{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,5]],"date-time":"2026-11-05T23:38:51Z","timestamp":1793921931427,"version":"4.8.0"},"reference-count":45,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2024,5,17]],"date-time":"2024-05-17T00:00:00Z","timestamp":1715904000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Canadian Institutes of Health Research","award":["RN488849-486128"],"award-info":[{"award-number":["RN488849-486128"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Maternal immune activation (MIA) is a risk factor for multiple neurodevelopmental disorders; however, animal models developed to explore MIA mechanisms are sensitive to experimental factors, which has led to complexity in previous reports of the MIA phenotype. We sought to characterize an MIA protocol throughout development to understand how prenatal immune insult alters the trajectory of important neurodevelopmental processes, including the microglial regulation of synaptic spines and complement signaling. We used polyinosinic:polycytidylic acid (polyI:C) to induce MIA on gestational day 9.5 in CD-1 mice, and measured their synaptic spine density, microglial synaptic pruning, and complement protein expression. We found reduced dendritic spine density in the somatosensory cortex starting at 3-weeks-of-age with requisite increases in microglial synaptic pruning and phagocytosis, suggesting spine density loss was caused by increased microglial synaptic pruning. Additionally, we showed dysregulation in complement protein expression persisting into adulthood. Our findings highlight disruptions in the prenatal environment leading to alterations in multiple dynamic processes through to postnatal development. This could potentially suggest developmental time points during which synaptic processes could be measured as risk factors or targeted with therapeutics for neurodevelopmental disorders.<\/jats:p>","DOI":"10.3390\/ijms25105480","type":"journal-article","created":{"date-parts":[[2024,5,17]],"date-time":"2024-05-17T06:53:49Z","timestamp":1715928829000},"page":"5480","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["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"],"prefix":"10.3390","volume":"25","author":[{"given":"Shuxin","family":"Yan","sequence":"first","affiliation":[{"name":"Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, 250 College St., Toronto, ON M5T 1R8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Le","family":"Wang","sequence":"additional","affiliation":[{"name":"Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, 250 College St., Toronto, ON M5T 1R8, Canada"},{"name":"Institute of Mental Health and Drug Discovery, Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), School of Mental Health, Wenzhou Medical University, Ouhai District, Wenzhou 325000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James Nicholas","family":"Samsom","sequence":"additional","affiliation":[{"name":"Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, 250 College St., Toronto, ON M5T 1R8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Ujic","sequence":"additional","affiliation":[{"name":"Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, 250 College St., Toronto, ON M5T 1R8, Canada"},{"name":"Institutes of Medical Science, University of Toronto, 1 King\u2019s College Cir., Toronto, ON M5S 1A8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Liu","sequence":"additional","affiliation":[{"name":"Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, 250 College St., Toronto, ON M5T 1R8, Canada"},{"name":"Institutes of Medical Science, University of Toronto, 1 King\u2019s College Cir., Toronto, ON M5S 1A8, Canada"},{"name":"Department of Psychiatry, University of Toronto, 250 College St., Toronto, ON M5T 1R8, Canada"},{"name":"Department of Physiology, University of Toronto, 1 King\u2019s College Cir., Toronto, ON M5S 1A8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,5,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1539","DOI":"10.1002\/bdr2.1416","article-title":"Maternal immune activation, central nervous system development and behavioral phenotypes","volume":"110","author":"Minakova","year":"2018","journal-title":"Birth Defects Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.bbi.2016.06.005","article-title":"Maternal infection during pregnancy and risk of autism spectrum disorders: A systematic review and meta-analysis","volume":"58","author":"Jiang","year":"2016","journal-title":"Brain Behav. Immun."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1186\/s13229-021-00464-4","article-title":"Fever during pregnancy as a risk factor for neurodevelopmental disorders: Results from a systematic review and meta-analysis","volume":"12","author":"Antoun","year":"2021","journal-title":"Mol. Autism"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.jpsychires.2021.05.039","article-title":"Maternal infection in gestation increases the risk of non-affective psychosis in offspring: A meta-analysis","volume":"139","author":"Saatci","year":"2021","journal-title":"J. Psychiatry Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1038\/nrneurol.2014.187","article-title":"Maternal immune activation and abnormal brain development across CNS disorders","volume":"10","author":"Knuesel","year":"2014","journal-title":"Nat. Rev. Neurol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1038\/s41582-021-00530-8","article-title":"Maternal immune activation and neuroinflammation in human neurodevelopmental disorders","volume":"17","author":"Han","year":"2021","journal-title":"Nat. Rev. Neurol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"NS20220064","DOI":"10.1042\/NS20220064","article-title":"Maternal immune activation and role of placenta in the prenatal programming of neurodevelopmental disorders","volume":"7","author":"Woods","year":"2023","journal-title":"Neuronal Signal"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1038\/s41398-021-01361-3","article-title":"Maternal immune activation generates anxiety in offspring: A translational meta-analysis","volume":"11","author":"Quagliato","year":"2021","journal-title":"Transl. Psychiatry"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1016\/j.neubiorev.2021.07.015","article-title":"Maternal immune activation in rodent models: A systematic review of neurodevelopmental changes in gene expression and epigenetic modulation in the offspring brain","volume":"129","author":"Woods","year":"2021","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1016\/j.bbi.2007.09.012","article-title":"Adult brain and behavioral pathological markers of prenatal immune challenge during early\/middle and late fetal development in mice","volume":"22","author":"Meyer","year":"2008","journal-title":"Brain Behav. Immun."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1016\/j.biopsych.2021.03.017","article-title":"Early or Late Gestational Exposure to Maternal Immune Activation Alters Neurodevelopmental Trajectories in Mice: An Integrated Neuroimaging, Behavioral, and Transcriptional Study","volume":"90","author":"Guma","year":"2021","journal-title":"Biol. Psychiatry"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e2114545119","DOI":"10.1073\/pnas.2114545119","article-title":"Differential effects of early or late exposure to prenatal maternal immune activation on mouse embryonic neurodevelopment","volume":"119","author":"Guma","year":"2022","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1159\/000530185","article-title":"The Outcomes of Maternal Immune Activation Induced with the Viral Mime tic Poly I:C on Microglia in Exposed Rodent Offspring","volume":"45","author":"Loewen","year":"2023","journal-title":"Dev. Neurosci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/S0165-3806(99)00113-3","article-title":"Microglia derive from progenitors, originating from the yolk sac, and which proliferate in the brain","volume":"117","author":"Alliot","year":"1999","journal-title":"Brain Res. Dev."},{"key":"ref_15","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":"Perdiguero","year":"2015","journal-title":"Nature"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"766267","DOI":"10.3389\/fnagi.2021.766267","article-title":"Aged Microglia in Neurodegenerative Diseases: Microglia Lifespan and Culture Methods","volume":"13","author":"Yoo","year":"2021","journal-title":"Front. Aging Neurosci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1456","DOI":"10.1126\/science.1202529","article-title":"Synaptic Pruning by Microglia Is Necessary for Normal Brain Development","volume":"333","author":"Paolicelli","year":"2011","journal-title":"Science"},{"key":"ref_18","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_19","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 m atter maturation","volume":"289","author":"Irfan","year":"2022","journal-title":"FEBS J."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1002\/dneu.22804","article-title":"Impact of maternal immune activation on dendritic spine development","volume":"81","author":"Pekala","year":"2021","journal-title":"Dev. Neurobiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"23","DOI":"10.3389\/fnins.2020.00023","article-title":"Complement System in Brain Architecture and Neurodevelopmental Disorders","volume":"14","author":"Magdalon","year":"2020","journal-title":"Front. Neurosci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1146\/annurev-neuro-061010-113810","article-title":"The complement system: An unexpected role in synaptic pruning during development and disease","volume":"35","author":"Stephan","year":"2012","journal-title":"Annu. Rev. Neurosci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1164","DOI":"10.1016\/j.cell.2007.10.036","article-title":"The classical complement cascade mediates CNS synapse elimination","volume":"131","author":"Stevens","year":"2007","journal-title":"Cell"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1038\/nature16549","article-title":"Schizophrenia risk from complex variation of complement component 4","volume":"530","author":"Sekar","year":"2016","journal-title":"Nature"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"7975","DOI":"10.1073\/pnas.0913449107","article-title":"Enhanced synaptic connectivity and epilepsy in C1q knockout mice","volume":"107","author":"Chu","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1016\/j.expneurol.2013.12.013","article-title":"Altered cognitive performance and synaptic function in the hippocampus of mice lacking C3","volume":"253","author":"Daborg","year":"2014","journal-title":"Exp. Neurol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Comer, A.L., Jinadasa, T., Sriram, B., Phadke, R.A., Kretsge, L.N., Nguyen, T.P.H., Antognetti, G., Gilbert, J.P., Lee, J., and Newmark, E.R. (2020). Increased expression of schizophrenia-associated gene C4 leads to hypoconnectivity of prefrontal cortex and reduced social interaction. PLoS Biol., 18.","DOI":"10.1371\/journal.pbio.3000604"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1186\/s12974-019-1683-1","article-title":"Classical complement cascade initiating C1q protein within neurons in the aged rhesus macaque dorsolateral prefrontal cortex","volume":"17","author":"Datta","year":"2020","journal-title":"J. Neuroinflamm."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1322","DOI":"10.1016\/j.neuron.2018.10.014","article-title":"Changes in the Synaptic Proteome in Tauopathy and Rescue of Tau-Induced Synapse Loss by C1q Antibodies","volume":"100","author":"Dejanovic","year":"2018","journal-title":"Neuron"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Su, P., Yan, S., Chen, K., Huang, L., Wang, L., Lee, F.H.F., Zhou, H., Lai, T.K.Y., Jiang, A., and Samsom, J. (2024). EF1\u03b1-associated protein complexes affect dendritic spine plasticity by regulating microglial phagocytosis in Fmr1 knock-out mice. Mol. Psychiatry, online ahead of print.","DOI":"10.1038\/s41380-023-02396-2"},{"key":"ref_31","unstructured":"Allen Institute for Brain Science (2023, November 21). Allen Mouse Brain Atlas [Dataset]. Available online: https:\/\/mouse.brain-map.org."},{"key":"ref_32","unstructured":"Allen Institute for Brain Science (2023, November 21). Allen Reference Atlas\u2014Mouse Brain [Brain Atlas]. Available online: https:\/\/atlas.brain-map.org."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Lier, J., Streit, W.J., and Bechmann, I. (2021). Beyond Activation: Characterizing Microglial Functional Phenotypes. Cells, 10.","DOI":"10.3390\/cells10092236"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/j.bbi.2015.07.022","article-title":"Impaired synaptic development in a maternal immune activation mouse model of neurodevelopmental disorders","volume":"50","author":"Coiro","year":"2015","journal-title":"Brain Behav. Immun."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1172","DOI":"10.1016\/j.biopsych.2010.09.022","article-title":"Prenatal interaction of mutant DISC1 and immune activation produces adult psychopathology","volume":"68","author":"Abazyan","year":"2010","journal-title":"Biol. Psychiatry"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.schres.2008.10.003","article-title":"Prenatal immune challenge induces developmental changes in the morphology of pyramidal neurons of the prefrontal cortex and hippocampus in rats","volume":"107","author":"Baharnoori","year":"2009","journal-title":"Schizophr. Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.bbr.2013.10.034","article-title":"Prenatal lipopolysaccharide exposure increases depression-like behaviors and reduces hippocampal neurogenesis in adult rats","volume":"259","author":"Lin","year":"2014","journal-title":"Behav. Brain Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1808","DOI":"10.1038\/s41380-020-0671-2","article-title":"Inhibition of colony stimulating factor 1 receptor corrects maternal inflammation-induced microglial and synaptic dysfunction and behavioral abnormalities","volume":"26","author":"Ikezu","year":"2021","journal-title":"Mol. Psychiatry"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1342","DOI":"10.1002\/jnr.22636","article-title":"Prenatal immune challenge compromises development of upper-layer but not deeper-layer neurons of the mouse cerebral cortex","volume":"89","author":"Soumiya","year":"2011","journal-title":"J. Neurosci. Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/j.bbi.2016.09.028","article-title":"Prenatal infection leads to ASD-like behavior and altered synaptic pruning in the mouse offspring","volume":"63","author":"Veldt","year":"2017","journal-title":"Brain Behav. Immun."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"558181","DOI":"10.3389\/fncel.2020.558181","article-title":"Sex Differences of Microglia and Synapses in the Hippocampal Dentate Gyrus of Adult Mouse Offspring Exposed to Maternal Immune Activation","volume":"14","author":"Hui","year":"2020","journal-title":"Front. Cell. Neurosci."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Mattei, D., Ivanov, A., Ferrai, C., Jordan, P., Guneykaya, D., Buonfiglioli, A., Schaafsma, W., Przanowski, P., Deuther-Conrad, W., and Brust, P. (2017). Maternal immune activation results in complex microglial transcriptome signature in the adult offspring that is reversed by minocycline treatment. Transl. Psychiatry, 7.","DOI":"10.1038\/tp.2017.80"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"64","DOI":"10.9758\/cpn.2017.15.1.64","article-title":"Increased Levels of C1q in the Prefrontal Cortex of Adult Offspring after Maternal Immune Activation: Prevention by 7,8-Dihydroxyflavone","volume":"15","author":"Han","year":"2017","journal-title":"Clin. Psychopharmacol. Neurosci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1554","DOI":"10.1038\/mp.2017.151","article-title":"The complement system: A gateway to gene-environment interactions in schizophrenia pathogenesis","volume":"22","author":"Nimgaonkar","year":"2017","journal-title":"Mol. Psychiatry"},{"key":"ref_45","first-page":"19","article-title":"Complement C3 Expression Is Decreased in Autism Spectrum Disorder Subjects and Contributes to Behavioral Deficits in Rodents","volume":"3","author":"Fagan","year":"2017","journal-title":"Mol. Neuropsychiatry"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/10\/5480\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:44:01Z","timestamp":1760107441000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/10\/5480"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,5,17]]},"references-count":45,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2024,5]]}},"alternative-id":["ijms25105480"],"URL":"https:\/\/doi.org\/10.3390\/ijms25105480","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,5,17]]}}}