Elimination of Microglia Improves Functional Outcomes Following Extensive Neuronal Loss in the Hippocampus
Open accessAbstract
With severe injury or disease, microglia become chronically activated and damage the local brain environment, likely contributing to cognitive decline. We previously discovered that microglia are dependent on colony-stimulating factor 1 receptor (CSF1R) signaling for survival in the healthy adult brain, and we have exploited this dependence to determine whether such activated microglia contribute deleteriously to functional recovery following a neuronal lesion. Here, we induced a hippocampal lesion in mice for 25 d via neuronal expression of diphtheria toxin A-chain, producing both a neuroinflammatory reaction and behavioral alterations. Following the 25 d lesion, we administered PLX3397, a CSF1R inhibitor, for 30 d to eliminate microglia. This post-lesion treatment paradigm improved functional recovery on elevated plus maze and Morris water maze, concomitant with reductions in elevated proinflammatory molecules, as well as normalization of lesion-induced alterations in synaptophysin and PSD-95. Further exploration of the effects of microglia on synapses in a second cohort of mice revealed that dendritic spine densities are increased with long-term microglial elimination, providing evidence that microglia shape the synaptic landscape in the adult mouse brain. Furthermore, in these same animals, we determined that microglia play a protective role during lesioning, whereby neuronal loss was potentiated in the absence of these cells. Collectively, we demonstrate that microglia exert beneficial effects during a diphtheria toxin-induced neuronal lesion, but impede recovery following insult. SIGNIFICANCE STATEMENT: It remains unknown to what degree, and by what mechanisms, chronically activated microglia contribute to cognitive deficits associated with brain insults. We induced a genetic neuronal lesion in mice for 25 d and found activated microglia to increase inflammation, alter synaptic surrogates, and impede behavioral recovery. These lesion-associated deficits were ameliorated with subsequent microglial elimination, underscoring the importance of developing therapeutics aimed at eliminating/modulating chronic microglial activation. Additionally, we found long-term microglial depletion globally increases dendritic spines by ∼35% in the adult brain, indicating that microglia continue to sculpt the synaptic landscape in the postdevelopmental brain under homeostatic conditions. Microglial manipulation can therefore be used to investigate the utility of increasing dendritic spine numbers in postnatal conditions displaying synaptic aberrations.
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In mouse models of AD, genetic or pharmacological depletion of microglia prevented microglia association with amyloid plaques and neuronal loss, leading to improved learning and memory without affecting amyloid plaque load.
“In mouse models of AD genetic or pharmacological depletion of microglia prevented microglia association with amyloid plaques and neuronal loss, which led to improved learning and memory without affecting amyloid plaque load in mouse brain (Dagher et al., 2015; Rice et al., 2015; Spangenberg et al., 2016).”
From Alzheimer's-associated PU.1 expression levels regulate microglial inflammatory response (2021) · cites this paper as Rice et al., 2015
The Abstract reports improved behavioral outcomes after pharmacological microglial elimination following a genetically induced hippocampal lesion in mice. This was not an amyloid-plaque AD model, and the paper does not report plaque association or plaque load. The Results state the opposite of the neuronal-loss claim: eliminating microglia during lesioning exacerbated neuronal loss. Page numbers were not available in our copy. (LLM, conf=0.90)
Experimental — accuracy not yet measuredCSF1R inhibition after a chronic hippocampal lesion model of brain injury improved behavioral recovery, reduced pro-inflammatory molecules, and increased dendritic spines.
“Similarly, CSF1R inhibition after a chronic hippocampal lesion model of brain injury improved behavioral recovery, reduced pro-inflammatory molecules, and increased dendritic spines (239).”
From The Inflammatory Continuum of Traumatic Brain Injury and Alzheimer’s Disease (2018) · cites this paper as [239]
The Abstract reports that CSF1R inhibition after a 25-day hippocampal lesion improved behavioral recovery and reduced elevated pro-inflammatory molecules. The Results (‘Microglia regulate dendritic spine densities in the intact brain’) report increased spine density with microglial elimination alone, but no further increase in overall spine numbers when elimination was combined with the lesion. The claim incorrectly presents the spine increase as an outcome of post-lesion treatment. (LLM, conf=0.92)
Experimental — accuracy not yet measuredMicroglia interact with and modulate neuronal and synaptic elements, with direct effects on learning and memory.
“evidence indicates that these cells interact with and modulate neuronal and synaptic elements, with direct effects on learning and memory [14], [15], [16], [17], [18], [19].”
From Microglia facilitate loss of perineuronal nets in the Alzheimer's disease brain (2020) · cites this paper as [16]
Microglial depletion enhances performance in certain memory tasks in healthy adult mice.
“Microglial depletion also enhances performance in certain memory tasks [12, 14, 16] and prevents the forgetting of remote memories, and in association, the dissociation of memory engram cells in healthy adult mice [18].”
From Microglia facilitate loss of perineuronal nets in the Alzheimer's disease brain (2020) · cites this paper as [16]
The long-term absence of microglia is not detrimental to murine cognitive function and may be beneficial.
“indicating that the long-term absence of microglia is not detrimental to murine cognitive function and may be beneficial, at least in this assay, which is consistent with our prior findings17,18.”
From Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model (2019) · cites this paper as [18]
PLX5622-treated wild-type mice tended to spend more time in the platform zone compared to wild-type mice in the MWM probe trial.
“In the MWM probe trial, PLX5622-treated wild-type mice tended to spend more time in the platform zone compared to wild-type mice (Fig. 3k), indicating that the long-term absence of microglia is not detrimental to murine cognitive function and may be beneficial, at least in this assay, which is consistent with our prior findings17,18.”
From Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model (2019) · cites this paper as [18]
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ResultSelf-citationMicroglia mediate forgetting via complement-dependent synaptic elimination
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ResultMicroglia morphophysiological diversity and its implications for the CNS
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“In a mouse hippocampal lesion model, depletion of microglia by 30-day treatment with a CSF1R inhibitor, PLX3397, improved functional recovery and reduced pro-inflammatory gene expression in hippocampus (Rice et al., 2015).”
BackgroundMethodInfluentialInflammation in Alzheimer’s disease: Lessons learned from microglia-depletion models
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“adult mice devoid of microglia compared to microglia-intact mice (Rice et al., 2015), suggesting that these cells continue to sculpt the synaptic landscape into adulthood.”
BackgroundInfluentialSelf-citationMicroglia facilitate loss of perineuronal nets in the Alzheimer's disease brain
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Self-citationClearance of cerebral Aβ in Alzheimer’s disease: reassessing the role of microglia and monocytes
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To Kill a Microglia: A Case for CSF1R Inhibitors
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“We and others have not observed significant alterations in blood and spleen myeloid cell populations (including circulating monocytes and tissuemacrophages) utilizing either PLX3397 (at a dose of 290mg/kg or lower) or the more selective inhibitor PLX5622 in mice; however, these studies are limited, and require further…”
BackgroundResultInfluentialSelf-citationElimination of microglia improves cognitive function following cranial irradiation
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“In other studies, microglial depletion has been reported to increase neuronal activity and dendritic spine density (Ji et al., 2013; Rice et al., 2015).”
BackgroundMicroglia-neuron crosstalk: Signaling mechanism and control of synaptic transmission
Marinelli, S., Basilico, B., Marrone, M. C., & Ragozzino, D. (2019) · Seminars in Cell & Developmental Biology · doi:10.1016/j.semcdb.2019.05.017 · Cited by 233 · see citing works
Microglial repopulation resolves inflammation and promotes brain recovery after injury: RICE et al.
Rice, R. A., Pham, J., Lee, R. J., Najafi, A. R., West, B. L., & Green, K. N. (2017) · Glia · doi:10.1002/glia.23135 · Cited by 228 · see citing works
“Importantly, chronically activated microglia induced by this neuronal lesion model are eliminated with CSF1R inhibitors to the same extent as in control mice (Rice et al., 2015).”
BackgroundMethodInfluentialSelf-citationPriming the Inflammatory Pump of the CNS after Traumatic Brain Injury
Witcher, K. G., Eiferman, D. S., & Godbout, J. P. (2015) · Trends in Neurosciences · doi:10.1016/j.tins.2015.08.002 · Cited by 222 · see citing works
Li, Y., Ritzel, R. M., Khan, N., Cao, T., He, J., Lei, Z., Matyas, J. J., Sabirzhanov, B. E., Liu, S., Li, H., et al. (2020) · Theranostics · doi:10.7150/thno.49199 · Cited by 210 · see citing works
“CNS disease models [38-42], indicating that CSF1R antagonists may be effective therapeutically for various CNS disorders associated with neuroinflammation.”
BackgroundMethodGreenhalgh, A. D., Zarruk, J. G., Healy, L. M., Jesudasan, S. J. B., Jhelum, P., Salmon, C. K., Formanek, A., Russo, M. V., Antel, J. P., McGavern, D. B., et al. (2018) · PLoS Biology · doi:10.1371/journal.pbio.2005264 · Cited by 212 · see citing works
“These findings may be of significance, as the rapid reaction of microglia in the early phases of injury are thought to be protective [35, 37, 38].”
BackgroundOld Maids: Aging and Its Impact on Microglia Function
Koellhoffer, E. C., McCullough, L. D., & Ritzel, R. M. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18040769 · Cited by 205 · see citing works
“Administration of the CSF1R inhibitor PLX3397 improved functional recovery and spared neuronal loss, in part by reducing chronic inflammation in 5–8 month old mice following a hippocampal lesion induced by diphtheria toxin exposure [77].”
BackgroundXu, F., Han, L., Wang, Y., Deng, D., Ding, Y., Zhao, S., Zhang, Q., Ma, L., & Chen, X. (2023) · BMC Medicine · doi:10.1186/s12916-022-02705-6 · Cited by 194 · see citing works
Early life stress perturbs the maturation of microglia in the developing hippocampus
Delpech, J.-C., Wei, L., Hao, J., Yu, X., Madore, C., Butovsky, O., & Kaffman, A. (2016) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2016.06.006 · Cited by 193 · see citing works
Microglia Are Irrelevant for Neuronal Degeneration and Axon Regeneration after Acute Injury
Hilla, A. M., Diekmann, H., & Fischer, D. (2017) · Journal of Neuroscience · doi:10.1523/jneurosci.0584-17.2017 · Cited by 176 · see citing works
“Secretion of neurotrophic factors and removal of potentially deleterious debris by activated microglia are reportedly neuroprotective and promote regeneration of severed axons (Kreutzberg, 1996; Streit, 2002; Hanisch and Kettenmann, 2007; Chen et al., 2012; Rice et al., 2015).”
BackgroundResultInfluentialMicroglia as hackers of the matrix: sculpting synapses and the extracellular space
Crapser, J. D., Arreola, M. A., Tsourmas, K. I., & Green, K. N. (2021) · Cellular & Molecular Immunology · doi:10.1038/s41423-021-00751-3 · Cited by 178 · see citing works
“Elimination of microglia or attenuation of microglial activation under neurodegenerative conditions or aging, however, leads to improved functional outcomes accompanied by restoration in spine number and synaptic surrogates [66, 67, 71, 77, 326, 327].”
BackgroundSelf-citationCrapser, J. D., Ochaba, J., Soni, N., Reidling, J. C., Thompson, L. M., & Green, K. N. (2020) · Brain · doi:10.1093/brain/awz363 · Cited by 157 · see citing works
“model for targeted elimination of microglia (Elmore et al., 2014; Asai et al., 2015; Dagher et al., 2015; Rice et al., 2015; Acharya et al., 2016; Feng et al., 2016; Spangenberg et al., 2016; Stafford et al., 2016; Szalay et al., 2016; Li et al., 2017; Bennett et al., 2018).”
Self-citationMicroglia Elimination Increases Neural Circuit Connectivity and Activity in Adult Mouse Cortex
Liu, Y., Spangenberg, E. E., Tang, B., Holmes, T. C., Green, K. N., & Xu, X. (2020) · Journal of Neuroscience · doi:10.1523/jneurosci.2140-20.2020 · Cited by 163 · see citing works
“…local excitatory and inhibitory neural circuits in the adult mouse visual cortex (Kuhlman et al., 2013; Sun et al., 2016; Xu et al., 2016), and have shown increased dendritic spine densities of excitatory cells in layer 5 following microglial depletion in the same region (Rice et al., 2015).”
BackgroundInfluentialSelf-citationTodd, L. J., Palazzo, I., Suarez, L., Liu, X., Volkov, L. I., Hoang, T. V., Campbell, W. A., Blackshaw, S., Quan, N., & Fischer, A. J. (2019) · Journal of Neuroinflammation · doi:10.1186/s12974-019-1505-5 · Cited by 164 · see citing works
Witcher, K. G., Bray, C. E., Dziabis, J. E., McKim, D. B., Benner, B. N., Rowe, R. K., Kokiko‐Cochran, O. N., Popovich, P. G., Lifshitz, J., Eiferman, D. S., et al. (2018) · Glia · doi:10.1002/glia.23523 · Cited by 153 · see citing works
“After recovery, injury was induced by filling the injury hub with saline and imposing a 10 ms pulse of saline (1.2 atm; 670–720 mV) onto the dura through the hub (Fenn et al., 2014; Lifshitz, Witgen, & Grady, 2007b; Rowe et al., 2016; Witgen, Lifshitz, & Grady, 2006).”
InfluentialStress induced microglial activation contributes to depression
Li, B., Yang, W., Ge, T., Wang, Y., & Cui, R. (2022) · Pharmacological Research · doi:10.1016/j.phrs.2022.106145 · Cited by 147 · see citing works
Alzheimer's-associated PU.1 expression levels regulate microglial inflammatory response
Pimenova, A. A., Herbinet, M., Gupta, I., Machlovi, S. I., Bowles, K. R., Marcora, E., & Goate, A. M. (2021) · Neurobiology of Disease · doi:10.1016/j.nbd.2020.105217 · Cited by 141 · see citing works
“In mouse models of AD genetic or pharmacological depletion of microglia prevented microglia association with amyloid plaques and neuronal loss, which led to improved learning and memory without affecting amyloid plaque load in mouse brain (Dagher et al., 2015; Rice et al., 2015; Spangenberg et al., 2016).”
Fu, H., Zhao, Y., Hu, D., Wang, S., Yu, T., & Zhang, L. (2020) · Cell Death and Disease · doi:10.1038/s41419-020-2733-4 · Cited by 141 · see citing works
A Tilted Axis: Maladaptive Inflammation and HPA Axis Dysfunction Contribute to Consequences of TBI
Tapp, Z. M., Godbout, J. P., & Kokiko‐Cochran, O. N. (2019) · Frontiers in Neurology · doi:10.3389/fneur.2019.00345 · Cited by 130 · see citing works
“This same model previously reported robust microglial reactivity that resolves following microglial elimination (40).”
BackgroundPhenotypic impacts of CSF1R deficiencies in humans and model organisms
Hume, D. A., Caruso, M., Ferrari-Cestari, M., SUMMERS, K. M., Pridans, C., & Irvine, K. M. (2019) · Journal of Leukocyte Biology · doi:10.1002/jlb.mr0519-143r · Cited by 121 · see citing works
The Inflammatory Continuum of Traumatic Brain Injury and Alzheimer’s Disease
Kokiko-Cochran, O. N., & Godbout, J. P. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00672 · Cited by 128 · see citing works
“Similarly, CSF1R inhibition after a chronic hippocampal lesion model of brain injury improved behavioral recovery, reduced pro-inflammatory molecules, and increased dendritic spines (239).”
BackgroundQiu, S., Palavicini, J. P., Wang, J., Gonzalez, N. S., He, S., Dustin, E., Zou, C., Ding, L., Bhattacharjee, A., Skike, C. E. V., et al. (2021) · Molecular Neurodegeneration · doi:10.1186/s13024-021-00488-7 · Cited by 126 · see citing works
Beckmann, N., Giorgetti, E., Neuhaus, A., Zurbruegg, S., Accart, N., Smith, P., Perdoux, J., Perrot, L., Nash, M., Desrayaud, S., et al. (2018) · Acta Neuropathologica Communications · doi:10.1186/s40478-018-0510-8 · Cited by 131 · see citing works
Han, J., Zhu, K., Zhang, X., & Harris, R. A. (2018) · Glia · doi:10.1002/glia.23529 · Cited by 114 · see citing works
“, 2018), then microglia-directed therapy, including specific microglia depletion strategies, can be regarded as a promising immunotherapy for neurological diseases (Du et al., 2017; Feng et al., 2017; Rice et al., 2015).”
BackgroundA limited capacity for microglial repopulation in the adult brain
Najafi, A. R., Crapser, J., Jiang, S., Ng, W., Mortazavi, A., West, B. L., & Green, K. N. (2018) · Glia · doi:10.1002/glia.23477 · Cited by 99 · see citing works
“…et al., 2012), as well as regulation of neurogenesis (Antony, Paquin, Nutt, Kaplan, & Miller, 2011); this function is maintained in the adult brain, where they continue to regulate neuronal structures and connections (Rice et al., 2015; Rice et al., 2017; Tremblay, Lowery, & Majewska, 2010).”
BackgroundSelf-citationThe role of microglia and their CX3CR1 signaling in adult neurogenesis in the olfactory bulb
Reshef, R., Kudryavitskaya, E., Shani-Narkiss, H., Isaacson, B., Rimmerman, N., Mizrahi, A., & Yirmiya, R. (2017) · eLife · doi:10.7554/elife.30809 · Cited by 108 · see citing works
“Interestingly, in late adulthood (i.e., in 10-months-old mice) microglia depletion was found to increase spine density (Rice et al., 2015).”
BackgroundMicroglia control glutamatergic synapses in the adult mouse hippocampus
Basilico, B., Ferrucci, L., Ratano, P., Golia, M. T., Grimaldi, A., Rosito, M., Ferretti, V., Reverte, I., Sanchini, C., Marrone, M. C., et al. (2021) · Glia · doi:10.1002/glia.24101 · Cited by 103 · see citing works
“In contrast, Rice and co-workers reported no change in the number of PSD-95 puncta in hippocampal CA1 neurons after 30 days of PLX3397-induced microglial depletion in control mice and an increase in PSD-95 in microglia-depleted mice through neuronal lesion (Rice et al, 2015).”
BackgroundInfluentialInsights Into the Role of CSF1R in the Central Nervous System and Neurological Disorders
Hu, B., Duan, S., Wang, Z., Li, X., Zhou, Y., Zhang, X., Zhang, Y., Xu, H., & Zheng, H. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.789834 · Cited by 105 · see citing works
Inflammation within the neurovascular unit: Focus on microglia for stroke injury and recovery
Eldahshan, W., Fagan, S. C., & Ergul, A. (2019) · Pharmacological Research · doi:10.1016/j.phrs.2019.104349 · Cited by 104 · see citing works
Baulch, J. E., Acharya, M. M., Allen, B. D., Ru, N., Chmielewski, N. N., Martirosian, V., Giedzinski, E., Syage, A. R., Park, A. L., Benke, S. N., et al. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1521668113 · Cited by 100 · see citing works
“Mice depleted of microglia retain higher levels of dendritic spine density and suffer few if any adverse neurocognitive outcomes (25).”
BackgroundWalker, D. G., Tang, T. M., & Lue, L. (2017) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2017.00244 · Cited by 93 · see citing works
“Studies by one group used two related CSF-1R inhibitors, PLX3397, or PLX5622 administered in the animal feed, produced almost complete ablation of microglia from the animal brain at the highest dose (Elmore et al., 2014, 2015; Rice et al., 2015, 2017; Spangenberg et al., 2016).”
BackgroundMethodNew Insights into Microglia–Neuron Interactions: A Neuron’s Perspective
Pósfai, B., Cserép, C., Orsolits, B., & Dénes, Á. (2019) · Neuroscience · doi:10.1016/j.neuroscience.2018.04.046 · Cited by 98 · see citing works
Microglia responses to interleukin‐6 and type I interferons in neuroinflammatory disease
West, P. K., Viengkhou, B., Campbell, I. L., & Hofer, M. J. (2019) · Glia · doi:10.1002/glia.23634 · Cited by 97 · see citing works
Li, D., Chen, M., Meng, T., & Fei, J. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-020-01799-0 · Cited by 96 · see citing works
Socodato, R., Portugal, C. C., Canedo, T., Rodrigues, A., Almeida, T. O., Henriques, J. F., Vaz, S. H., Magalhães, J., Silva, C. M., Baptista, F. I., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.107796 · Cited by 94 · see citing works
Coleman, L. G., Zou, J., & Crews, F. T. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-019-1678-y · Cited by 87 · see citing works
Jadhav, N., Ajgaonkar, S., Saha, P., Gurav, P., Pandey, A., Basudkar, V., Gada, Y., Panda, S., Jadhav, S. S., Mehta, D. S., et al. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.896920 · Cited by 88 · see citing works
Dementia, Depression, and Associated Brain Inflammatory Mechanisms after Spinal Cord Injury
Li, Y., Cao, T., Ritzel, R. M., He, J., Faden, A. I., & Wu, J. (2020) · Cells · doi:10.3390/cells9061420 · Cited by 84 · see citing works
Klément, W., Garbelli, R., Zub, E., Rossini, L., Tassi, L., Girard, B. J. T., Blaquière, M., Bertaso, F., Perroy, J., de Bock, F., et al. (2018) · Neurobiology of Disease · doi:10.1016/j.nbd.2018.02.002 · Cited by 84 · see citing works
Reactive gliosis in traumatic brain injury: a comprehensive review
Amlerova, Z., Chmelová, M., Anděrová, M., & Vargová, L. (2024) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2024.1335849 · Cited by 86 · see citing works
Strackeljan, L., Baczynska, E., Cangalaya, C., Baidoe-Ansah, D., Wlodarczyk, J., Kaushik, R., & Dityatev, A. (2021) · Cells · doi:10.3390/cells10081862 · Cited by 71 · see citing works
“Increased spine density after microglia depletion suggests that these cells play a crucial role in the homeostatic maintenance of dendritic spine densities during adulthood [45].”
BackgroundAttenuation of neuroinflammation reverses Adriamycin-induced cognitive impairments
Allen, B. D., Apodaca, L. A., Syage, A. R., Markarian, M., Baddour, A. A. D., Minasyan, H., Alikhani, L., Lu, C., West, B. L., Giedzinski, E., et al. (2019) · Acta Neuropathologica Communications · doi:10.1186/s40478-019-0838-8 · Cited by 76 · see citing works
Self-citationLncRNA-Meg3 promotes Nlrp3-mediated microglial inflammation by targeting miR-7a-5p
Meng, J., Ding, T., Chen, Y., Long, T., Xu, Q., Lian, W.-Q., & Liu, W. (2020) · International Immunopharmacology · doi:10.1016/j.intimp.2020.107141 · Cited by 78 · see citing works
Heinz, R., Brandenburg, S., Nieminen-Kelhä, M., Kremenetskaia, I., Boehm‐Sturm, P., Vajkoczy, P., & Schneider, U. C. (2021) · Journal of Neuroinflammation · doi:10.1186/s12974-021-02085-3 · Cited by 74 · see citing works
“The fact that PLX3397 treatment needs several days (in some literature up to weeks [28, 40]) for maximum depletion of microglia might exhibit a potential weakness in this “realistic” treatment scenario, as compared to a pre-treatment scenario.”
ResultMacrophage depletion protects against cisplatin-induced ototoxicity and nephrotoxicity
Sung, C. Y. W., Hayase, N., Yuen, P. S. T., Lee, J., Fernandez, K. A., Hu, X., Cheng, H., Star, R. A., Warchol, M. E., & Cunningham, L. L. (2024) · Science Advances · doi:10.1126/sciadv.adk9878 · Cited by 79 · see citing works
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 · see citing works
“Behavioral testing showed improved learning on the elevated plus maze and the Morris water maze (MWM) following PLX3397 treatment; however, the probe trial (a test of recall in the MWM) was unaffected by depletion of microglia (Rice et al., 2015).”
BackgroundMatisz, C. E., & Gruber, A. J. (2021) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2021.12.020 · Cited by 70 · see citing works
Li, T., Zhao, J., Xie, W., Yuan, W., Guo, J., Pang, S., Gan, W.-B., Gómez-Nicola, D., & Zhang, S. (2021) · Journal of Neuroinflammation · doi:10.1186/s12974-021-02127-w · Cited by 72 · see citing works
Wang, Y., Wernersbach, I., Strehle, J., Li, S., Appel, D., Klein, M., Ritter, K., Hummel, R., Tegeder, I., & Schäfer, M. K. E. (2022) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2022.07.164 · Cited by 69 · see citing works
Du, X., Xu, Y., Chen, S., & Fang, M. (2020) · Neural Plasticity · doi:10.1155/2020/8825954 · Cited by 69 · see citing works
“The precise mechanism was also revealed that microglial density and survival were dependent on CSF1R signaling and inhibition of CSF1R in microglia contributed to the dendritic spines and neurons recovery in ischemia stroke [29].”
BackgroundVogel Ciernia, A., Careaga, M., LaSalle, J. M., & Ashwood, P. (2018) · Glia · doi:10.1002/glia.23261 · Cited by 69 · see citing works
“…the adult mouse brain by pharmacological treatment did not negatively impact adult behavior (Elmore et al., 2014, 2015) and improved behavioral deficits in an Alzheimer’s disease model (Rice et al., 2015), suggesting microglial contributions to neuro-immune dysfunction can be reversed in the adult.”
BackgroundMicroglia depletion fails to abrogate inflammation-induced sickness in mice and rats
Vichaya, E. G., Malik, S., Sominsky, L., Ford, B. G., Spencer, S. J., & Dantzer, R. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-020-01832-2 · Cited by 68 · see citing works
Attenuated CSF‐1R signalling drives cerebrovascular pathology
Delaney, C. P., Farrell, M., Doherty, C. P., Brennan, K., O’Keeffe, E., Greene, C., Byrne, K., Kelly, E., Birmingham, N., Hickey, P. P., et al. (2020) · EMBO Molecular Medicine · doi:10.15252/emmm.202012889 · Cited by 68 · see citing works
“…PLX3397 and PLX5622 has been shown to be effective in depleting up to 99% of microglia within 3 weeks of administration in chow (Luo et al , 2013; Rice et al , 2015; Dagher et al , 2015; Renee et al , 2015; Spangenberg et al , 2016, 2019; Bohlen et al , 2017; Singh et al , 2017; Elmore et al ,…”
Henning, L., Antony, H., Breuer, A., Müller, J., Seifert, G., Audinat, É., Singh, P., Brosseron, F., Heneka, M. T., Steinhäuser, C., et al. (2022) · Glia · doi:10.1002/glia.24265 · Cited by 67 · see citing works
“Zstacks were recorded at 0.36 μm (TNFR1), 0.42 μm (CD68), 1 μm (IBA1 & GFAP morphology, CD169), or 2 μm (GJ coupling & Hippocampal sclerosis) intervals.”
MethodInfluentialThe Role of Microglia and Peripheral Monocytes in Retinal Damage after Corneal Chemical Injury
Paschalis, E. I., Lei, F., Zhou, C., Kapoulea, V., Thanos, A., Dana, R., Vavvas, D. G., Chodosh, J., & Dohlman, C. H. (2018) · American Journal Of Pathology · doi:10.1016/j.ajpath.2018.03.005 · Cited by 65 · see citing works
Hohsfield, L. A., Najafi, A. R., Ghorbanian, Y., Soni, N., Hingco, E. E., Kim, S. J., Jue, A. D., Swarup, V., Inlay, M. A., & Green, K. N. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-020-01931-0 · Cited by 64 · see citing works
Self-citationZhai, Q., Zhang, Y., Ye, M., Zhu, S., Sun, J., Wang, Y., Deng, B., Ma, D., & Wang, Q. (2023) · British Journal of Anaesthesia · doi:10.1016/j.bja.2023.04.044 · Cited by 66 · see citing works
Mitigation of helium irradiation-induced brain injury by microglia depletion
Allen, B. D., Syage, A. R., Maroso, M., Baddour, A. A. D., Luong, V., Minasyan, H., Giedzinski, E., West, B. L., Soltész, I., Limoli, C. L., et al. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-020-01790-9 · Cited by 61 · see citing works
“Similarly, depletion of microglia prior to neuronal insult aggravated the injury, whereas microglia elimination following the neuronal injury promoted recovery [27].”
BackgroundResultSelf-citationNebeling, F. C., Poll, S., Justus, L. C., Mittag, M., Steffen, J., Keppler, K., & Fuhrmann, M. (2023) · eLife · doi:10.7554/elife.83176 · Cited by 64 · see citing works
“This hypothesis derives from studies showing the necessity of normal microglia function for synaptic integrity and learningdependent synapse formation (Bessis et al., 2007; Lim et al., 2013; Miyamoto et al., 2016; Paolicelli et al., 2011; Parkhurst et al., 2013; Pfeiffer et al., 2016; Reshef et al., 2017; Rice et al.,…”
BackgroundRimmerman, N., Verdiger, H., Goldenberg, H., Naggan, L., Robinson, E., Kozela, E., Gelb, S., Reshef, R., Ryan, K. M., Ayoun, L., et al. (2021) · Molecular Psychiatry · doi:10.1038/s41380-021-01338-0 · Cited by 62 · see citing works
Gu, R., Zhang, F., Chen, G., Han, C., Liu, J., Ren, Z., Zhu, Y., Waddington, J. L., Zheng, L. T., & Zhen, X. (2016) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2016.10.018 · Cited by 62 · see citing works
“Like monocytes/macrophages, activated microglia produce and release proinflammatory cytokines and neurotoxic mediators after stimulation with lipopolysaccharide (LPS) or interferon (IFN)-γ in vitro (Dong and Zhen，2015; Rice et al.，2015).”
BackgroundAggravated brain injury after neonatal hypoxic ischemia in microglia-depleted mice
Tsuji, S., Martino, E. D., Mukai, T., Tsuji, S., Murakami, T., Harris, R. A., Blomgren, K., & Ådén, U. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-020-01792-7 · Cited by 63 · see citing works
“Previous studies have employed microglial-depletion models of adult stroke, Alzheimer’s disease, and retinal disease [26, 28, 30, 33, 51, 52].”
MethodHinkle, J. J., Olschowka, J. A., Love, T. M., Williams, J. P., & O’Banion, M. K. (2019) · Scientific Reports · doi:10.1038/s41598-019-55366-6 · Cited by 61 · see citing works
Microglial Interferon Signaling and White Matter
McDonough, A., Lee, R. V., & Weinstein, J. R. (2017) · Neurochemical Research · doi:10.1007/s11064-017-2307-8 · Cited by 62 · see citing works
“Prolonged treatment with a CSF1R antagonist prevented neuronal loss in a mouse model of AD [48] and improved functional outcome following extensive neuronal loss in the hippocampus [49].”
InfluentialSelf-citationThe Immune System's Role in the Consequences of Mild Traumatic Brain Injury (Concussion)
Verboon, L. N., Patel, H. C., & Greenhalgh, A. D. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.620698 · Cited by 58 · see citing works
Gushchina, S. V., Pryce, G., Yip, P. K., Wu, D., Pallier, P. N., Giovannoni, G., Baker, D., & Bo, X. (2018) · Glia · doi:10.1002/glia.23464 · Cited by 52 · see citing works
Extracellular Vesicles miRNA Cargo for Microglia Polarization in Traumatic Brain Injury
Panaro, M. A., Benameur, T., & Porro, C. (2020) · Biomolecules · doi:10.3390/biom10060901 · Cited by 54 · see citing works
Extracellular microvesicles promote microglia‐mediated pro‐inflammatory responses to ethanol
Crews, F. T., Zou, J., & Coleman, L. G. (2021) · Journal of Neuroscience Research · doi:10.1002/jnr.24813 · Cited by 54 · see citing works
“…MVs. Microglia can be depleted both in vivo and ex vivo with pharmacological inhibition of CSF1R, with no detectable nonmicroglial cell death or behavioral dysfunction (Coleman et al., 2020; Han et al., 2017; Hughes & Bergles, 2014; Rice et al., 2015; Varvel et al., 2012; Walter & Crews, 2017).”
BackgroundVitamin K2 Holds Promise for Alzheimer’s Prevention and Treatment
Popescu, A., & German, M. (2021) · Nutrients · doi:10.3390/nu13072206 · Cited by 55 · see citing works
Li, X., Gao, X., Zhang, W., Liu, M., Han, Z., Li, M., Lei, P., & Liu, Q. (2022) · Cell Death and Disease · doi:10.1038/s41419-021-04424-x · Cited by 52 · see citing works
“Moreover, removal of CSF1R inhibition stimulates the rapid repopulation of the entire brain with new microglial cells [4, 5], leading to effective replacement of the entire microglia population, a process takes approximately 2–3 weeks to complete.”
Groh, J., Ribechini, E., Stadler, D., Schilling, T., Lutz, M. B., & Martini, R. (2016) · Glia · doi:10.1002/glia.22962 · Cited by 51 · see citing works
“Some studies also use Sn expression in order to identify peripherally derived infiltrating myeloid cells (Gao et al., 2015; Rice et al., 2015).”
BackgroundMicroglia suppress the secondary progression of autoimmune encephalomyelitis
Tanabe, S., Saitoh, S., Miyajima, H., Itokazu, T., & Yamashita, T. (2019) · Glia · doi:10.1002/glia.23640 · Cited by 52 · see citing works
“This agreed with previous studies showing that PLX3397 treatment did not disrupt BBB permeability in the presence of brain ischemia or neuronal lesions (Rice et al., 2015; Szalay et al., 2016).”
ResultTran, K. M., Kawauchi, S., Kramár, E. A., Rezaie, N., Liang, H. Y., Sakr, J., Gómez-Arboledas, Á., Arreola, M. A., da Cunha, C., Phan, J., et al. (2023) · Molecular Neurodegeneration · doi:10.1186/s13024-023-00598-4 · Cited by 50 · see citing works
Self-citationJackson, L., Dumanli, S., Johnson, M. H., Fagan, S. C., & Ergul, A. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-020-01815-3 · Cited by 50 · see citing works
Gargouri, B., Yousif, N. M., Bouchard, M., Fetoui, H., & Fiebich, B. L. (2018) · Journal of Neuroinflammation · doi:10.1186/s12974-018-1198-1 · Cited by 48 · see citing works
- Authors
- Rice, R. A., Spangenberg, E. E., Yamate-Morgan, H., Lee, R. J., Arora, R. P. S., Hernandez, M. X., Tenner, A. J., West, B. L., & Green, K. N.
- Affiliations
- University of California, Irvine (US)
- Plexxikon (United States) (US)
- Venue
- Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2015-07-08
- Volume
- 35
- Issue
- 27
- Pages
- 9977-9989
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC4495246
- OpenAlex
- W1920357305
- Cited by
- 270
- References
- 41
- Citations by year
- 2026: 7 · 2025: 16 · 2024: 27 · 2023: 40 · 2022: 19 · 2021: 43 · 2020: 35 · 2019: 26 · 2018: 20 · 2017: 15 · 2016: 19 · 2015: 2
- FWCI
- 9.98
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Neuroscience (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- Alzheimer's Association
- Whitehall Foundation
- Plexxikon
- National Institutes of Health (UL1TR001414, AG016573, AG00538, AG000096)
- National Institute on Aging (P01AG000538, AG-016573, AG 00538, AG000096, PPG AG 00538, P50AG016573, T32AG000096)
- National Institute of Neurological Disorders and Stroke (F31NS086409, R01NS083801)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- microglia, CSF1R inhibition, PLX3397, hippocampal lesions, neuronal loss, neuroinflammation, cognitive recovery, dendritic spines, synaptic plasticity, PSD-95, synaptophysin, diphtheria toxin A chain
- MeSH terms
- Aminopyridines, Animals, Behavioral Symptoms, Blood-Brain Barrier, Brain Injuries, Cognition Disorders, Disease Models, Animal, Doxycycline, Female, Hippocampus, Male, Mice, Transgenic, Neurons, Phosphopyruvate Hydratase, Pyrroles, Synaptophysin, Microglia, Maze Learning, Recovery of Function, Dendritic Spines, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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