Repopulated microglia after pharmacological depletion decrease dendritic spine density in adult mouse brain.
PLX5622
activation
microglia
microglia repopulation
spine density
Journal
Glia
ISSN: 1098-1136
Titre abrégé: Glia
Pays: United States
ID NLM: 8806785
Informations de publication
Date de publication:
23 May 2024
23 May 2024
Historique:
revised:
29
04
2024
received:
15
06
2023
accepted:
02
05
2024
medline:
23
5
2024
pubmed:
23
5
2024
entrez:
23
5
2024
Statut:
aheadofprint
Résumé
Microglia are innate immune cells in the brain and show exceptional heterogeneity. They are key players in brain physiological development regulating synaptic plasticity and shaping neuronal networks. In pathological disease states, microglia-induced synaptic pruning mediates synaptic loss and targeting microglia was proposed as a promising therapeutic strategy. However, the effect of microglia depletion and subsequent repopulation on dendritic spine density and neuronal function in the adult brain is largely unknown. In this study, we investigated whether pharmacological microglia depletion affects dendritic spine density after long-term permanent microglia depletion and after short-term microglia depletion with subsequent repopulation. Long-term microglia depletion using colony-stimulating-factor-1 receptor (CSF1-R) inhibitor PLX5622 resulted in increased overall spine density, especially of mushroom spines, and increased excitatory postsynaptic current amplitudes. Short-term PLX5622 treatment with subsequent repopulation of microglia had an opposite effect resulting in activated microglia with increased synaptic phagocytosis and consequently decreased spine density and reduced excitatory neurotransmission, while Barnes maze and elevated plus maze testing was unaffected. Moreover, RNA sequencing data of isolated repopulated microglia showed an activated and proinflammatory phenotype. Long-term microglia depletion might be a promising therapeutic strategy in neurological diseases with pathological microglial activation, synaptic pruning, and synapse loss. However, repopulation after depletion induces activated microglia and results in a decrease of dendritic spines possibly limiting the therapeutic application of microglia depletion. Instead, persistent modulation of pathological microglia activity might be beneficial in controlling synaptic damage.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Else Kröner-Fresenius-Stiftung
Organisme : Deutsche Forschungsgemeinschaft
ID : GE2519/8-1
Organisme : Deutsche Forschungsgemeinschaft
ID : GE2519/9-1
Organisme : Hermann und Lilly Schilling-Stiftung für Medizinische Forschung
Organisme : Interdisziplinäres Zentrum für Klinische Forschung (IZKF) Jena
Informations de copyright
© 2024 The Authors. GLIA published by Wiley Periodicals LLC.
Références
Badimon, A., Strasburger, H. J., Ayata, P., Chen, X., Nair, A., Ikegami, A., Hwang, P., Chan, A. T., Graves, S. M., Uweru, J. O., Ledderose, C., Kutlu, M. G., Wheeler, M. A., Kahan, A., Ishikawa, M., Wang, Y. C., Loh, Y. E., Jiang, J. X., Surmeier, D. J., … Schaefer, A. (2020). Negative feedback control of neuronal activity by microglia. Nature, 586(7829), 417–423. https://doi.org/10.1038/s41586-020-2777-8
Basilico, B., Ferrucci, L., Ratano, P., Golia, M. T., Grimaldi, A., Rosito, M., Ferretti, V., Reverte, I., Sanchini, C., Marrone, M. C., Giubettini, M., De Turris, V., Salerno, D., Garofalo, S., St‐Pierre, M. K., Carrier, M., Renzi, M., Pagani, F., Modi, B., … Ragozzino, D. (2022). Microglia control glutamatergic synapses in the adult mouse hippocampus. Glia, 70(1), 173–195. https://doi.org/10.1002/glia.24101
Bedolla, A., Taranov, A., Luo, F., Wang, J., Turcato, F., Fugate, E. M., Greig, N. H., Lindquist, D. M., Crone, S. A., Goto, J., & Luo, Y. (2022). Diphtheria toxin induced but not CSF1R inhibitor mediated microglia ablation model leads to the loss of CSF/ventricular spaces in vivo that is independent of cytokine upregulation. Journal of Neuroinflammation, 19(1), 3. https://doi.org/10.1186/s12974-021-02367-w
Bentley, D. R., Balasubramanian, S., Swerdlow, H. P., Smith, G. P., Milton, J., Brown, C. G., Hall, K. P., Evers, D. J., Barnes, C. L., Bignell, H. R., Boutell, J. M., Bryant, J., Carter, R. J., Keira Cheetham, R., Cox, A. J., Ellis, D. J., Flatbush, M. R., Gormley, N. A., Humphray, S. J., … Smith, A. J. (2008). Accurate whole human genome sequencing using reversible terminator chemistry. Nature, 456(7218), 53–59. https://doi.org/10.1038/nature07517
Bruttger, J., Karram, K., Wortge, S., Regen, T., Marini, F., Hoppmann, N., Klein, M., Blank, T., Yona, S., Wolf, Y., Mack, M., Pinteaux, E., Müller, W., Zipp, F., Binder, H., Bopp, T., Prinz, M., Jung, S., & Waisman, A. (2015). Genetic cell ablation reveals clusters of local self‐renewing microglia in the mammalian central nervous system. Immunity, 43(1), 92–106. https://doi.org/10.1016/j.immuni.2015.06.012
Ceanga, M., Guenther, M., Ingrisch, I., & Kunze, A. (2021). Characterization of hippocampal adult‐borne granule cells in a transient cerebral ischemia model. Bio‐Protocol, 11(2), e3890. https://doi.org/10.21769/BioProtoc.3890
Chitu, V., Gokhan, S., Nandi, S., Mehler, M. F., & Stanley, E. R. (2016). Emerging roles for CSF‐1 receptor and its ligands in the nervous system. Trends in Neurosciences, 39(6), 378–393. https://doi.org/10.1016/j.tins.2016.03.005
Chung, H. Y., Wickel, J., Brunkhorst, F. M., & Geis, C. (2020). Sepsis‐associated encephalopathy: From delirium to dementia? Journal of Clinical Medicine, 9(3), 703. https://doi.org/10.3390/jcm9030703
Chung, H. Y., Wickel, J., Hahn, N., Mein, N., Schwarzbrunn, M., Koch, P., Ceanga, M., Haselmann, H., Baade‐Büttner, C., von Stackelberg, N., Hempel, N., Schmidl, L., Groth, M., Andreas, N., Götze, J., Coldewey, S. M., Bauer, M., Mawrin, C., Dargvainiene, J., … Geis, C. (2023). Microglia mediate neurocognitive deficits by eliminating C1q‐tagged synapses in sepsis‐associated encephalopathy. Science Advances, 9(21), eabq7806. https://doi.org/10.1126/sciadv.abq7806
Cornell, J., Salinas, S., Huang, H. Y., & Zhou, M. (2022). Microglia regulation of synaptic plasticity and learning and memory. Neural Regeneration Research, 17(4), 705–716. https://doi.org/10.4103/1673-5374.322423
Dagher, N. N., Najafi, A. R., Kayala, K. M., Elmore, M. R., White, T. E., Medeiros, R., West, B. L., & Green, K. N. (2015). Colony‐stimulating factor 1 receptor inhibition prevents microglial plaque association and improves cognition in 3xTg‐AD mice. Journal of Neuroinflammation, 12, 139. https://doi.org/10.1186/s12974-015-0366-9
De Schepper, S., Ge, J. Z., Crowley, G., Ferreira, L. S. S., Garceau, D., Toomey, C. E., Sokolova, D., Rueda‐Carrasco, J., Shin, S. H., Kim, J. S., Childs, T., Lashley, T., Burden, J. J., Sasner, M., Sala Frigerio, C., Jung, S., & Hong, S. (2023). Perivascular cells induce microglial phagocytic states and synaptic engulfment via SPP1 in mouse models of Alzheimer's disease. Nature Neuroscience, 26(3), 406–415. https://doi.org/10.1038/s41593-023-01257-z
Dobin, A., Davis, C. A., Schlesinger, F., Drenkow, J., Zaleski, C., Jha, S., Batut, P., Chaisson, M., & Gingeras, T. R. (2013). STAR: Ultrafast universal RNA‐seq aligner. Bioinformatics, 29(1), 15–21. https://doi.org/10.1093/bioinformatics/bts635
Edgar, R., Domrachev, M., & Lash, A. E. (2002). Gene expression omnibus: NCBI gene expression and hybridization array data repository. Nucleic Acids Research, 30(1), 207–210. https://doi.org/10.1093/nar/30.1.207
Elmore, M. R., Najafi, A. R., Koike, M. A., Dagher, N. N., Spangenberg, E. E., Rice, R. A., Kitazawa, M., Matusow, B., Nguyen, H., West, B. L., & Green, K. N. (2014). Colony‐stimulating factor 1 receptor signaling is necessary for microglia viability, unmasking a microglia progenitor cell in the adult brain. Neuron, 82(2), 380–397. https://doi.org/10.1016/j.neuron.2014.02.040
Erblich, B., Zhu, L., Etgen, A. M., Dobrenis, K., & Pollard, J. W. (2011). Absence of colony stimulation factor‐1 receptor results in loss of microglia, disrupted brain development and olfactory deficits. PLoS One, 6(10), e26317. https://doi.org/10.1371/journal.pone.0026317
Green, K. N., Crapser, J. D., & Hohsfield, L. A. (2020). To kill a microglia: A case for CSF1R inhibitors. Trends in Immunology, 41(9), 771–784. https://doi.org/10.1016/j.it.2020.07.001
Grünewald, B., Wickel, J., Hahn, N., Hörhold, F., Rupp, H., Chung, H.‐Y., Haselmann, H., Strauss, A. S., Schmidl, L., Hempel, N., Grünewald, L., Urbach, A., Bauer, M., Toyka, K. V., Blaess, M., Claus, R. A., König, R., & Geis, C. (2021). Targeted rescue of synaptic plasticity improves cognitive decline after severe systemic inflammation. bioRxiv. https://doi.org/10.1101/2021.03.04.433352
Guneykaya, D., Ivanov, A., Hernandez, D. P., Haage, V., Wojtas, B., Meyer, N., Maricos, M., Jordan, P., Buonfiglioli, A., Gielniewski, B., Ochocka, N., Cömert, C., Friedrich, C., Artiles, L. S., Kaminska, B., Mertins, P., Beule, D., Kettenmann, H., & Wolf, S. A. (2018). Transcriptional and translational differences of microglia from male and female brains. Cell Reports, 24(10), 2773–2783 e2776. https://doi.org/10.1016/j.celrep.2018.08.001
Han, J., Fan, Y., Zhou, K., Blomgren, K., & Harris, R. A. (2021). Uncovering sex differences of rodent microglia. Journal of Neuroinflammation, 18(1), 74. https://doi.org/10.1186/s12974-021-02124-z
Han, J., Fan, Y., Zhou, K., Zhu, K., Blomgren, K., Lund, H., Zhang, X. M., & Harris, R. A. (2020). Underestimated peripheral effects following pharmacological and conditional genetic microglial depletion. International Journal of Molecular Sciences, 21(22), 8603. https://doi.org/10.3390/ijms21228603
Helm, M. S., Dankovich, T. M., Mandad, S., Rammner, B., Jahne, S., Salimi, V., Koerbs, C., Leibrandt, R., Urlaub, H., Schikorski, T., & Rizzoli, S. O. (2021). A large‐scale nanoscopy and biochemistry analysis of postsynaptic dendritic spines. Nature Neuroscience, 24(8), 1151–1162. https://doi.org/10.1038/s41593-021-00874-w
Henry, R. J., Ritzel, R. M., Barrett, J. P., Doran, S. J., Jiao, Y., Leach, J. B., Szeto, G. L., Wu, J., Stoica, B. A., Faden, A. I., & Loane, D. J. (2020). Microglial depletion with CSF1R inhibitor during chronic phase of experimental traumatic brain injury reduces neurodegeneration and neurological deficits. The Journal of Neuroscience, 40, 2960–2974. https://doi.org/10.1523/JNEUROSCI.2402-19.2020
Hwang, D., Seyedsadr, M. S., Ishikawa, L. L. W., Boehm, A., Sahin, Z., Casella, G., Jang, S., Gonzalez, M. V., Garifallou, J. P., Hakonarson, H., Zhang, W., Xiao, D., Rostami, A., Zhang, G. X., & Ciric, B. (2022). CSF‐1 maintains pathogenic but not homeostatic myeloid cells in the central nervous system during autoimmune neuroinflammation. Proceedings of the National Academy of Sciences of the United States of America, 119(14), e2111804119. https://doi.org/10.1073/pnas.2111804119
Kettenmann, H., Kirchhoff, F., & Verkhratsky, A. (2013). Microglia: New roles for the synaptic stripper. Neuron, 77(1), 10–18. https://doi.org/10.1016/j.neuron.2012.12.023
Liao, Y., Smyth, G. K., & Shi, W. (2014). featureCounts: An efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics, 30(7), 923–930. https://doi.org/10.1093/bioinformatics/btt656
Love, M. I., Huber, W., & Anders, S. (2014). Moderated estimation of fold change and dispersion for RNA‐seq data with DESeq2. Genome Biology, 15(12), 550. https://doi.org/10.1186/s13059-014-0550-8
Lynch, M. A. (2022). Exploring sex‐related differences in microglia may be a game‐changer in precision medicine. Frontiers in Aging Neuroscience, 14, 868448. https://doi.org/10.3389/fnagi.2022.868448
Mansfeld, J., Urban, N., Priebe, S., Groth, M., Frahm, C., Hartmann, N., Gebauer, J., Ravichandran, M., Dommaschk, A., Schmeisser, S., Kuhlow, D., Monajembashi, S., Bremer‐Streck, S., Hemmerich, P., Kiehntopf, M., Zamboni, N., Englert, C., Guthke, R., Kaleta, C., … Ristow, M. (2015). Branched‐chain amino acid catabolism is a conserved regulator of physiological ageing. Nature Communications, 6, 10043. https://doi.org/10.1038/ncomms10043
Nimmerjahn, A., Kirchhoff, F., & Helmchen, F. (2005). Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science, 308(5726), 1314–1318. https://doi.org/10.1126/science.1110647
Paolicelli, R. C., Bolasco, G., Pagani, F., Maggi, L., Scianni, M., Panzanelli, P., Giustetto, M., Ferreira, T. A., Guiducci, E., Dumas, L., Ragozzino, D., & Gross, C. T. (2011). Synaptic pruning by microglia is necessary for normal brain development. Science, 333(6048), 1456–1458. https://doi.org/10.1126/science.1202529
Parkhurst, C. N., Yang, G., Ninan, I., Savas, J. N., Yates, J. R., 3rd, Lafaille, J. J., Hempstead, B. L., Littman, D. R., & Gan, W. B. (2013). Microglia promote learning‐dependent synapse formation through brain‐derived neurotrophic factor. Cell, 155(7), 1596–1609. https://doi.org/10.1016/j.cell.2013.11.030
Presumey, J., Bialas, A. R., & Carroll, M. C. (2017). Complement system in neural synapse elimination in development and disease. Advances in Immunology, 135, 53–79. https://doi.org/10.1016/bs.ai.2017.06.004
Schafer, D. P., & Stevens, B. (2015). Microglia function in central nervous system development and plasticity. Cold Spring Harbor Perspectives in Biology, 7(10), a020545. https://doi.org/10.1101/cshperspect.a020545
Sieber, M. W., Guenther, M., Kohl, M., Witte, O. W., Claus, R. A., & Frahm, C. (2010). Inter‐age variability of bona fide unvaried transcripts normalization of quantitative PCR data in ischemic stroke. Neurobiology of Aging, 31(4), 654–664. https://doi.org/10.1016/j.neurobiolaging.2008.05.023
Spangenberg, E., Severson, P. L., Hohsfield, L. A., Crapser, J., Zhang, J., Burton, E. A., Zhang, Y., Spevak, W., Lin, J., Phan, N. Y., Habets, G., Rymar, A., Tsang, G., Walters, J., Nespi, M., Singh, P., Broome, S., Ibrahim, P., Zhang, C., … Green, K. N. (2019). Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer's disease model. Nature Communications, 10(1), 3758. https://doi.org/10.1038/s41467-019-11674-z
Spierenburg, G., van der Heijden, L., van Langevelde, K., Szuhai, K., Bovee, J., van de Sande, M. A. J., & Gelderblom, H. (2022). Tenosynovial giant cell tumors (TGCT): Molecular biology, drug targets and non‐surgical pharmacological approaches. Expert Opinion on Therapeutic Targets, 26(4), 333–345. https://doi.org/10.1080/14728222.2022.2067040
Spiteri, A. G., Ni, D., Ling, Z. L., Macia, L., Campbell, I. L., Hofer, M. J., & King, N. J. C. (2022). PLX5622 reduces disease severity in lethal CNS infection by off‐target inhibition of peripheral inflammatory monocyte production. Frontiers in Immunology, 13, 851556. https://doi.org/10.3389/fimmu.2022.851556
Uriarte Huarte, O., Richart, L., Mittelbronn, M., & Michelucci, A. (2021). Microglia in health and disease: The strength to be diverse and reactive. Frontiers in Cellular Neuroscience, 15, 660523. https://doi.org/10.3389/fncel.2021.660523
Waisman, A., Ginhoux, F., Greter, M., & Bruttger, J. (2015). Homeostasis of microglia in the adult brain: Review of novel microglia depletion systems. Trends in Immunology, 36(10), 625–636. https://doi.org/10.1016/j.it.2015.08.005