteros et al., 2018); chemokine fractalkine CX3CL1-CX3CR1 mediated signaling (Gunner et al., 2019; Hoshiko et al., 2012; Paolicelli et al., 2011); and TREM2 mediated signaling (Filipello et al., 2018).”
Fractalkine/CX3CR1-Dependent Modulation of Synaptic and Network Plasticity in Health and Disease
Camacho-Hernández, N. P., & Peña‐Ortega, F. (2023) · Neural Plasticity · doi:10.1155/2023/4637073 · Cited by 52
“Synaptic activity is the ongoing synchronous and asynchronous communication among neurons, determined by action potential neurotransmitter release, stochastic action potential-independent vesicle fusions, and electric coupling [61, 96, 103, 166, 167] Synaptic activity is influenced by pre- and postsynaptic structure a…”
BackgroundInfluentialPimentel‐Coelho, P. M., Michaud, J.-P., & Rivest, S. (2013) · Journal of Neuroscience · doi:10.1523/jneurosci.0535-13.2013 · Cited by 51
“In addition, recent studies have reported several CX3CR1-mediated microglia functions during postnatal brain development (Paolicelli et al., 2011; Hoshiko et al., 2012) and, therefore, it is possible that changes in fractalkine expression and/or in microglial function after the injury could result…”
BackgroundGlial neuroimmune signaling in opioid reward
Zhang, H., Largent‐Milnes, T. M., & Vanderah, T. W. (2019) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2019.11.012 · Cited by 50
“Studies found that genetic deletion of CX3CR1 resulted in a transient reduction of microglia number as well as decreased entry of microglia into the developing brain regions (Hoshiko et al., 2012; Paolicelli et al., 2011).”
BackgroundEnvironmental Signals on Microglial Function during Brain Development, Neuroplasticity, and Disease
Chagas, L. D. S., Sandre, P. C., Ribeiro, N. C. A. R. E., Marcondes, H., Silva, P. O., Savino, W., & Serfaty, C. A. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21062111 · Cited by 53
“This interaction is also important for microglial colonization to the somatosensory, motor cortex, and hippocampus during early postnatal development, which is impaired in the absence of fractalkine signaling [23].”
BackgroundNakanishi, H., Ni, J., Nonaka, S., & Hayashi, Y. (2020) · Neurochemistry International · doi:10.1016/j.neuint.2020.104905 · Cited by 49
“…molecules, including Cx3cr1 and killer cell activating receptor-associated protein/DNAX activating protein of 12 kDa (KARAP/DAP12), significantly change the synaptic strength in the hippocampus and cerebral cortex (Roumier et al., 2004; Paolicelli et al., 2011; Hoshiko et al., 2012).”
BackgroundOrigin and Emergence of Microglia in the CNS—An Interesting (Hi)story of an Eccentric Cell
Dermitzakis, I., Μanthou, M. E., Meditskou, S., Tremblay, M., Petratos, S., Zoupi, L., Boziki, M. K., Kesidou, E., Simeonidou, C., & Theotokis, P. (2023) · Current Issues in Molecular Biology · doi:10.3390/cimb45030171 · Cited by 55
“CX3CL1 16q21 C-X3-C motif chemokine ligand 1 Mice Migration [72]”
BackgroundInfluentialThe Impact of Microglia on Neurodevelopment and Brain Function in Autism
Luo, Y., & Wang, Z. (2024) · Biomedicines · doi:10.3390/biomedicines12010210 · Cited by 55
“Research on CX3CR1 knockout mice found that CX3CR1 knockout led to a decrease in microglia in the brains of early postnatal mice, suggesting that CX3CR1 is a key factor in the normal migration ability of microglia [125].”
BackgroundTian, L., Hui, C. W., Bisht, K., Tan, Y., Sharma, K. P., Chen, S., Zhang, X., & Tremblay, M. (2017) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2017.01.007 · Cited by 52
Little cells of the little brain: microglia in cerebellar development and function
Stoessel, M. B., & Majewska, A. K. (2021) · Trends in Neurosciences · doi:10.1016/j.tins.2021.04.001 · Cited by 49
Reduced Fractalkine Levels Lead to Striatal Synaptic Plasticity Deficits in Huntington’s Disease
Kim, A. A., García-García, E., Straccia, M., Comella-Bolla, A., Miguez, A., Masana, M., Alberch, J., Canals, J. M., & Rodríguez, M. J. (2020) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.00163 · Cited by 47
The behavior and functions of embryonic microglia
Hattori, Y. (2021) · Anatomical Science International · doi:10.1007/s12565-021-00631-w · Cited by 53
Irfan, M., Evonuk, K. S., & DeSilva, T. M. (2022) · The FEBS Journal · doi:10.1111/febs.16190 · Cited by 39
The molecular determinants of microglial developmental dynamics
Barry-Carroll, L., & Gómez‐Nicola, D. (2024) · Nature reviews. Neuroscience · doi:10.1038/s41583-024-00813-1 · Cited by 49
Hattori, Y., & Miyata, T. (2018) · Genes to Cells · doi:10.1111/gtc.12632 · Cited by 43
de Cossío, L. F., Lacabanne, C., Bordeleau, M., Castino, G., Kyriakakis, P., & Tremblay, M. (2021) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2021.07.025 · Cited by 43
Faustino, J. V., Chip, S., Derugin, N., Jullienne, A., Hamer, M., Haddad, E., Butovsky, O., Obenaus, A., & Vexler, Z. S. (2019) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1177/0271678x18817663 · Cited by 42
Endocannabinoid signaling in microglia
Marinelli, S., Marrone, M. C., Domenico, M. D., & Marinelli, S. (2022) · Glia · doi:10.1002/glia.24281 · Cited by 42
“…activity and synaptic plasticity (Akiyoshi et al., 2018; Badimon et al., 2020; Basilico et al., 2019; Filipello et al., 2018; Gunner et al., 2019; Hoshiko et al., 2012; Lehrman et al., 2018; Nguyen et al., 2020; Paolicelli et al., 2011; Schafer et al., 2012; Sipe et al., 2016; Wang et al.,…”
BackgroundParadoxical effects of minocycline in the developing mouse somatosensory cortex
Arnoux, I., Hoshiko, M., Diez, A. S., & Audinat, É. (2013) · Glia · doi:10.1002/glia.22612 · Cited by 39
“Here, we investigated whether minocycline affects MG properties by the end of the first postnatal week when these cells influence the development of synapses in the somatosensory cortex (Hoshiko et al., 2012).”
BackgroundInfluentialSelf-citationChip, S., Fernández‐López, D., Fan, L., Faustino, J. V., Derugin, N., & Vexler, Z. S. (2016) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2016.11.005 · Cited by 40
miR-142-3p Regulates BDNF Expression in Activated Rodent Microglia Through Its Target CAMK2A
Gupta, N., Jadhav, S., Tan, K.-L., Saw, G., Mallilankaraman, K. B., & Dheen, S. T. (2020) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.00132 · Cited by 40
Antibiotics Treatment Modulates Microglia–Synapses Interaction
Cordella, F., Sanchini, C., Rosito, M., Ferrucci, L., Pediconi, N., Cortese, B., Guerrieri, F., Pascucci, G. R., Antonangeli, F., Peruzzi, G., et al. (2021) · Cells · doi:10.3390/cells10102648 · Cited by 38
“Indeed, in these mice, the lack of neuron–microglia crosstalk through the CX3CL1/CX3CR1 axis is known to delay synaptic maturation and connectivity [22,24,25,34,35].”
BackgroundHiraga, S.-I., Itokazu, T., Hoshiko, M., Takaya, H., Nishibe, M., & Yamashita, T. (2020) · JCI Insight · doi:10.1172/jci.insight.131801 · Cited by 40
Self-citationSowa, J. E., & Tokarski, K. (2021) · Pharmacological Reports · doi:10.1007/s43440-021-00323-2 · Cited by 41
Astrocytes and Microglia in Stress-Induced Neuroinflammation: The African Perspective
Olude, M. A., Mouihate, A., Mustapha, O. A., Farina, C., Quintana, F. J., & Olopade, J. O. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.795089 · Cited by 37
Basic Concept of Microglia Biology and Neuroinflammation in Relation to Psychiatry
Mattei, D., & Notter, T. (2019) · Current topics in behavioral neurosciences · doi:10.1007/7854_2018_83 · Cited by 37
Pandur, E., Tamási, K., Pap, R., Varga, E., Miseta, A., & Sipos, K. (2019) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-019-00694-4 · Cited by 37
Patrolling monocytes play a critical role in CX3CR1-mediated neuroprotection during excitotoxicity
Bellavance, M., Gosselin, D., Yong, V. W., Stys, P. K., & Rivest, S. (2014) · Brain Structure and Function · doi:10.1007/s00429-014-0759-z · Cited by 39
“was recently reported to require Cx3cr1-competent microglial cells (Paolicelli et al. 2011; Rogers et al. 2011; Hoshiko et al. 2012; Wake et al. 2013; Ueno et al. 2013).”
BackgroundAmro, Z., Yool, A. J., & Collins‐Praino, L. E. (2021) · Brain Behavior & Immunity - Health · doi:10.1016/j.bbih.2021.100242 · Cited by 39
Central Nervous System: (Immunological) Ivory Tower or Not?
Marin, I. A., & Kipnis, J. (2016) · Neuropsychopharmacology · doi:10.1038/npp.2016.122 · Cited by 36
“Upon extension of microglial processes, microglial receptors such as CX3CR1, CR3, CD200R, or TREM2/DAP12 may recognize ligands on the neuronal membrane (Hoshiko et al, 2012; Paolicelli et al, 2011; Poliani et al, 2015; Schafer et al, 2012).”
BackgroundThe Glial Cells Respond to Spinal Cord Injury
Wang, R., Zhou, R., Chen, Z., Gao, S., & Zhou, F. (2022) · Frontiers in Neurology · doi:10.3389/fneur.2022.844497 · Cited by 35
“Microglia can also activate “synaptic stripping” through the fractalkine/CX3CR1 signaling pathway (47).”
BackgroundRegulation of microglia phagocytosis and potential involvement of exercise
Li, C., Wang, Y., Xing, Y., Han, J., Zhang, Y., Zhang, A., Hu, J., Hua, Y., & Bai, Y. (2022) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2022.953534 · Cited by 37
CX3CL1 Pathway as a Molecular Target for Treatment Strategies in Alzheimer’s Disease
Bivona, G., Iemmolo, M., & Ghersi, G. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24098230 · Cited by 35
“Hippocampus and cortex neurons highly express CX3CL1 [44,45], with the chemokine exerting neuroprotective and neurotrophic effects.”
BackgroundPaquette, S. E., Martin, N. R., Rodd, A. L., Manz, K. E., Allen, E., Camarillo, M., Pennell, A., Weller, H. I., Pennell, K. D., & Plavicki, J. S. (2023) · Environmental Health Perspectives · doi:10.1289/ehp12861 · Cited by 36
Placental transfer of NMDAR antibodies causes reversible alterations in mice
García‐Serra, A., Radosevic, M., Pupak, A., Brito, V., Ríos, J., Aguilar, E., Maudes, E., Ariño, H., Spatola, M., Mannara, F., et al. (2020) · Neurology Neuroimmunology & Neuroinflammation · doi:10.1212/nxi.0000000000000915 · Cited by 34
An overview of microglia ontogeny and maturation in the homeostatic and pathological brain
Mendes, M. S., & Majewska, A. K. (2021) · European Journal of Neuroscience · doi:10.1111/ejn.15225 · Cited by 35
“In the developing barrel cortex, thalamocortical synapses are also immature in CX3CR1 KO mice (Hoshiko et al., 2012).”
BackgroundNeuro-Immune Cross-Talk in the Striatum: From Basal Ganglia Physiology to Circuit Dysfunction
Mancini, A., Ghiglieri, V., Parnetti, L., Calabresi, P., & Filippo, M. D. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.644294 · Cited by 38
The Contribution of Microglia to the Development and Maturation of the Visual System
Dixon, M., Greferath, U., Fletcher, E. L., & Jobling, A. I. (2021) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2021.659843 · Cited by 40
“Further investigation showed Csf1r knockdown to delay neurogenesis and neural differentiation, with most major retinal cell types absent in the mutant (Huang et al., 2012).”
BackgroundMovers and shakers: Microglial dynamics and modulation of neural networks
Whitelaw, B. S., Stoessel, M. B., & Majewska, A. K. (2022) · Glia · doi:10.1002/glia.24323 · Cited by 34
“Similarly, in the developing barrel cortex, CX3CR1 controls the timing of microglial invasion into the “barrels,” or the specific regions receiving input from the thalamic sensory neurons (Hoshiko et al., 2012).”
BackgroundInfluentialEagleson, K. L., Milner, T. A., Xie, Z., & Levitt, P. (2013) · Journal of Comparative Neurology · doi:10.1002/cne.23343 · Cited by 32
“…the Met-ir observed in the current study may be associated microglial cells, an intriguing possibility, as these cells have been implicated in synapse elimination and refinement during normal development (Tremblay et al., 2010; Paolicelli et al., 2011; Hoshiko et al., 2012; Schafer et al., 2012).”
BackgroundMicroglia in Alzheimer’s Disease: An Unprecedented Opportunity as Prospective Drug Target
Kulkarni, B., Martins, N. A., & Kumar, D. (2022) · Molecular Neurobiology · doi:10.1007/s12035-021-02661-x · Cited by 38
“Among other functions, this ligand maintains the resting state of the microglia by expressing an inhibitory signal, and the obstruction in glutamatergic synapse maturation has shown that the CX3Cl1/CX3CR1 signaling is significant for developmental stages of brain [76].”
BackgroundLiu, T., Lu, J., Łukasiewicz, K., Pan, B., & Zuo, Y. (2021) · Neurobiology of Stress · doi:10.1016/j.ynstr.2021.100342 · Cited by 32
“, 2019); on the other hand, microglia modulate synaptic pruning and plasticity, shape synaptic transmission, and ultimately contribute to behavioral regulations (Hoshiko et al., 2012; Miyamoto et al., 2016; Paolicelli et al., 2011; Parkhurst et al., 2013; Rogers et al., 2011; Schafer et al., 2012; Sipe et al., 2016; T…”
BackgroundGesuita, L., Cavaccini, A., Argunşah, A. Ö., Favuzzi, E., Ibrahim, L. A., Stachniak, T. J., Gennaro, M. D., Utz, S. G., Greter, M., & Karayannis, T. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.111209 · Cited by 34
TREM2 and Microglia Contribute to the Synaptic Plasticity: from Physiology to Pathology
Yu, C.-J., Wang, M., Ruiyang, L., Wei, T., Yang, H.-C., Yin, Y., Mi, Y., Qin, Q., & Tang, Y. (2022) · Molecular Neurobiology · doi:10.1007/s12035-022-03100-1 · Cited by 34
“Fractalkine/CX3C chemokine ligand 1 (FKN, CX3CL1), expressed mainly in neurons, is a transmembrane glycoprotein and belongs to the CX3C chemokine family [76].”
BackgroundMicroglia: Activity‐dependent regulators of neural circuits
Durán Laforet, V., & Schafer, D. P. (2024) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.15105 · Cited by 32
“31,55 However, in the barrel cortex, microglia numbers are similar in wild-type and CX3CR1/CX3CL1-deficient mice after whisker removal.”
Background
Metadata
- Authors
- Hoshiko, M., Arnoux, I., Avignone, E., Yamamoto, N., & Audinat, E.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- The University of Osaka (JP)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2012-10-24
- Volume
- 32
- Issue
- 43
- Pages
- 15106-15111
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6704837
- OpenAlex
- W1996055705
- Cited by
- 384
- References
- 33
- Citations by year
- 2026: 12 · 2025: 22 · 2024: 36 · 2023: 29 · 2022: 40 · 2021: 41 · 2020: 35 · 2019: 39 · 2018: 30 · 2017: 23 · 2016: 19 · 2015: 14 · 2014: 22 · 2013: 22
- FWCI
- 9.33
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Funders
- Uehara Memorial Foundation
- Ministry of Education, Culture, Sports, Science and Technology (23115102)
- Japan Society for the Promotion of Science (20021018)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- CX3CR1, fractalkine, microglia, synapse maturation, thalamocortical synapses, barrel cortex, postnatal development, microglial recruitment, glutamate receptors, microglia-neuron interaction, somatosensory cortex
- MeSH terms
- CX3C Chemokine Receptor 1, Age Factors, Animals, Animals, Newborn, Developmental Disabilities, Electric Stimulation, Female, Male, Mice, Inbred C57BL, Mice, Transgenic, Somatosensory Cortex, Synapses, Thalamus, Microglia, Gene Expression Regulation, Developmental, Excitatory Amino Acid Antagonists, Statistics, Nonparametric, GABA Antagonists, Excitatory Postsynaptic Potentials, Receptors, Chemokine, Green Fluorescent Proteins, Serotonin Plasma Membrane Transport Proteins, Mice, Chemokine CX3CL1, In Vitro Techniques
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