[en] Molecular diversity of microglia, the resident immune cells in the CNS, is reported. Whether microglial subsets characterized by the expression of specific proteins constitute subtypes with distinct functions has not been fully elucidated. Here we describe a microglial subtype expressing the enzyme arginase-1 (ARG1; that is, ARG1+ microglia) that is found predominantly in the basal forebrain and ventral striatum during early postnatal mouse development. ARG1+ microglia are enriched in phagocytic inclusions and exhibit a distinct molecular signature, including upregulation of genes such as Apoe, Clec7a, Igf1, Lgals3 and Mgl2, compared to ARG1- microglia. Microglial-specific knockdown of Arg1 results in deficient cholinergic innervation and impaired dendritic spine maturation in the hippocampus where cholinergic neurons project, which in turn results in impaired long-term potentiation and cognitive behavioral deficiencies in female mice. Our results expand on microglia diversity and provide insights into microglia subtype-specific functions.
Disciplines :
Neurology Life sciences: Multidisciplinary, general & others Biochemistry, biophysics & molecular biology Genetics & genetic processes
Author, co-author :
Stratoulias, Vassilis ; Institute of Environmental Medicine, Toxicology Unit, Karolinska Institutet, Stockholm, Sweden. vassilis.stratoulias@ki.se ; Neuroscience Center, HiLIFE, University of Helsinki, Helsinki, Finland. vassilis.stratoulias@ki.se
Ruiz, Rocío ; Instituto de Biomedicina de Sevilla, IBiS/Hospital Universitario Virgen del Rocío/CSIC, Universidad de Sevilla, Seville, Spain
Kanatani, Shigeaki ; Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
Osman, Ahmed M; Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
Keane, Lily; Institute of Environmental Medicine, Toxicology Unit, Karolinska Institutet, Stockholm, Sweden
Armengol, Jose A ; Department of Physiology, Anatomy and Cellular Biology, University of Pablo de Olavide, Seville, Spain
Rodríguez-Moreno, Antonio ; Department of Physiology, Anatomy and Cellular Biology, University of Pablo de Olavide, Seville, Spain
Murgoci, Adriana-Natalia; Institute of Environmental Medicine, Toxicology Unit, Karolinska Institutet, Stockholm, Sweden
García-Domínguez, Irene ; Instituto de Biomedicina de Sevilla, IBiS/Hospital Universitario Virgen del Rocío/CSIC, Universidad de Sevilla, Seville, Spain
Alonso-Bellido, Isabel; Instituto de Biomedicina de Sevilla, IBiS/Hospital Universitario Virgen del Rocío/CSIC, Universidad de Sevilla, Seville, Spain
González Ibáñez, Fernando ; Department of Molecular Medicine, Université Laval, and Axe Neurosciences, Centre de Recherche du CHU de Québec-Université Laval, Laval, Quebec, Canada ; Division of Medical Sciences, University of Victoria, Victoria, British Columbia, Canada
Picard, Katherine ; Department of Molecular Medicine, Université Laval, and Axe Neurosciences, Centre de Recherche du CHU de Québec-Université Laval, Laval, Quebec, Canada ; Division of Medical Sciences, University of Victoria, Victoria, British Columbia, Canada
Vázquez-Cabrera, Guillermo; Institute of Environmental Medicine, Toxicology Unit, Karolinska Institutet, Stockholm, Sweden ; Instituto de Biomedicina de Sevilla, IBiS/Hospital Universitario Virgen del Rocío/CSIC, Universidad de Sevilla, Seville, Spain
Posada-Pérez, Mercedes; Institute of Environmental Medicine, Toxicology Unit, Karolinska Institutet, Stockholm, Sweden ; Instituto de Biomedicina de Sevilla, IBiS/Hospital Universitario Virgen del Rocío/CSIC, Universidad de Sevilla, Seville, Spain
Vernoux, Nathalie; Department of Molecular Medicine, Université Laval, and Axe Neurosciences, Centre de Recherche du CHU de Québec-Université Laval, Laval, Quebec, Canada
Tejera, Dario; Department of Neurodegenerative Diseases and Gerontopsychiatry, University of Bonn, Bonn, Germany
Grabert, Kathleen ; Institute of Environmental Medicine, Toxicology Unit, Karolinska Institutet, Stockholm, Sweden
Cheray, Mathilde ; Institute of Environmental Medicine, Toxicology Unit, Karolinska Institutet, Stockholm, Sweden
González-Rodríguez, Patricia; Institute of Environmental Medicine, Toxicology Unit, Karolinska Institutet, Stockholm, Sweden
Pérez-Villegas, Eva M; Department of Physiology, Anatomy and Cellular Biology, University of Pablo de Olavide, Seville, Spain
Martínez-Gallego, Irene; Department of Physiology, Anatomy and Cellular Biology, University of Pablo de Olavide, Seville, Spain
Lastra-Romero, Alejandro; Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
Brodin, David ; Bioinformatics and Expression Analysis Core Facility, Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden
Avila-Cariño, Javier; Department of Molecular Biology and Umeå Centre for Microbial Research (UCMR), Umeå University, Umeå, Sweden
Cao, Yang ; Clinical Epidemiology and Biostatistics, School of Medical Sciences, Örebro University, Örebro, Sweden ; Unit of Integrative Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
Airavaara, Mikko ; Neuroscience Center, HiLIFE, University of Helsinki, Helsinki, Finland ; Faculty of Pharmacy, Drug Research Program, University of Helsinki, Helsinki, Finland
Uhlén, Per; Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
HENEKA, Michael ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) ; Department of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA, USA
Tremblay, Marie-Ève ; Department of Molecular Medicine, Université Laval, and Axe Neurosciences, Centre de Recherche du CHU de Québec-Université Laval, Laval, Quebec, Canada ; Division of Medical Sciences, University of Victoria, Victoria, British Columbia, Canada
Blomgren, Klas ; Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden ; Department of Paediatric Oncology, Karolinska University Hospital, Stockholm, Sweden
Venero, Jose L ; Instituto de Biomedicina de Sevilla, IBiS/Hospital Universitario Virgen del Rocío/CSIC, Universidad de Sevilla, Seville, Spain
Joseph, Bertrand ; Institute of Environmental Medicine, Toxicology Unit, Karolinska Institutet, Stockholm, Sweden. bertrand.joseph@ki.se
Sigrid Juséliuksen Säätiö Svenska Kulturfonden Academy of Finland Barncancerfonden Spanish Ministerio de Ciencia e Innovación Mexican Council of Science and Technology Wenner-Gren Foundation Cancerfonden Åke Wiberg Stiftelse ERA-NET NEURON Neuroinflammation Fonds de Recherche du Québec - Santé ERA-NET NEURON Neuroinflammation Canada Research Chair (Tier 2) in Neurobiology of Aging and Cognition Swedish governmental grants for researchers working in healthcare Spanish Ministerio de Ciencia e Innovación Spanish Junta de Andalucia Vetenskapsrådet Hjärnfonden Radiumhemmets Forskningsfonder Karolinska Institutet
Funding text :
We thank the Bioinformatics and Expression Analysis core facility, the Biomedicum Flow Cytometry core facility and the Biomedicum Imaging core facility (with grants from the Strategic Research Area in Neuroscience (StratNeuro) and the Strategic Research Area in Stemc Cells and Regenerative Medicine (StratRegen) supported by the Swedish government) at the Karolinska Institutet for technical support. We would like to thank S. Vazquez and B. Ben-Azu for technical support. We are grateful to P.C. Nahirney for the use of a transmission electron microscope and B. Gowen for technical assistance. This research is supported by the Swedish Research Council and the Swedish Brain Foundation (P.U. and B.J.), the Sigrid Jusélius Foundation, the Svenska Kulturfonden and Academy of Finland (33552, V.S.), the Swedish Cancer Foundation (P.U. and B.J.), the Swedish Cancer Society (K.G., P.U. and B.J.), the Karolinska Institutet Foundation (P.G.-R. and B.J.), the Mexican Council of Science and Technology (F.G.I.), the Fonds de recherche du Québec—Santé (K.P.), the Wenner-Gren Foundation (K.G.), the Åke Wibergs Stiftelse (M.C.), the Spanish Ministerio de Ciencia e Innovación/FEDER/UE PID2021-124096OB-I00 (J.L.V.), PID 2019-109569GB-100 (J.A.A.) and BFU2015-68655 (A.R.-M.), the Spanish Junta de Andalucia/FEDER/EU P18-RT-1372 and the Spanish FEDER I+D+i-USE US-1264806 (J.L.V.), the Swedish Childhood Cancer Foundation (K.B., L.K., P.U. and B.J.), the Swedish governmental grants for researchers working in healthcare (K.B.), the Canada Research Chair (Tier 2) in Neurobiology of Aging and Cognition (M.-E.T.), the TracInflam grant from ERA-NET NEURON Neuroinflammation (B.J., M.-E.T. and M.T.H.) and the Academy of Finland (V.S. and M.A.; 309489, 324177). We acknowledge and respect that the University of Victoria is located on the territory of the lək̓ʷəŋən peoples and that the Songhees, Esquimalt and WSÁNEÆ peoples have relationships to this land.We thank the Bioinformatics and Expression Analysis core facility, the Biomedicum Flow Cytometry core facility and the Biomedicum Imaging core facility (with grants from the Strategic Research Area in Neuroscience (StratNeuro) and the Strategic Research Area in Stemc Cells and Regenerative Medicine (StratRegen) supported by the Swedish government) at the Karolinska Institutet for technical support. We would like to thank S. Vazquez and B. Ben-Azu for technical support. We are grateful to P.C. Nahirney for the use of a transmission electron microscope and B. Gowen for technical assistance. This research is supported by the Swedish Research Council and the Swedish Brain Foundation (P.U. and B.J.), the Sigrid Jusélius Foundation, the Svenska Kulturfonden and Academy of Finland (33552, V.S.), the Swedish Cancer Foundation (P.U. and B.J.), the Swedish Cancer Society (K.G., P.U. and B.J.), the Karolinska Institutet Foundation (P.G.-R. and B.J.), the Mexican Council of Science and Technology (F.G.I.), the Fonds de recherche du Québec—Santé (K.P.), the Wenner-Gren Foundation (K.G.), the Åke Wibergs Stiftelse (M.C.), the Spanish Ministerio de Ciencia e Innovación/FEDER/UE PID2021-124096OB-I00 (J.L.V.), PID 2019-109569GB-100 (J.A.A.) and BFU2015-68655 (A.R.-M.), the Spanish Junta de Andalucia/FEDER/EU P18-RT-1372 and the Spanish FEDER I+D+i-USE US-1264806 (J.L.V.), the Swedish Childhood Cancer Foundation (K.B., L.K., P.U. and B.J.), the Swedish governmental grants for researchers working in healthcare (K.B.), the Canada Research Chair (Tier 2) in Neurobiology of Aging and Cognition (M.-E.T.), the TracInflam grant from ERA-NET NEURON Neuroinflammation (B.J., M.-E.T. and M.T.H.) and the Academy of Finland (V.S. and M.A.; 309489, 324177). We acknowledge and respect that the University of Victoria is located on the territory of the lək̓ʷəŋən peoples and that the Songhees, Esquimalt and WSÁNEÆ peoples have relationships to this land.
Tau, G. Z. & Peterson, B. S. Normal development of brain circuits. Neuropsychopharmacology 35, 147–168 (2010). DOI: 10.1038/npp.2009.115
Monier, A. et al. Entry and distribution of microglial cells in human embryonic and fetal cerebral cortex. J. Neuropathol. Exp. Neurol. 66, 372–382 (2007). DOI: 10.1097/nen.0b013e3180517b46
Ginhoux, F. et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330, 841–845 (2010). DOI: 10.1126/science.1194637
De, S. et al. Two distinct ontogenies confer heterogeneity to mouse brain microglia. Development 145, dev152306 (2018). DOI: 10.1242/dev.152306
Squarzoni, P. et al. Microglia modulate wiring of the embryonic forebrain. Cell Rep. 8, 1271–1279 (2014). DOI: 10.1016/j.celrep.2014.07.042
Thion, M. S., Ginhoux, F. & Garel, S. Microglia and early brain development: an intimate journey. Science 362, 185–189 (2018). DOI: 10.1126/science.aat0474
Zengeler, K. E. & Lukens, J. R. Innate immunity at the crossroads of healthy brain maturation and neurodevelopmental disorders. Nat. Rev. Immunol. 21, 454–468 (2021).
Stratoulias, V., Venero, J. L., Tremblay, M. & Joseph, B. Microglial subtypes: diversity within the microglial community. EMBO J. 38, e101997 (2019). DOI: 10.15252/embj.2019101997
Keane, L., Cheray, M., Blomgren, K. & Joseph, B. Multifaceted microglia—key players in primary brain tumour heterogeneity. Nat. Rev. Neurol. 17, 243–259 (2021). DOI: 10.1038/s41582-021-00463-2
Hambardzumyan, D., Gutmann, D. H. & Kettenmann, H. The role of microglia and macrophages in glioma maintenance and progression. Nat. Neurosci. 19, 20–27 (2016). DOI: 10.1038/nn.4185
Hickman, S., Izzy, S., Sen, P., Morsett, L. & El Khoury, J. Microglia in neurodegeneration. Nat. Neurosci. 21, 1359–1369 (2018). DOI: 10.1038/s41593-018-0242-x
Shen, X. et al. Glioma-induced inhibition of caspase-3 in microglia promotes a tumor-supportive phenotype. Nat. Immunol. 17, 1282–1290 (2016). DOI: 10.1038/ni.3545
Burguillos, M. A. et al. Caspase signalling controls microglia activation and neurotoxicity. Nature 472, 319–324 (2011). DOI: 10.1038/nature09788
Masuda, T. et al. Spatial and temporal heterogeneity of mouse and human microglia at single-cell resolution. Nature 566, 388–392 (2019). DOI: 10.1038/s41586-019-0924-x
Van Hove, H. et al. A single-cell atlas of mouse brain macrophages reveals unique transcriptional identities shaped by ontogeny and tissue environment. Nat. Neurosci. 22, 1021–1035 (2019). DOI: 10.1038/s41593-019-0393-4
Li, Q. et al. Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing. Neuron 101, 207–223 (2019). DOI: 10.1016/j.neuron.2018.12.006
Hammond, T. R. et al. Single-cell RNA sequencing of microglia throughout the mouse lifespan and in the injured brain reveals complex cell-state changes. Immunity 50, 253–271 (2019). DOI: 10.1016/j.immuni.2018.11.004
Jordão, M. J. C. et al. Single-cell profiling identifies myeloid cell subsets with distinct fates during neuroinflammation. Science 363, eaat7554 (2019). DOI: 10.1126/science.aat7554
Osman, A. M. et al. Radiation triggers a dynamic sequence of transient microglial alterations in juvenile brain. Cell Rep. 31, 107699 (2020). DOI: 10.1016/j.celrep.2020.107699
Schafer, D. P. et al. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron 74, 691–705 (2012). DOI: 10.1016/j.neuron.2012.03.026
Parkhurst, C. N. et al. Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor. Cell 155, 1596–1609 (2013). DOI: 10.1016/j.cell.2013.11.030
Wlodarczyk, A. et al. A novel microglial subset plays a key role in myelinogenesis in developing brain. EMBO J. 36, 3292–3308 (2017). DOI: 10.15252/embj.201696056
Lenz, K. M., Nugent, B. M., Haliyur, R. & McCarthy, M. M. Microglia are essential to masculinization of brain and behavior. J. Neurosci. 33, 2761–2772 (2013). DOI: 10.1523/JNEUROSCI.1268-12.2013
Sorge, R. E. et al. Different immune cells mediate mechanical pain hypersensitivity in male and female mice. Nat. Neurosci. 18, 1081–1083 (2015). DOI: 10.1038/nn.4053
Reese, T. A. et al. Chitin induces accumulation in tissue of innate immune cells associated with allergy. Nature 447, 92–96 (2007). DOI: 10.1038/nature05746
Renier, N., et al. Mapping of brain activity by automated volume analysis of immediate early genes. Cell 165, 1789–1802 (2016).
Ballinger, E. C., Ananth, M., Talmage, D. A. & Role, L. W. Basal forebrain cholinergic circuits and signaling in cognition and cognitive decline. Neuron 91, 1199–1218 (2016). DOI: 10.1016/j.neuron.2016.09.006
Semba, K. Phylogenetic and ontogenetic aspects of the basal forebrain cholinergic neurons and their innervation of the cerebral cortex. Prog. Brain Res. 145, 3–43 (2004).
Goldmann, T. et al. Origin, fate and dynamics of macrophages at central nervous system interfaces. Nat. Immunol. 17, 797–805 (2016). DOI: 10.1038/ni.3423
Butovsky, O. & Weiner, H. L. Microglial signatures and their role in health and disease. Nat. Rev. Neurosci. 19, 622–635 (2018). DOI: 10.1038/s41583-018-0057-5
Bennett, M. L. et al. New tools for studying microglia in the mouse and human CNS. Proc. Natl Acad. Sci. USA 113, E1738–E1746 (2016). DOI: 10.1073/pnas.1525528113
Krasemann, S. et al. The TREM2–APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases. Immunity 47, 566–581 (2017). DOI: 10.1016/j.immuni.2017.08.008
Keren-Shaul, H. et al. A unique microglia type associated with restricting development of Alzheimer’s disease. Cell 169, 1276–1290 (2017). DOI: 10.1016/j.cell.2017.05.018
Tremblay, M., Lowery, R. L. & Majewska, A. K. Microglial interactions with synapses are modulated by visual experience. PLoS Biol. 8, e1000527 (2010). DOI: 10.1371/journal.pbio.1000527
Sin, Y. Y., Baron, G., Schulze, A. & Funk, C. D. Arginase-1 deficiency. J. Mol. Med. 93, 1287–1296 (2015). DOI: 10.1007/s00109-015-1354-3
Jain-Ghai, S., Nagamani, S. C., Blaser, S., Siriwardena, K. & Feigenbaum, A. Arginase I deficiency: severe infantile presentation with hyperammonemia: more common than reported? Mol. Genet Metab. 104, 107–111 (2011). DOI: 10.1016/j.ymgme.2011.06.025
Dean, D. M. & Sanders, M. M. Ten years after: reclassification of steroid-responsive genes. Mol. Endocrinol. 10, 1489–1495 (1996).
Cloots, R. H. E. et al. Arginase 1 deletion in myeloid cells affects the inflammatory response in allergic asthma, but not lung mechanics, in female mice. BMC Pulm. Med. 17, 158 (2017). DOI: 10.1186/s12890-017-0490-7
Mohapel, P., Leanza, G., Kokaia, M. & Lindvall, O. Forebrain acetylcholine regulates adult hippocampal neurogenesis and learning. Neurobiol. Aging 26, 939–946 (2005). DOI: 10.1016/j.neurobiolaging.2004.07.015
Amaral, D. Lavenex, P. in The Hippocampus Book (eds Anderson, P. et al.) Ch. 3 (Oxford Univ. Press, 2007).
Aznavour, N., Mechawar, N. & Descarries, L. Comparative analysis of cholinergic innervation in the dorsal hippocampus of adult mouse and rat: a quantitative immunocytochemical study. Hippocampus 12, 206–217 (2002). DOI: 10.1002/hipo.1108
Ramón, S. & Cajal, Y. Textura del Sistema Nervioso del Hombre y de los Vertebrados (Imprenta y Librería de Nicolás Moya, Madrid (1899–1904), 1904).
Berry, K. P. & Nedivi, E. Spine dynamics: are they all the same? Neuron 96, 43–55 (2017). DOI: 10.1016/j.neuron.2017.08.008
Pérez-Villegas, E. M. et al. Mutation of the HERC 1 ubiquitin ligase impairs associative learning in the lateral amygdala. Mol. Neurobiol. 55, 1157–1168 (2018). DOI: 10.1007/s12035-016-0371-8
Alvarez, V. A. & Sabatini, B. L. Anatomical and physiological plasticity of dendritic spines. Annu. Rev. Neurosci. 30, 79–97 (2007). DOI: 10.1146/annurev.neuro.30.051606.094222
Bisht, K. et al. Dark microglia: a new phenotype predominantly associated with pathological states. Glia 64, 826–839 (2016). DOI: 10.1002/glia.22966
Butovsky, O. et al. Identification of a unique TGF-β-dependent molecular and functional signature in microglia. Nat. Neurosci. 17, 131–143 (2014). DOI: 10.1038/nn.3599
Hickman, S. E. et al. The microglial sensome revealed by direct RNA sequencing. Nat. Neurosci. 16, 1896–1905 (2013). DOI: 10.1038/nn.3554
Lin, S. C., Brown, R. E., Hussain Shuler, M. G., Petersen, C. C. & Kepecs, A. Optogenetic dissection of the basal forebrain neuromodulatory control of cortical activation, plasticity, and cognition. J. Neurosci. 35, 13896–13903 (2015). DOI: 10.1523/JNEUROSCI.2590-15.2015
Allaway, K. C. & Machold, R. Developmental specification of forebrain cholinergic neurons. Dev. Biol. 421, 1–7 (2017). DOI: 10.1016/j.ydbio.2016.11.007
Thal, L. J., Gilbertson, E., Armstrong, D. M. & Gage, F. H. Development of the basal forebrain cholinergic system: phenotype expression prior to target innervation. Neurobiol. Aging 13, 67–72 (1992). DOI: 10.1016/0197-4580(92)90011-L
Drever, B. D., Riedel, G. & Platt, B. The cholinergic system and hippocampal plasticity. Behav. Brain Res 221, 505–514 (2011). DOI: 10.1016/j.bbr.2010.11.037
Hering, H. & Sheng, M. Dendritic spines: structure, dynamics and regulation. Nat. Rev. Neurosci. 2, 880–888 (2001). DOI: 10.1038/35104061
Engert, F. & Bonhoeffer, T. Dendritic spine changes associated with hippocampal long-term synaptic plasticity. Nature 399, 66–70 (1999). DOI: 10.1038/19978
Whitlock, J. R., Heynen, A. J., Shuler, M. G. & Bear, M. F. Learning induces long-term potentiation in the hippocampus. Science 313, 1093–1097 (2006). DOI: 10.1126/science.1128134
Malenka, R. C. & Nicoll, R. A. Long-term potentiation—a decade of progress? Science 285, 1870–1874 (1999). DOI: 10.1126/science.285.5435.1870
Hampel, H. et al. The cholinergic system in the pathophysiology and treatment of Alzheimer’s disease. Brain 141, 1917–1933 (2018). DOI: 10.1093/brain/awy132
Heneka, M. T. et al. Neuroinflammation in Alzheimer’s disease. Lancet Neurol. 14, 388–405 (2015). DOI: 10.1016/S1474-4422(15)70016-5
Zhu, D., Montagne, A. & Zhao, Z. Alzheimer’s pathogenic mechanisms and underlying sex difference. Cell. Mol. Life Sci. 78, 4907–4920 (2021). DOI: 10.1007/s00018-021-03830-w
Carrillo-Jimenez, A. et al. TET2 regulates the neuroinflammatory response in microglia. Cell Rep. 29, 697–713 (2019). DOI: 10.1016/j.celrep.2019.09.013
Ativie, F. et al. Cannabinoid 1 receptor signaling on hippocampal GABAergic neurons influences microglial activity. Front. Mol. Neurosci. 11, 295 (2018). DOI: 10.3389/fnmol.2018.00295
Renier, N. et al. iDISCO: a simple, rapid method to immunolabel large tissue samples for volume imaging. Cell 159, 896–910 (2014). DOI: 10.1016/j.cell.2014.10.010
Tomer, R., Ye, L., Hsueh, B. & Deisseroth, K. Advanced CLARITY for rapid and high-resolution imaging of intact tissues. Nat. Protoc. 9, 1682–1697 (2014). DOI: 10.1038/nprot.2014.123
Schindelin, J. et al. Fiji: an open-source platform for biological-image analysis. Nat. Methods 9, 676–682 (2012). DOI: 10.1038/nmeth.2019
Bria, A. & Iannello, G. TeraStitcher—a tool for fast automatic 3D-stitching of teravoxel-sized microscopy images. BMC Bioinformatics 13, 316 (2012). DOI: 10.1186/1471-2105-13-316
Klein, S., Staring, M., Murphy, K., Viergever, M. A. & Pluim, J. P. elastix: a toolbox for intensity-based medical image registration. IEEE Trans. Med. Imaging 29, 196–205 (2010). DOI: 10.1109/TMI.2009.2035616
Shamonin, D. P. et al. Fast parallel image registration on CPU and GPU for diagnostic classification of Alzheimer’s disease. Front. Neuroinform. 7, 50 (2013). DOI: 10.3389/fninf.2013.00050
Tremblay, M. E., Riad, M. & Majewska, A. Preparation of mouse brain tissue for immunoelectron microscopy. J. Vis. Exp. 41, e2021 (2010).
Bisht, K., El Hajj, H., Savage, J. C., Sánchez, M. G. & Tremblay, M. Correlative light and electron microscopy to study microglial interactions with β-amyloid plaques. J. Vis. Exp. 112, e54060 (2016).
Peters, A., Palay S. L. & Webster H. D. The Fine Structure of the Nervous System: Neurons and Their Supporting Cells 3rd edn. (Oxford Univ. Press, 1991).
Nahirney, P. C. & Tremblay, M. E. Brain ultrastructure: putting the pieces together. Front. Cell Dev. Biol. 9, 629503 (2021). DOI: 10.3389/fcell.2021.629503
Miyazono, Y. et al. Uncoupled mitochondria quickly shorten along their long axis to form indented spheroids, instead of rings, in a fission-independent manner. Sci. Rep. 8, 350 (2018). DOI: 10.1038/s41598-017-18582-6
Holtzman, E., Novikoff, A. B. & Villaverde, H. Lysosomes and GERL in normal and chromatolytic neurons of the rat ganglion nodosum. J. Cell Biol. 33, 419–435 (1967). DOI: 10.1083/jcb.33.2.419
Nandy, K. Properties of neuronal lipofuscin pigment in mice. Acta Neuropathol. 19, 25–32 (1971). DOI: 10.1007/BF00690951
Henry, M. S. et al. Delta opioid receptor signaling promotes resilience to stress under the repeated social defeat paradigm in mice. Front. Mol. Neurosci. 11, 100 (2018). DOI: 10.3389/fnmol.2018.00100
Cubillos-Rojas, M. et al. The HERC2 ubiquitin ligase is essential for embryonic development and regulates motor coordination. Oncotarget 7, 56083–56106 (2016). DOI: 10.18632/oncotarget.11270
Bachiller, S. et al. The HERC1 E3 ubiquitin ligase is essential for normal development and for neurotransmission at the mouse neuromuscular junction. Cell. Mol. Life Sci. 72, 2961–2971 (2015). DOI: 10.1007/s00018-015-1878-2
Falcón-Moya, R. et al. Astrocyte-mediated switch in spike timing-dependent plasticity during hippocampal development. Nat. Commun. 11, 4388 (2020). DOI: 10.1038/s41467-020-18024-4
Pérez-Rodríguez, M. et al. Adenosine receptor-mediated developmental loss of spike timing-dependent depression in the hippocampus. Cereb. Cortex 29, 3266–3281 (2019). DOI: 10.1093/cercor/bhy194
Boza-Serrano, A. et al. Galectin-3, a novel endogenous TREM2 ligand, detrimentally regulates inflammatory response in Alzheimer’s disease. Acta Neuropathol. 138, 251–273 (2019). DOI: 10.1007/s00401-019-02013-z
Suárez-Pereira, I. et al. The absence of caspase-8 in the dopaminergic system leads to mild autism-like behavior. Front. Cell Dev. Biol. 10, 839715 (2022). DOI: 10.3389/fcell.2022.839715
García-Domínguez, I. et al. Selective deletion of caspase-3 gene in the dopaminergic system exhibits autistic-like behaviour. Prog. Neuropsychopharmacol. Biol. Psychiatry 104, 110030 (2021). DOI: 10.1016/j.pnpbp.2020.110030
