{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T05:58:05Z","timestamp":1793944685561,"version":"4.8.0"},"reference-count":125,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,1,24]],"date-time":"2026-01-24T00:00:00Z","timestamp":1769212800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"German Research Foundation","doi-asserted-by":"publisher","award":["GA 654\/13-2"],"award-info":[{"award-number":["GA 654\/13-2"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>As the brain\u2019s resident macrophages, microglia on the one side are increasingly recognized as essential players in discrete developmental stages, where immune, metabolic, and activity-derived signals are coordinately integrated to guide brain development. On the other side, the precise temporal and molecular coordination of microglial maturation is imperative for the structural and functional integrity of the developing central nervous system (CNS). In this review, we synthesize recent data that reposition microglia from a uniform population of immune sentinels to temporally programmed and regionally specialized regulators of circuit maturation. This involves dissecting the embryonic origins and migratory pathways of microglial progenitors in mouse and human systems and illustrating how gradual transcriptional and morphological maturation aligns the biology of microglia with progressive phases of neurogenesis, synaptic fine-tuning, myelination, and vascular stabilization. In addition, we discuss how individual gene mutations, inflammatory insults during perinatal life, and environmental disturbances intersect with these temporal programs to alter microglial phenotypes and compromise circuit formation. With a special emphasis on epilepsy and autism spectrum disorder, often sharing the common etiology, we illustrate how early malfunction of microglia may drive neural network dysfunction.<\/jats:p>","DOI":"10.3390\/ijms27031185","type":"journal-article","created":{"date-parts":[[2026,1,26]],"date-time":"2026-01-26T08:14:23Z","timestamp":1769415263000},"page":"1185","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Microglial Maturation and Functional Heterogeneity: Mechanistic Links to Neurodevelopmental Disorders"],"prefix":"10.3390","volume":"27","author":[{"given":"Pariya","family":"Khodabakhsh","sequence":"first","affiliation":[{"name":"Institute of Physiology, Department of Neurophysiology, Eberhard Karls University of T\u00fcbingen, 72074 T\u00fcbingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7400-5654","authenticated-orcid":false,"given":"Olga","family":"Garaschuk","sequence":"additional","affiliation":[{"name":"Institute of Physiology, Department of Neurophysiology, Eberhard Karls University of T\u00fcbingen, 72074 T\u00fcbingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3458","DOI":"10.1016\/j.neuron.2022.10.020","article-title":"Microglia states and nomenclature: A field at its crossroads","volume":"110","author":"Paolicelli","year":"2022","journal-title":"Neuron"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1016\/j.celrep.2016.12.041","article-title":"Coupled proliferation and apoptosis maintain the rapid turnover of microglia in the adult brain","volume":"18","author":"Askew","year":"2017","journal-title":"Cell Rep."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2127","DOI":"10.1016\/j.devcel.2022.07.015","article-title":"The spatiotemporal dynamics of microglia across the human lifespan","volume":"57","author":"Menassa","year":"2022","journal-title":"Dev. Cell"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1387","DOI":"10.1038\/nn1997","article-title":"Microglia: Active sensor and versatile effector cells in the normal and pathologic brain","volume":"10","author":"Hanisch","year":"2007","journal-title":"Nat. Neurosci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1007\/978-1-4939-9658-2_3","article-title":"Physiology of microglia","volume":"2034","author":"Garaschuk","year":"2019","journal-title":"Microglia Methods Protoc."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1381","DOI":"10.1038\/s41593-025-01931-4","article-title":"Microglia heterogeneity, modeling and cell-state annotation in development and neurodegeneration","volume":"28","author":"Fumagalli","year":"2025","journal-title":"Nat. Neurosci."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Luo, Y., and Wang, Z. (2024). The impact of Microglia on Neurodevelopment and Brain function in Autism. Biomedicines, 12.","DOI":"10.3390\/biomedicines12010210"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1016\/j.stem.2022.02.004","article-title":"Decoding the temporal and regional specification of microglia in the developing human brain","volume":"29","author":"Li","year":"2022","journal-title":"Cell Stem Cell"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1186\/s12974-023-02809-7","article-title":"Analysis of the microglia transcriptome across the human lifespan using single cell RNA sequencing","volume":"20","author":"Yaqubi","year":"2023","journal-title":"J. Neuroinflamm."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1126\/science.aba5906","article-title":"Human fetal microglia acquire homeostatic immune-sensing properties early in development","volume":"369","author":"Kracht","year":"2020","journal-title":"Science"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2152","DOI":"10.1016\/j.immuni.2023.07.016","article-title":"Human microglia maturation is underpinned by specific gene regulatory networks","volume":"56","author":"Han","year":"2023","journal-title":"Immunity"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"aad8670","DOI":"10.1126\/science.aad8670","article-title":"Microglia development follows a stepwise program to regulate brain homeostasis","volume":"353","author":"Winter","year":"2016","journal-title":"Science"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1038\/nn.3318","article-title":"Microglia emerge from erythromyeloid precursors via Pu. 1-and Irf8-dependent pathways","volume":"16","author":"Kierdorf","year":"2013","journal-title":"Nat. Neurosci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1126\/science.1194637","article-title":"Fate mapping analysis reveals that adult microglia derive from primitive macrophages","volume":"330","author":"Ginhoux","year":"2010","journal-title":"Science"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1002\/glia.22393","article-title":"Development and homeostasis of \u201cresident\u201d myeloid cells: The case of the microglia","volume":"61","author":"Schulz","year":"2013","journal-title":"Glia"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1038\/nature13989","article-title":"Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors","volume":"518","author":"Klapproth","year":"2015","journal-title":"Nature"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1038\/s41586-020-2316-7","article-title":"Deciphering human macrophage development at single-cell resolution","volume":"582","author":"Bian","year":"2020","journal-title":"Nature"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1016\/j.immuni.2015.03.011","article-title":"C-Myb+ erythro-myeloid progenitor-derived fetal monocytes give rise to adult tissue-resident macrophages","volume":"42","author":"Hoeffel","year":"2015","journal-title":"Immunity"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1868","DOI":"10.1038\/mp.2017.180","article-title":"Corticostriatal circuit defects in Hoxb8 mutant mice","volume":"23","author":"Nagarajan","year":"2017","journal-title":"Mol. Psychiatry"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"dev200200","DOI":"10.1242\/dev.200200","article-title":"Defining the Hoxb8 cell lineage during murine definitive hematopoiesis","volume":"149","author":"De","year":"2022","journal-title":"Development"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1016\/j.cell.2020.03.021","article-title":"Early fate defines microglia and non-parenchymal brain macrophage development","volume":"181","author":"Utz","year":"2020","journal-title":"Cell"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1038\/s41586-022-04596-2","article-title":"Specification of CNS macrophage subsets occurs postnatally in defined niches","volume":"604","author":"Masuda","year":"2022","journal-title":"Nature"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1038\/s41467-017-02492-2","article-title":"Yolk sac macrophage progenitors traffic to the embryo during defined stages of development","volume":"9","author":"Stremmel","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1631","DOI":"10.1038\/s41467-020-15409-3","article-title":"Transient microglial absence assists postmigratory cortical neurons in proper differentiation","volume":"11","author":"Hattori","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.devcel.2025.08.012","article-title":"Early microglia progenitors colonize the embryonic CNS via integrin-mediated migration from the pial surface","volume":"61","author":"Petry","year":"2025","journal-title":"Dev. Cell"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"104901","DOI":"10.1016\/j.neures.2025.04.004","article-title":"Microglial Colonization Routes and Their Impacts on Cellular Diversity","volume":"216","author":"Hattori","year":"2025","journal-title":"Neurosci. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1927","DOI":"10.1002\/glia.23204","article-title":"Siglec-H is a microglia-specific marker that discriminates microglia from CNS-associated macrophages and CNS-infiltrating monocytes","volume":"65","author":"Konishi","year":"2017","journal-title":"Glia"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1016\/j.immuni.2018.01.011","article-title":"High-dimensional single-cell mapping of central nervous system immune cells reveals distinct myeloid subsets in health, aging, and disease","volume":"48","author":"Mrdjen","year":"2018","journal-title":"Immunity"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"eaat7554","DOI":"10.1126\/science.aat7554","article-title":"Single-cell profiling identifies myeloid cell subsets with distinct fates during neuroinflammation","volume":"363","author":"Sankowski","year":"2019","journal-title":"Science"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1146\/annurev-immunol-093019-110159","article-title":"Microglia and central nervous system\u2013associated macrophages\u2014From origin to disease modulation","volume":"39","author":"Prinz","year":"2021","journal-title":"Annu. Rev. Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"112092","DOI":"10.1016\/j.celrep.2023.112092","article-title":"CD206+ macrophages transventricularly infiltrate the early embryonic cerebral wall to differentiate into microglia","volume":"42","author":"Hattori","year":"2023","journal-title":"Cell Rep."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1271","DOI":"10.1016\/j.celrep.2020.01.010","article-title":"Microglia heterogeneity in the single-cell era","volume":"30","author":"Masuda","year":"2020","journal-title":"Cell Rep."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1038\/s41593-019-0393-4","article-title":"A single-cell atlas of mouse brain macrophages reveals unique transcriptional identities shaped by ontogeny and tissue environment","volume":"22","author":"Martens","year":"2019","journal-title":"Nat. Neurosci."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Shimamura, T., Kitashiba, M., Nishizawa, K., and Hattori, Y. (2025). Physiological roles of embryonic microglia and their perturbation by maternal inflammation. Front. Cell. Neurosci., 19.","DOI":"10.3389\/fncel.2025.1552241"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2884","DOI":"10.1002\/glia.24458","article-title":"Plaque vicinity as a hotspot of microglial turnover in a mouse model of Alzheimer\u2019s disease","volume":"71","author":"Olmedillas","year":"2023","journal-title":"Glia"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1002\/cne.21123","article-title":"Distribution and differentiation of microglia in the human encephalon during the first two trimesters of gestation","volume":"499","author":"Monier","year":"2006","journal-title":"J. Comp. Neurol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1038\/s41583-024-00813-1","article-title":"The molecular determinants of microglial developmental dynamics","volume":"25","year":"2024","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Easley-Neal, C., Foreman, O., Sharma, N., Zarrin, A.A., and Weimer, R.M. (2019). CSF1R ligands IL-34 and CSF1 are differentially required for microglia development and maintenance in white and gray matter brain regions. Front. Immunol., 10.","DOI":"10.3389\/fimmu.2019.02199"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1002\/glia.24134","article-title":"Compromised fractalkine signaling delays microglial occupancy of emerging modules in the multisensory midbrain","volume":"70","author":"Brett","year":"2022","journal-title":"Glia"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1016\/j.devcel.2018.08.005","article-title":"Il34-Csf1r pathway regulates the migration and colonization of microglial precursors","volume":"46","author":"Wu","year":"2018","journal-title":"Dev. Cell"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1111\/j.1469-7580.2010.01245.x","article-title":"Early microglial colonization of the human forebrain and possible involvement in periventricular white-matter injury of preterm infants","volume":"217","author":"Verney","year":"2010","journal-title":"J. Anat."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1097\/nen.0b013e3180517b46","article-title":"Entry and distribution of microglial cells in human embryonic and fetal cerebral cortex","volume":"66","author":"Monier","year":"2007","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1523\/JNEUROSCI.1201-21.2021","article-title":"Embryonic pericytes promote microglial homeostasis and their effects on neural progenitors in the developing cerebral cortex","volume":"42","author":"Hattori","year":"2022","journal-title":"J. Neurosci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.neures.2022.09.006","article-title":"The microglia-blood vessel interactions in the developing brain","volume":"187","author":"Hattori","year":"2023","journal-title":"Neurosci. Res."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Shigemoto-Mogami, Y., Nakayama-Kitamura, K., and Sato, K. (2024). The arrangements of the microvasculature and surrounding glial cells are linked to blood\u2013brain barrier formation in the cerebral cortex. Front. Neuroanat., 18.","DOI":"10.3389\/fnana.2024.1438190"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1016\/j.jneuroim.2014.11.018","article-title":"Microglial numbers attain adult levels after undergoing a rapid decrease in cell number in the third postnatal week","volume":"278","author":"Nikodemova","year":"2015","journal-title":"J. Neuroimmunol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"3689","DOI":"10.1111\/ejn.14740","article-title":"Maturation of the microglial population varies across mesolimbic nuclei","volume":"52","author":"Hope","year":"2020","journal-title":"Eur. J. Neurosci."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1929","DOI":"10.1113\/JP272134","article-title":"Microglia across the lifespan: From origin to function in brain development, plasticity and cognition","volume":"595","author":"Tay","year":"2017","journal-title":"J. Physiol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"e70186","DOI":"10.1111\/jnc.70186","article-title":"Colony Stimulating Factor-1 (CSF-1) and Interleukin-34 (IL-34) Differentially Alter White Matter and Gray Matter Microglia and Oligodendrocyte Progenitor Cells","volume":"169","author":"Rumberger","year":"2025","journal-title":"J. Neurochem."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1038\/ni.2360","article-title":"IL-34 is a tissue-restricted ligand of CSF1R required for the development of Langerhans cells and microglia","volume":"13","author":"Wang","year":"2012","journal-title":"Nat. Immunol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1016\/j.it.2020.07.001","article-title":"To kill a microglia: A case for CSF1R inhibitors","volume":"41","author":"Green","year":"2020","journal-title":"Trends Immunol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"dev194449","DOI":"10.1242\/dev.194449","article-title":"CNS macrophages differentially rely on an intronic Csf1r enhancer for their development","volume":"147","author":"Munro","year":"2020","journal-title":"Development"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"936","DOI":"10.1016\/j.ajhg.2019.03.010","article-title":"Homozygous mutations in CSF1R cause a pediatric-onset leukoencephalopathy and can result in congenital absence of microglia","volume":"104","author":"Oosterhof","year":"2019","journal-title":"Am. J. Hum. Genet."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"e63800","DOI":"10.1002\/ajmg.a.63800","article-title":"Leukoencephalopathy with calcifications, developmental brain abnormalities and skeletal dysplasia due to homozygosity for a hypomorphic CSF1R variant: A report of three siblings","volume":"194","author":"Beerepoot","year":"2024","journal-title":"Am. J. Med. Genet."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"925","DOI":"10.1016\/j.ajhg.2019.03.004","article-title":"Bi-allelic CSF1R mutations cause skeletal dysplasia of dysosteosclerosis-pyle disease spectrum and degenerative encephalopathy with brain malformation","volume":"104","author":"Guo","year":"2019","journal-title":"Am. J. Hum. Genet."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"836","DOI":"10.1016\/j.it.2020.07.003","article-title":"The role of TGF\u03b2 signaling in microglia maturation and activation","volume":"41","author":"Spittau","year":"2020","journal-title":"Trends Immunol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"2840","DOI":"10.1038\/s41467-025-57684-y","article-title":"Radial glia integrin avb8 regulates cell autonomous microglial TGF\u03b21 signaling that is necessary for microglial identity","volume":"16","author":"McKinsey","year":"2025","journal-title":"Nat. Commun."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1772","DOI":"10.1523\/JNEUROSCI.2459-16.2017","article-title":"TREM2 promotes microglial survival by activating Wnt\/\u03b2-catenin pathway","volume":"37","author":"Zheng","year":"2017","journal-title":"J. Neurosci."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"2361","DOI":"10.1093\/brain\/awab231","article-title":"MOG autoantibodies trigger a tightly-controlled FcR and BTK-driven microglia proliferative response","volume":"144","author":"Pellerin","year":"2021","journal-title":"Brain"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"112425","DOI":"10.1016\/j.celrep.2023.112425","article-title":"Microglia colonize the developing brain by clonal expansion of highly proliferative progenitors, following allometric scaling","volume":"42","author":"Greulich","year":"2023","journal-title":"Cell Rep."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1002\/glia.24124","article-title":"Context-dependent transcriptional regulation of microglial proliferation","volume":"70","author":"Belhocine","year":"2022","journal-title":"Glia"},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Hattori, Y. (2023). The multifaceted roles of embryonic microglia in the developing brain. Front. Cell. Neurosci., 17.","DOI":"10.3389\/fncel.2023.988952"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"2236","DOI":"10.1002\/glia.70064","article-title":"Functional diversity of two novel embryonic microglial subpopulations and their developmental trajectories in developing mouse brains","volume":"73","author":"Cheng","year":"2025","journal-title":"Glia"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"108047","DOI":"10.1016\/j.celrep.2020.108047","article-title":"Fractalkine-dependent microglial pruning of viable oligodendrocyte progenitor cells regulates myelination","volume":"32","author":"White","year":"2020","journal-title":"Cell Rep."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1111\/j.1460-9568.2007.05309.x","article-title":"Microglia-derived interleukin-6 and leukaemia inhibitory factor promote astrocytic differentiation of neural stem\/progenitor cells","volume":"25","author":"Nakanishi","year":"2007","journal-title":"Eur. J. Neurosci."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"736","DOI":"10.1093\/jnen\/nlx056","article-title":"Biology of microglia in the developing brain","volume":"76","author":"Kaur","year":"2017","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1068","DOI":"10.1016\/j.immuni.2025.04.022","article-title":"Microglial and TREM2 dialogues in the developing brain","volume":"58","author":"Morini","year":"2025","journal-title":"Immunity"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"2110","DOI":"10.1111\/febs.16190","article-title":"Microglia phagocytose oligodendrocyte progenitor cells and synapses during early postnatal development: Implications for white versus gray matter maturation","volume":"289","author":"Irfan","year":"2022","journal-title":"FEBS J."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1016\/j.neuron.2012.03.026","article-title":"Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner","volume":"74","author":"Schafer","year":"2012","journal-title":"Neuron"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1228","DOI":"10.1038\/s41467-018-03566-5","article-title":"Microglia remodel synapses by presynaptic trogocytosis and spine head filopodia induction","volume":"9","author":"Weinhard","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"12540","DOI":"10.1038\/ncomms12540","article-title":"Microglia contact induces synapse formation in developing somatosensory cortex","volume":"7","author":"Miyamoto","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1596","DOI":"10.1016\/j.cell.2013.11.030","article-title":"Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor","volume":"155","author":"Parkhurst","year":"2013","journal-title":"Cell"},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Testa, A.M., Vignozzi, L., Corallo, D., Aveic, S., Viola, A., Allegra, M., and Angioni, R. (2024). Hypoxic Human Microglia Promote Angiogenesis Through Extracellular Vesicle Release. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms252312508"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1016\/j.cell.2017.11.042","article-title":"Microbiome influences prenatal and adult microglia in a sex-specific manner","volume":"172","author":"Thion","year":"2018","journal-title":"Cell"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1146\/annurev-neuro-110920-023056","article-title":"Microglia and neurodevelopmental disorders","volume":"45","author":"Lukens","year":"2022","journal-title":"Annu. Rev. Neurosci."},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Cowan, M., and Petri, W.A. (2018). Microglia: Immune regulators of neurodevelopment. Front. Immunol., 9.","DOI":"10.3389\/fimmu.2018.02576"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1126\/science.aat0474","article-title":"Microglia and early brain development: An intimate journey","volume":"362","author":"Thion","year":"2018","journal-title":"Science"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1007\/s00401-023-02629-2","article-title":"Microglial contribution to the pathology of neurodevelopmental disorders in humans","volume":"146","author":"Matuleviciute","year":"2023","journal-title":"Acta Neuropathol."},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Fan, G., Ma, J., Ma, R., Suo, M., Chen, Y., Zhang, S., Zeng, Y., and Chen, Y. (2023). Microglia modulate neurodevelopment in autism spectrum disorder and schizophrenia. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms242417297"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"102674","DOI":"10.1016\/j.conb.2022.102674","article-title":"Microglia-mediated synaptic pruning as a key deficit in neurodevelopmental disorders: Hype or hope?","volume":"79","author":"Mordelt","year":"2023","journal-title":"Curr. Opin. Neurobiol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1038\/s41572-024-00546-6","article-title":"Developmental and epileptic encephalopathies","volume":"10","author":"Scheffer","year":"2024","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1016\/S2352-4642(24)00196-2","article-title":"The expanding field of genetic developmental and epileptic encephalopathies: Current understanding and future perspectives","volume":"8","author":"Specchio","year":"2024","journal-title":"Lancet Child Adolesc. Health"},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Vasquez, A., and Fine, A.L. (2025). Management of developmental and epileptic encephalopathies. Seminars in Neurology, Thieme Medical Publishers, Inc.","DOI":"10.1055\/a-2534-3267"},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"\u00c7ar\u00e7ak, N., Onat, F., and Sitnikova, E. (2023). Astrocytes as a target for therapeutic strategies in epilepsy: Current insights. Front. Mol. Neurosci., 16.","DOI":"10.3389\/fnmol.2023.1183775"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.cytogfr.2025.06.009","article-title":"Innate Immune Activation and Neuroinflammatory Pathways in Epilepsy","volume":"84","author":"Solanki","year":"2025","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1038\/s41586-020-2777-8","article-title":"Negative feedback control of neuronal activity by microglia","volume":"586","author":"Badimon","year":"2020","journal-title":"Nature"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"2157","DOI":"10.1111\/epi.18361","article-title":"Immunity and neuroinflammation in early stages of life and epilepsy","volume":"66","author":"Rocha","year":"2025","journal-title":"Epilepsia"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1404","DOI":"10.1038\/s41593-025-01979-2","article-title":"GABA-dependent microglial elimination of inhibitory synapses underlies neuronal hyperexcitability in epilepsy","volume":"28","author":"Chen","year":"2025","journal-title":"Nat. Neurosci."},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Chen, I.-C., Ho, S.-Y., Tsai, C.-W., Chen, E.-L., and Liou, H.-H. (2024). Microglia-impaired phagocytosis contributes to the epileptogenesis in a mouse model of Dravet syndrome. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms252312721"},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Goisis, R.C., Chiavegato, A., Gomez-Gonzalo, M., Marcon, I., Requie, L.M., Scholze, P., Carmignoto, G., and Losi, G. (2022). GABA tonic currents and glial cells are altered during epileptogenesis in a mouse model of Dravet syndrome. Front. Cell. Neurosci., 16, Correction in Front. Cell. Neurosci. 2022, 16, 1066985. https:\/\/doi.org\/10.3389\/fncel.2022.1066985.","DOI":"10.3389\/fncel.2022.919493"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"e2027232024","DOI":"10.1523\/JNEUROSCI.2027-23.2024","article-title":"Human iPSC-derived microglia sense and dampen hyperexcitability of cortical neurons carrying the epilepsy-associated SCN2A-L1342P mutation","volume":"45","author":"Que","year":"2025","journal-title":"J. Neurosci."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1111\/epi.13429","article-title":"Microglial activation during epileptogenesis in a mouse model of tuberous sclerosis complex","volume":"57","author":"Zhang","year":"2016","journal-title":"Epilepsia"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1796","DOI":"10.1111\/epi.14526","article-title":"The specificity and role of microglia in epileptogenesis in mouse models of tuberous sclerosis complex","volume":"59","author":"Zhang","year":"2018","journal-title":"Epilepsia"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1002\/epi4.12564","article-title":"Astrocyte reactivity in a mouse model of SCN8A epileptic encephalopathy","volume":"7","author":"Thompson","year":"2022","journal-title":"Epilepsia Open"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"109968","DOI":"10.1016\/j.neuropharm.2024.109968","article-title":"Contribution of microglia to the epileptiform activity that results from neonatal hypoxia","volume":"253","author":"Leavy","year":"2024","journal-title":"Neuropharmacology"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1038\/s41386-025-02227-8","article-title":"Inflammatory mechanisms contribute to long-term cognitive deficits induced by perinatal asphyxia via interleukin-1","volume":"51","author":"Kelemen","year":"2025","journal-title":"Neuropsychopharmacology"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"21378","DOI":"10.1038\/s41598-020-78294-2","article-title":"Maternal immune activation induces sustained changes in fetal microglia motility","volume":"10","author":"Ozaki","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"2611","DOI":"10.1016\/j.immuni.2021.10.006","article-title":"Prenatal interleukin 6 elevation increases glutamatergic synapse density and disrupts hippocampal connectivity in offspring","volume":"54","author":"Mirabella","year":"2021","journal-title":"Immunity"},{"key":"ref_99","first-page":"S73","article-title":"Microglia and status epilepticus in the immature brain","volume":"8","year":"2023","journal-title":"Epilepsia Open"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"e00403","DOI":"10.1002\/brb3.403","article-title":"A postnatal peak in microglial development in the mouse hippocampus is correlated with heightened sensitivity to seizure triggers","volume":"5","author":"Kim","year":"2015","journal-title":"Brain Behav."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"dev202252","DOI":"10.1242\/dev.202252","article-title":"Fetal brain response to maternal inflammation requires microglia","volume":"151","author":"Stogsdill","year":"2024","journal-title":"Development"},{"key":"ref_102","doi-asserted-by":"crossref","unstructured":"Mastenbroek, L., Kooistra, S., Eggen, B., and Prins, J. (2024). The role of microglia in early neurodevelopment and the effects of maternal immune activation. Seminars in Immunopathology, Springer.","DOI":"10.1007\/s00281-024-01017-6"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"101971","DOI":"10.1016\/j.pneurobio.2020.101971","article-title":"Microglial innate memory and epigenetic reprogramming in neurological disorders","volume":"200","author":"Leal","year":"2021","journal-title":"Prog. Neurobiol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"1216","DOI":"10.1038\/s41390-022-02239-w","article-title":"Maternal immune activation alters fetal and neonatal microglia phenotype and disrupts neurogenesis in mice","volume":"93","author":"Loayza","year":"2023","journal-title":"Pediatr. Res."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.nbd.2015.02.010","article-title":"Functional and structural deficits of the dentate gyrus network coincide with emerging spontaneous seizures in an Scn1a mutant Dravet Syndrome model during development","volume":"77","author":"Tsai","year":"2015","journal-title":"Neurobiol. Dis."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1628","DOI":"10.1002\/glia.22967","article-title":"Sodium channels in astroglia and microglia","volume":"64","author":"Pappalardo","year":"2016","journal-title":"Glia"},{"key":"ref_107","doi-asserted-by":"crossref","unstructured":"Jeong, Y., Lim, H.K., Kim, H., Lee, J., Lee, S., and Suh, M. (Epilepsia, 2025). C1q neutralization during epileptogenesis attenuates complement-mediated synaptic elimination and epileptiform activity, Epilepsia, online ahead of print.","DOI":"10.1111\/epi.18678"},{"key":"ref_108","doi-asserted-by":"crossref","unstructured":"Sun, Y., Jukkola, P., Akinlaja, Y., Garaschuk, O., and Pfeiffer, F. (2025). Oligodendrocyte precursor cells establish contacts with somata of active neurons. bioRxiv, bioRxiv:2025.03.28.646001.","DOI":"10.1101\/2025.03.28.646001"},{"key":"ref_109","doi-asserted-by":"crossref","unstructured":"Yan, S., Wang, L., Samsom, J.N., Ujic, D., and Liu, F. (2024). PolyI: C maternal immune activation on E9. 5 causes the deregulation of microglia and the complement system in mice, leading to decreased synaptic spine density. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25105480"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"9133","DOI":"10.1523\/JNEUROSCI.1820-08.2008","article-title":"Status epilepticus induces a particular microglial activation state characterized by enhanced purinergic signaling","volume":"28","author":"Avignone","year":"2008","journal-title":"J. Neurosci."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1186\/s12974-015-0421-6","article-title":"Altered morphological dynamics of activated microglia after induction of status epilepticus","volume":"12","author":"Avignone","year":"2015","journal-title":"J. Neuroinflamm."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"106249","DOI":"10.1016\/j.nbd.2023.106249","article-title":"Microglia in epilepsy","volume":"185","author":"Yu","year":"2023","journal-title":"Neurobiol. Dis."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"106183","DOI":"10.1016\/j.bbi.2025.106183","article-title":"Early microglia-mediated neuroinflammation after status epilepticus causes behavioral dysfunction and neurocognitive deficits but not epilepsy in mice","volume":"131","author":"Thergarajan","year":"2025","journal-title":"Brain Behav. Immun."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.jpsychires.2020.07.013","article-title":"Microglia mediated neuroinflammation in autism spectrum disorder","volume":"130","author":"Liao","year":"2020","journal-title":"J. Psychiatr. Res."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1001\/jamapsychiatry.2013.272","article-title":"Microglial activation in young adults with autism spectrum disorder","volume":"70","author":"Suzuki","year":"2013","journal-title":"JAMA Psychiatry"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"106071","DOI":"10.1016\/j.bbi.2025.106071","article-title":"Microglial involvement in autism spectrum disorder: Insights from human data and iPSC models","volume":"130","author":"Michels","year":"2025","journal-title":"Brain Behav. Immun."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"bhaf109","DOI":"10.1093\/cercor\/bhaf109","article-title":"Microglial regulation of white matter development and its disruption in autism spectrum disorder","volume":"35","author":"Canada","year":"2025","journal-title":"Cereb. Cortex"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"2125","DOI":"10.1002\/glia.23637","article-title":"Microglia roles in synaptic plasticity and myelination in homeostatic conditions and neurodevelopmental disorders","volume":"67","author":"Bar","year":"2019","journal-title":"Glia"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1016\/j.bbi.2019.12.007","article-title":"In vivo characterization of functional states of cortical microglia during peripheral inflammation","volume":"87","author":"Riester","year":"2020","journal-title":"Brain Behav. Immun."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.bbi.2021.05.021","article-title":"In vivo mechanisms of cortical network dysfunction induced by systemic inflammation","volume":"96","author":"Odoj","year":"2021","journal-title":"Brain Behav. Immun."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"1576","DOI":"10.1038\/mp.2016.103","article-title":"Deficient autophagy in microglia impairs synaptic pruning and causes social behavioral defects","volume":"22","author":"Kim","year":"2017","journal-title":"Mol. Psychiatry"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"e1184","DOI":"10.1038\/tp.2017.173","article-title":"Rare genetic variants in CX3CR1 and their contribution to the increased risk of schizophrenia and autism spectrum disorders","volume":"7","author":"Ishizuka","year":"2017","journal-title":"Transl. Psychiat."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1016\/j.immuni.2018.04.016","article-title":"The Microglial Innate Immune Receptor TREM2 Is Required for Synapse Elimination and Normal Brain Connectivity","volume":"48","author":"Filipello","year":"2018","journal-title":"Immunity"},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1038\/nrn.2017.110","article-title":"Errant gardeners: Glial-cell-dependent synaptic pruning and neurodevelopmental disorders","volume":"18","author":"Neniskyte","year":"2017","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"2424","DOI":"10.1038\/s41380-024-02518-4","article-title":"Microglial over-pruning of synapses during development in autism-associated SCN2A-deficient mice and human cerebral organoids","volume":"29","author":"Wu","year":"2024","journal-title":"Mol. Psychiatry"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/3\/1185\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,26]],"date-time":"2026-01-26T08:15:48Z","timestamp":1769415348000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/3\/1185"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,24]]},"references-count":125,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2026,2]]}},"alternative-id":["ijms27031185"],"URL":"https:\/\/doi.org\/10.3390\/ijms27031185","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,24]]}}}