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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, 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
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredIn the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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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Basilico, B., Ferrucci, L., Khan, A., Angelantonio, S. D., Ragozzino, D., & Reverte, I. (2022) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2022.1022431 · Cited by 52
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Self-citationA Microglia Sublineage Protects from Sex-Linked Anxiety Symptoms and Obsessive Compulsion
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BackgroundMicroglia regulate neuronal activity via structural remodeling of astrocytes
Gu, N., Makashova, O. E., Laporte, C., Chen, C. Q., Li, B., Chevillard, P., Lean, G., Yang, J., Wong, C., Fan, J., et al. (2025) · Neuron · doi:10.1016/j.neuron.2025.07.024 · Cited by 46
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The role of microglia in ischemic preconditioning
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“…progenitors (Elmore et al., 2014; Huang et al., 2018), functional consequences of microglial depletion and replenishment (Elmore, Lee, West, & Green, 2015; Rice et al., 2017), and biological roles of microglia in injury and disease models (Hilla, Diekmann, & Fischer, 2017; Rice et al., 2015).”
BackgroundOptogenetic Glia Manipulation: Possibilities and Future Prospects
Cho, W.-H., Barcelon, E. E., & Lee, S. J. (2016) · Experimental Neurobiology · doi:10.5607/en.2016.25.5.197 · Cited by 37
The basic science of optic nerve regeneration
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“In one study, microglia were neuroprotective during a prolonged experimentally induced injury but microglial presence following the injury hindered recovery (194).”
BackgroundPhagocytic Glial Cells in Brain Homeostasis
Kono, R., Ikegaya, Y., & Koyama, R. (2021) · Cells · doi:10.3390/cells10061348 · Cited by 41
“On the other hand, removal of microglia by the CSF1 receptor inhibitor PLX3397 from 8 to 12 weeks of age did not change the number of synapses, which was consistent with a previous report [70].”
ResultAdams, R. C., Carter‐Cusack, D., Shaikh, S., Llanes, G. T., Johnston, R. L., Quaife-Ryan, G. A., Boyle, G. M., Koufariotis, L. T., Möller, A., Blazar, B. R., et al. (2021) · Blood · doi:10.1182/blood.2021011671 · Cited by 38
An overview of microglia ontogeny and maturation in the homeostatic and pathological brain
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“To determine the contribution of Sema3A from microglia in the mouse model, mice treated with PLX3397, which depleted microglia in retina [30, 38, 39], underwent ONC.”
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Self-citationYegla, B., Boles, J. S., Kumar, A., & Foster, T. C. (2021) · Glia · doi:10.1002/glia.23975 · Cited by 33
“The pro-inflammatory cytokine, IL-1β, decreases basal synaptic transmission (Bellinger, Madamba, & Siggins, 1993; Lynch, 1998; Rothwell & Luheshi, 2000), and hippocampal IL-1β levels were elevated in young and aged depleted groups.”
BackgroundAndrew, P. M., & Lein, P. J. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.674325 · Cited by 38
“…evidence showing that the functional role of microglia shifts over the course of the neuroinflammatory response following acute brain injury in a variety of neurologic diseases not related to seizures (Rice et al., 2015; Szalay et al., 2016; Jin et al., 2017; Rice et al., 2017; Lloyd et al., 2019).”
BackgroundMicroglia are involved in the protection of memories formed during sleep deprivation
Gentry, N. W., McMahon, T., Yamazaki, M., Webb, J. M., Arnold, T. D., Rosi, S., Ptáček, L. J., & Fu, Y. (2021) · Neurobiology of Sleep and Circadian Rhythms · doi:10.1016/j.nbscr.2021.100073 · Cited by 31
FDA-Approved Kinase Inhibitors in Preclinical and Clinical Trials for Neurological Disorders
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“As markers to detect inflammatory reactions, GFAP and Iba1 directly reflect the function of the brain and are significantly associated with cognitive changes [33].”
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Lessons Learned about Neurodegeneration from Microglia and Monocyte Depletion Studies
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“However, elimination subsequent to lesion formation improved cognitive recovery and reduced inflammatory signaling (Rice et al., 2015), demonstrating a deleterious response of microglia after as opposed to during lesion formation, again stressing how important accurate timing in microglia depletion studies is to obtai…”
BackgroundResultInfluentialThe Microglial Response to Neurodegenerative Disease
Song, W. M., & Colonna, M. (2018) · Advances in immunology · doi:10.1016/bs.ai.2018.04.002 · Cited by 30
Fonseca‐Gomes, J., Costa-Coelho, T., Ferreira-Manso, M., Inteiro-Oliveira, S., Vaz, S. H., Alemãn-Serrano, N., Atalaia-Barbacena, H., Ribeiro‐Rodrigues, L., Ramalho, R. M., Pinto, R. R., et al. (2024) · Molecular Therapy · doi:10.1016/j.ymthe.2024.08.022 · Cited by 27
“33 Treatment with TAT-TrkB prevented the decreased anxious-like behavior in 5XFAD mice, while having no effect in WT mice (Figure 5I).”
Microglial depletion and repopulation: a new era of regenerative medicine?
Coleman, L. G., Barnett, A., & Crews, F. T. (2020) · Neural Regeneration Research · doi:10.4103/1673-5374.300439 · Cited by 27
“This method has been shown to reduce neuroinflammation and improve recovery following induction of extensive neuronal loss in the hippocampus caused by diphtheria toxin injection (Rice et al., 2015).”
BackgroundMethodWyatt‐Johnson, S. K., Sommer, A. L., Shim, K., & Brewster, A. L. (2021) · Frontiers in Neurology · doi:10.3389/fneur.2021.651096 · Cited by 26
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“As opposed to the latter, upon CSF-1Ri treatment, there was robust macrophage ablation below wt levels, similar to effects on microglia in the CNS when a similar inhibitor was used (Elmore et al., 2014; Rice et al., 2015).”
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Revisiting the critical roles of reactive microglia in traumatic brain injury
Zhao, J., Zhou, Y., Zhou, C.-W., Zhan, K., Yang, M., Wen, M., & Zhu, L. (2025) · International Journal of Surgery · doi:10.1097/js9.0000000000002420 · Cited by 30
“Evidence indicates that the microglial response occurring within minutes to hours after an injury is beneficial and contributes to the containment of CNS lesions [ 91-93 ] .”
Ahmed, S., Polis, B., Jamwal, S., Sanganahalli, B. G., Kaswan, Z. A. M., Islam, R., Kim, D., Bowers, C. A., Giuliano, L., Biederer, T., et al. (2024) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2024.08.010 · Cited by 32
“These findings are consistent with previous work showing that a small pool of microglia survives the initial ablation and proliferates to restore normal number of microglia within 1 – 2 weeks (Bruttger et al., 2015; Nelson and Lenz, 2017; Rice et al., 2015; Schalbetter et al., 2022).”
ResultTorres-Rodríguez, O. I., Ortiz-Nazario, E., Rivera-Escobales, Y., Velázquez, B., Alonso-Colón, M., & Porter, J. T. (2023) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2022.1014767 · Cited by 24
“, 2020), while others found similar sensitivity to PLX3397 in male and female rodents (Rice et al., 2015; Ma et al., 2020; Delizannis et al., 2021).”
BackgroundMicroglial ROCK is essential for chronic methylmercury‐induced neurodegeneration
Shinozaki, Y., Danjo, Y., & Koizumi, S. (2019) · Journal of Neurochemistry · doi:10.1111/jnc.14817 · Cited by 23
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Repurposing of pexidartinib for microglia depletion and renewal
Weyer, M.-P., Strehle, J., Schäfer, M. K. E., & Tegeder, I. (2023) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2023.108565 · Cited by 23
Differential transcriptional response profiles in human myeloid cell populations
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The Role of Microglial Depletion Approaches in Pathological Condition of CNS
Tahmasebi, F., & Barati, S. (2023) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-023-01326-8 · Cited by 21
“They confirmed improved functional recovery and decreased proinflammatory gene expression in the hippocampus after microglial ablation (Rice et al. 2015).”
BackgroundRole of age and neuroinflammation in the mechanism of cognitive deficits in sickle cell disease
Hardy, R. A., Rached, N. A., Jones, J. A., Archer, D. R., & Hyacinth, H. I. (2020) · Experimental Biology and Medicine · doi:10.1177/1535370220958011 · Cited by 23
“Our findings that both neuroinflammation and lower dendritic spine density are potential contributors to the presence of cognitive and behavioral deficits in SCD are strengthened by studies that indicate that the presence and interaction between the two factors are associated with cognitive decline.(73,74) These facto…”
BackgroundImmune Regulation of Adult Neurogenic Niches in Health and Disease
Chintamen, S., Imessadouene, F., & Kernie, S. G. (2021) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.571071 · Cited by 22
“Microglia depletion was suggested as a potential therapeutic strategy in other forms of neurodegeneration (Rice et al., 2015).”
BackgroundAndries, L., Groef, L. D., & Moons, L. (2019) · Current Eye Research · doi:10.1080/02713683.2019.1669664 · Cited by 19
“elimination via PLX3397 facilitates functional recovery, likely through a combination of a reduced secretion of proinflammatory substances, a decrease in phagocytic activity, and by preventingmicroglia-induced synaptic alterations.(96)Moreover, preliminary data from our lab, obtained from optic nerve regeneration stud…”
BackgroundZhang, Z., Niu, K., Huang, T., Guo, J., Xarbat, G., Gong, X., Gao, Y., Liu, F., Shan, C., Su, W., et al. (2025) · npj Parkinson s Disease · doi:10.1038/s41531-024-00846-4 · Cited by 21
“PLX5622 treatment did not result in astro-gliosis, as no increase in GFAP expression following CSF-1R inhibition was visible, which is consistent with previous reports of astrocyte numbers observed after administering the CSF-1R inhibitor 10,50,51 .”
Microglial modulation of neuronal network function and plasticity
Peña‐Ortega, F. (2025) · Journal of Neurophysiology · doi:10.1152/jn.00458.2024 · Cited by 19
Microglial depletion abolishes ischemic preconditioning in white matter
Hamner, M. A., McDonough, A., Gong, D. C., Todd, L. J., Rojas, G., Hodecker, S. C., Ransom, C. B., Reh, T. A., Ransom, B. R., & Weinstein, J. R. (2021) · Glia · doi:10.1002/glia.24132 · Cited by 18
“A second limitation is that CSF1R antagonism could be exerting effects that are independent of microglial viability (Nissen et al., 2018).”
BackgroundMethodInfluentialWendt, S., Johnson, S., Weilinger, N. L., Groten, C., Sorrentino, S., Frew, J., Yang, L., Choi, H. B., Nygaard, H. B., & MacVicar, B. A. (2022) · Redox Biology · doi:10.1016/j.redox.2022.102448 · Cited by 20
“These data indicate that microglia are not the primary source of neuronal Ox-stress in DNs surrounding Aβ plaques and further suggest that neuroprotective as well as neurotoxic phenotypes of microglia act in parallel since removal of microglia also reduces neuronal loss and improves memory formation [36,37].”
BackgroundJoo, H., Bae, J., Lee, J.-S., Bang, Y.-M., Lee, B.-J., Park, J.-W., Lee, K., Cho, J.-H., & Bu, Y. (2018) · Planta Medica · doi:10.1055/a-0753-0400 · Cited by 18
Neuroregeneration: Regulation in Neurodegenerative Diseases and Aging
Бобкова, Н. В., Полтавцева, Р. А., Leonov, S. V., & Sukhikh, G. T. (2020) · Biochemistry (Moscow) · doi:10.1134/s0006297920140060 · Cited by 17
“On the other hand, recent studies suggest that specific therapeutic approaches, such as the use of low molecular weight TrkB agonist [108, 109] and manipulation of microglia [110, 111] leading to the upregulation of endogenous neurogenesis, could be promising in the recovery of brain functions after severe Alzheimer’s…”
BackgroundJian, H., Wu, K., Lv, Y., Du, J., Hou, M., Zhang, C., Gao, J., Zhou, H., & Feng, S. (2024) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2024.10.288 · Cited by 16
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“The outcome of the microglia response to injury can vary based on timing relative to the injury (Rice et al., 2015) or developmental stage (Graeber et al., 1998; Melzer et al., 2001).”
InfluentialSimon, K. U., Neto, E. W., Tramontin, N. D. S., Canteiro, P. B., Pereira, B. D. C., Zaccaron, R. P., Silveira, P. C. L., & Muller, A. P. (2019) · Peptides · doi:10.1016/j.peptides.2019.170175 · Cited by 16
Blood Aggravates Histological and Functional Damage after Acute Subdural Hematoma in Rats
Jussen, D., Krenzlin, H., Papaioannou, C., Ens, S., Kempski, O. S., & Alessandri, B. (2016) · Journal of Neurotrauma · doi:10.1089/neu.2016.4464 · Cited by 16
“48 There seems to be a temporal split up of cytokine production and delayed microglial activation.”
Strategies to dissect microglia-synaptic interactions during aging and in Alzheimer's disease
Heuer, S. E., Bloss, E. B., & Howell, G. R. (2024) · Neuropharmacology · doi:10.1016/j.neuropharm.2024.109987 · Cited by 16
Yan, L., Li, Y., Fan, F., Gou, M., Xuan, F.-L., Feng, W., Chithanathan, K., Li, W., Huang, J., Li, H., et al. (2023) · BMC Medicine · doi:10.1186/s12916-023-02959-8 · Cited by 16
“CSF1Ri-induced microglial ablation enhanced fear learning and memory [26, 27] while microglial repopulation corrected repetitive behaviour and social deficits [28, 29].”
BackgroundMitochonic acid 5 regulates mitofusin 2 to protect microglia
Tan, J., Chen, S., Lei, Q., Yi, S., Wu, N., Wang, Y., Xiao, Z., & Wu, H. (2021) · Neural Regeneration Research · doi:10.4103/1673-5374.306094 · Cited by 13
“Activated microglia can promote regeneration of severed axons, secretion of neurotrophic factors, and the removal of potentially deleterious debris (Streit, 2002; Chen et al., 2012; Rice et al., 2015).”
WKYMVm/FPR2 Alleviates Spinal Cord Injury by Attenuating the Inflammatory Response of Microglia
Zhang, W., Chen, J., Guo, W., Kong, G., Wang, L., Cheng, X., Zeng, X., Wan, Y., & Li, X. (2022) · Mediators of Inflammation · doi:10.1155/2022/4408099 · Cited by 14
“During the development of SCI, M1-polarized microglia produce a large number of proinflammatory cytokines, which are harmful to both damaged and healthy neurons [17, 18] and lead to secondary injury [19].”
BackgroundExploring microglial replacement: From disease models to clinical translation
Zhou, K., Wang, Y., Xu, Y., Zhang, Y., & Zhu, C. (2025) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2025.06.011 · Cited by 13
Wang, H., Lu, X., Ye, Y., Huang, C., Fang, Y., Yang, R., Sun, M., Ren, J., Song, R., Xu, F., et al. (2025) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2025.04.010 · Cited by 13
Zhang, B., Ran, Y., Wu, S., Zhang, F., Huang, H., Zhu, C., Zhang, S., & Zhang, X. (2021) · Frontiers in Neurology · doi:10.3389/fneur.2021.607370 · Cited by 13
Zhang, Q., Li, Y., & Zhuo, Y. (2022) · Molecular Neurobiology · doi:10.1007/s12035-022-02781-y · Cited by 13
Colony stimulating factor 1: friend or foe of neurons?
Bo, X., & Bo, L. (2021) · Neural Regeneration Research · doi:10.4103/1673-5374.322451 · Cited by 12
“studies, such as on the effect of CSF1/CSF1R inhibition in hippocampal lesions (Rice et al., 2015).”
BackgroundMicroglia activation mediates circadian rhythm disruption-induced cognitive impairment in mice
Meng, D., Yang, M., Zhang, H., Zhang, L., Song, H., Liu, Y., Zeng, Y., Yang, B. K., Wang, X., Chen, Y., et al. (2023) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2023.578102 · Cited by 12
Microglial repopulation restricts ocular inflammation and choroidal neovascularization in mice
Song, Y., Liao, Y., Liu, T., Chen, Y., Wang, F., Zhou, Z., Zhang, W., & Li, J. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1366841 · Cited by 13
Bano, N., Khan, S., Ahamad, S., Dar, N. J., Alanazi, H. H., Nazir, A., & Bhat, S. A. (2025) · Ageing Research Reviews · doi:10.1016/j.arr.2025.102735 · Cited by 13
Dye, C. N., Franceschelli, D. V., Leuner, B., & Lenz, K. M. (2023) · Neuropsychopharmacology · doi:10.1038/s41386-023-01624-1 · Cited by 14
“The absence of microglia has been linked to increased dendritic spine density [54], and increases in dendritic spines have also been shown in the postpartum brain [47, 55, 56].”
BackgroundCoburn, M., Eskandari‐Sedighi, G., Hasselmann, J., England, W., Shabestari, S. K., Mansour, K., McQuade, A., Mgerian, M., Chadarevian, J. P., Tu, C. H., et al. (2025) · Alzheimer s & Dementia · doi:10.1002/alz.70930 · Cited by 12
Andrew, P. M., MacMahon, J. A., Bernardino, P. N., Tsai, Y., Hobson, B. A., Porter, V. A., Huddleston, S. L., Luo, A., Bruun, D. A., Saito, N. H., et al. (2024) · Journal of Neuroinflammation · doi:10.1186/s12974-024-03272-8 · Cited by 13
“For example, depletion of microglia, the brain’s resident immune cells, prior to injury exacerbates damage in several models of CNS insult, including pilocarpine-induced SE [36–38], while microglial depletion later in the inflammatory response improves recovery [37–39].”
BackgroundBattis, K., Florio, J. B., Mante, M., Lana, A. J., Naumann, I., Gauer, C., Lambrecht, V., Müller, S. J., Cobo, I., Fixsen, B. R., et al. (2022) · Journal of Neuroscience · doi:10.1523/jneurosci.0417-22.2022 · Cited by 13
Suk, K. (2026) · Experimental Neurology · doi:10.1016/j.expneurol.2026.115737 · Cited by 11
Liu, J., Zhang, X., Xu, Y., & Zhang, S. (2023) · Molecular Neurobiology · doi:10.1007/s12035-023-03557-8 · Cited by 11
“At normal physiological state, microglia maintain a relatively steady cell density with low prolif-eration-rate [1–3], and actively monitor the surrounding microenvironment via their highly branched processes [4, 5].”
Chemoradiation impairs normal developmental cortical thinning in medulloblastoma
Kundu, P., Li, M., Durkee, B. Y., Hiniker, S. M., Bush, K. K., von Eyben, R., Monje, M., Yeom, K. W., Donaldson, S. S., & Gibbs, I. C. (2017) · Journal of Neuro-Oncology · doi:10.1007/s11060-017-2453-5 · Cited by 10
Gaidhani, N., Tucci, F. C., Kem, W. R., Beaton, G., & Uteshev, V. V. (2021) · British Journal of Pharmacology · doi:10.1111/bph.15392 · Cited by 10
“…ischaemic stroke injury and recovery remains uncertain (Qin et al., 2019) because both pro-inflammatory (Franco et al., 2012; Ma et al., 2017; Rice et al., 2015; Sawano et al., 2015; Yenari et al., 2006) and anti- inflammatory (Jin et al., 2017; Lalancette-Hebert et al., 2007; Lambertsen et…”
Glial cells as a promising therapeutic target of glaucoma: beyond the IOP
Shinozaki, Y., Namekata, K., Guo, X., & Harada, T. (2024) · Frontiers in Ophthalmology · doi:10.3389/fopht.2023.1310226 · Cited by 9
Lowery, R. L., Latchney, S. E., Peer, R. P., Lamantia, C. E., Lordy, K. A., Opanashuk, L. A., McCall, M. N., & Majewska, A. K. (2022) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2022.01.013 · Cited by 9
Kim, M., Oh, S., Kim, S., Kim, I., Kim, J., Han, J. H., Ahn, J. W., Chung, S., Jang, J., Shin, J. E., et al. (2024) · Inflammation and Regeneration · doi:10.1186/s41232-024-00349-y · Cited by 8
“This reduction in neuroinflammation improves the histological and functional outcomes of brain disease [54, 64–66].”
BackgroundVarghese, N. J., & Morrison, B. (2022) · Journal of Neurotrauma · doi:10.1089/neu.2022.0284 · Cited by 10
Yang, L., Gomm, A., Bai, P., Ding, W., Tanzi, R. E., Wang, C., Shen, S., & Zhang, C. M. (2024) · Anesthesia & Analgesia · doi:10.1213/ane.0000000000007239 · Cited by 8
Sharon, A., Jankowski, M. M., Shmoel, N., Erez, H., & Spira, M. E. (2023) · Acta Biomaterialia · doi:10.1016/j.actbio.2023.01.002 · Cited by 7
Clausi, M. G., Stessin, A. M., Zhao, Z., Tsirka, S. E., & Ryu, S. (2021) · Scientific Reports · doi:10.1038/s41598-021-84600-3 · Cited by 9
Nebeling, F. C., Poll, S., Schmid, L., Mittag, M., Steffen, J., Keppler, K., & Fuhrmann, M. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/515759 · Cited by 7
Ahmed, S., Polis, B., Jamwal, S., Sanganahalli, B. G., Kaswan, Z. A. M., Islam, R., Kim, D., Bowers, C. A., Giuliano, L., Biederer, T., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.02.14.580284 · Cited by 7
“…from WT littermates (Fig S3), consistent with previous work showing that a small pool of microglia survives the initial ablation and proliferates to restore normal number of microglia within 1-2 weeks (Bruttger et al., 2015; Nelson and Lenz, 2017; Rice et al., 2015; Schalbetter et al., 2022).”
ResultCX3CR1 modulates migration of resident microglia towards brain injuryPreprint
Wagner, J., Hoyer, C., Antony, H., Lundgrén, K., Soliymani, R., Crux, S., Justus, L. C., Keppler, K., Steffen, J., Kurts, C., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.09.23.614458 · Cited by 7
“This migration process is driven by adenosine triphosphate (ATP) via the purinergic G protein-coupled P2Y receptor 8 .”
BackgroundInfluentialXie, M., Wang, T., Feng, J., Ma, D., Feng, L., & Hao, Y. (2025) · Current Neuropharmacology · doi:10.2174/1570159x23666250225091729 · Cited by 7
“[366] Epilepsy Sirolimus (rapamycin) mTOR inhibitors Inhibit microglia response.”
Unraveling the complexity of microglial responses in traumatic brain and spinal cord injury
Henry, R. J., & Loane, D. J. (2025) · Handbook of clinical neurology · doi:10.1016/b978-0-443-19102-2.00015-6 · Cited by 7
Epigenetic Modulators of Monocytic Function: Implication for Steady State and Disease in the CNS
Papavasiliou, F. N., Chung, Y. C., Gagnidze, K., Hajdarovic, K. H., Cole, D. C., & Bulloch, K. (2016) · Frontiers in Immunology · doi:10.3389/fimmu.2015.00661 · Cited by 6
Basak, J. M., Falk, M., Dingman, A., Moore, A., Tiemeier, E., Aimale, G., & Quillinan, N. (2025) · Experimental Neurology · doi:10.1016/j.expneurol.2025.115364 · Cited by 6
Pathogenetic aspects of the development of acute focal cerebral ischemia
Сергеевна, Ч. А., Chukanova, E. I., Nadareishvili, G. G., Gulieva, M. S., & Gusev, E. I. (2017) · S S Korsakov Journal of Neurology and Psychiatry · doi:10.17116/jnevro20171171224-10 · Cited by 5
Riquier, A. J., & Sollars, S. I. (2022) · Developmental Neurobiology · doi:10.1002/dneu.22904 · Cited by 5
“In addition to the NTS, qualitatively comparable findings were observed in cortical and hippocampal sections, consistent with the systematic depletion present with other methods of CSF1R inhibitor administration (e.g., Elmore et al., 2015; Rice et al., 2015).”
ResultCommentary: How Do Microglia Regulate Neural Circuit Connectivity and Activity in the Adult Brain?
Liu, Y., Green, K. N., Holmes, T. C., & Xu, X. (2022) · Neuroscience Insights · doi:10.1177/26331055211071124 · Cited by 4
Self-citationAliashrafzadeh, H., Liu, D., Alba, S. D., Akbar, I., Lui, A., Vanleuven, J., Martin, R. M., Wang, Z., & Liu, D. (2025) · Exploration of Drug Science · doi:10.37349/eds.2025.1008116 · Cited by 5
“…for the potential treatment of ICH [304–306], SAH [307], obesity-related cerebrovascular dysfunction [308], cognitive decline due to brain damage [309], tauopathy [310], AD [311, 312], HD [313], MS [314–316], spinocerebellar ataxia type 1 (SCA1) that is a genetic, neurodegenerative disorder that…”
Chu, E., Mychasiuk, R., Green, T. R. F., Zamani, A., Dill, L. K., Sharma, R., Raftery, A. L., Tsantikos, E., Hibbs, M. L., & Semple, B. D. (2023) · Frontiers in Neuroscience · doi:10.3389/fnins.2023.1276495 · Cited by 4
Microglial depletion rescues spatial memory impairment caused by LPS administration in adult mice
Zong, T., Li, N., Han, F., Liu, J., Deng, M., Li, V. W. T., Zhang, M., Zhou, Y., & Yu, M. (2024) · PeerJ · doi:10.7717/peerj.18552 · Cited by 5
“In contrast, longer periods of depletion (up to 24 weeks) have been found to improve spatial learning and memory ( Elmore et al., 2014 ; Rice et al., 2015 ; Spangenberg et al., 2019 ).”
Metadata
- 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
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