Abstract
Background
Activation of microglia, increase in cortical neuron density, and reduction in GABAergic interneurons are some of the key findings in postmortem autism spectrum disorders (ASD) subjects. The aim of this study was to investigate how maternal immune activation (MIA) programs microglial phenotypes and abnormal neurogenesis in offspring mice.
Methods
MIA was induced by injection of lipopolysaccharide (LPS, i.p.) to pregnant mice at embryonic (E) day 12.5. Microglial phenotypes and neurogenesis were investigated between E15.5 to postnatal (P) day 21 by immunohistochemistry, flow cytometry, and cytokine array.
Results
MIA led to a robust increase in fetal and neonatal microglia in neurogenic regions. Homeostatic E15.5 and P4 microglia are heterogeneous, consisting of M1 (CD86+/CD206−) and mixed M1/M2 (CD86+/CD206+)-like subpopulations. MIA significantly reduced M1 but increased mixed M1/M2 microglia, which was associated with upregulation of numerous cytokines with pleotropic property. MIA resulted in a robust increase in Ki67+/Nestin+ and Tbr2+ neural progenitor cells in the subventricular zone (SVZ) of newborn mice. At juvenile stage, a male-specific reduction of Parvalbumin+ but increase in Reelin+ interneurons in the medial prefrontal cortex was found in MIA offspring mice.
Conclusions
MIA programs microglia towards a pleotropic phenotype that may drive excessive neurogenesis in ASD patients.
Impact
-
Maternal immune activation (MIA) alters microglial phenotypes in the brain of fetal and neonatal mouse offspring.
-
MIA leads to excessive proliferation and overproduction of neural progenitors in the subventricular zone (SVZ).
-
MIA reduces parvalbumin+ while increases Reelin+ interneurons in the prefrontal cortex.
-
Our study sheds light on neurobiological mechanisms of abnormal neurogenesis in certain neurodevelopmental disorders, such as autism spectrum disorder (ASD).
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 14 print issues and online access
$259.00 per year
only $18.50 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Data availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request
References
Estes, M. L. & McAllister, A. K. Maternal immune activation: implications for neuropsychiatric disorders. Science 353, 772–777 (2016).
Bergdolt, L. & Dunaevsky, A. Brain changes in a maternal immune activation model of neurodevelopmental brain disorders. Prog. Neurobiol. 175, 1–19 (2019).
Knuesel, I. et al. Maternal immune activation and abnormal brain development across CNS disorders. Nat. Rev. Neurol. 10, 643–660 (2014).
Al-Haddad, B. J. S. et al. The fetal origins of mental illness. Am. J. Obstet. Gynecol. 221, 549–562 (2019).
Carlezon, W. A. Jr. et al. Maternal and early postnatal immune activation produce sex-specific effects on autism-like behaviors and neuroimmune function in mice. Sci. Rep. 9, 16928 (2019).
Haida, O. et al. Sex-dependent behavioral deficits and neuropathology in a maternal immune activation model of autism. Transl. Psychiatry 9, 124 (2019).
Fernandez de Cossio, L., Guzman, A., van der Veldt, S. & Luheshi, G. N. Prenatal infection leads to ASD-like behavior and altered synaptic pruning in the mouse offspring. Brain Behav. Immun. 63, 88–98 (2017).
Smolders, S., Notter, T., Smolders, S. M. T., Rigo, J. M. & Brone, B. Controversies and prospects about microglia in maternal immune activation models for neurodevelopmental disorders. Brain Behav. Immun. 73, 51–65 (2018).
Gilbert, J. & Man, H. Y. Fundamental elements in autism: from neurogenesis and neurite growth to synaptic plasticity. Front. Cell. Neurosci. 11, 359 (2017).
Packer, A. Neocortical neurogenesis and the etiology of autism spectrum disorder. Neurosci. Biobehav. Rev. 64, 185–195 (2016).
Courchesne, E. et al. Neuron number and size in prefrontal cortex of children with autism. JAMA 306, 2001–2010 (2011).
Stoner, R. et al. Patches of disorganization in the neocortex of children with autism. N. Engl. J. Med. 370, 1209–1219 (2014).
Courchesne, E. & Pierce, K. Brain overgrowth in autism during a critical time in development: implications for frontal pyramidal neuron and interneuron development and connectivity. Int. J. Dev. Neurosci. 23, 153–170 (2005).
Courchesne, E. Brain development in autism: early overgrowth followed by premature arrest of growth. Ment. Retard. Dev. Disabil. Res. Rev. 10, 106–111 (2004).
Marchetto, M. C. et al. Altered proliferation and networks in neural cells derived from idiopathic autistic individuals. Mol. Psychiatry 22, 820–835 (2017).
Baines, K. J. et al. Maternal immune activation alters fetal brain development and enhances proliferation of neural precursor cells in rats. Front. Immunol. 11, 1145 (2020).
Le Belle, J. E. et al. Maternal inflammation contributes to brain overgrowth and autism-associated behaviors through altered redox signaling in stem and progenitor cells. Stem Cell Rep. 3, 725–734 (2014).
Ma, Y., Wang, J., Wang, Y. & Yang, G. Y. The biphasic function of microglia in ischemic stroke. Prog. Neurobiol. 157, 247–272 (2017).
Loane, D. J. & Kumar, A. Microglia in the TBI brain: the good, the bad, and the dysregulated. Exp. Neurol. 275, 316–327 (2016).
Pang, Y. et al. Intranasal insulin protects against substantia nigra dopaminergic neuronal loss and alleviates motor deficits induced by 6-OHDA in rats. Neuroscience 318, 157–165 (2016).
Bloem, B. et al. Topographic mapping between basal forebrain cholinergic neurons and the medial prefrontal cortex in mice. J. Neurosci. 34, 16234–16246 (2014).
Takagi, S., Furube, E., Nakano, Y., Morita, M. & Miyata, S. Microglia are continuously activated in the circumventricular organs of mouse brain. J. Neuroimmunol. 331, 74–86 (2019).
Kokona, D., Ebneter, A., Escher, P. & Zinkernagel, M. S. Colony-stimulating factor 1 receptor inhibition prevents disruption of the blood-retina barrier during chronic inflammation. J. Neuroinflammation 15, 340 (2018).
Canetta, S. et al. Maternal immune activation leads to selective functional deficits in offspring parvalbumin interneurons. Mol. Psychiatry 21, 956–968 (2016).
Cai, Z., Pan, Z. L., Pang, Y., Evans, O. B. & Rhodes, P. G. Cytokine induction in fetal rat brains and brain injury in neonatal rats after maternal lipopolysaccharide administration. Pediatr. Res. 47, 64–72 (2000).
Chua, J. S., Cowley, C. J., Manavis, J., Rofe, A. M. & Coyle, P. Prenatal exposure to lipopolysaccharide results in neurodevelopmental damage that is ameliorated by zinc in mice. Brain Behav. Immun. 26, 326–336 (2012).
Cunningham, C. L., Martinez-Cerdeno, V. & Noctor, S. C. Microglia regulate the number of neural precursor cells in the developing cerebral cortex. J. Neurosci. 33, 4216–4233 (2013).
Hsueh, P. T. et al. Expression of cerebral serotonin related to anxiety-like behaviors in C57bl/6 offspring induced by repeated subcutaneous prenatal exposure to low-dose lipopolysaccharide. PLoS ONE 12, e0179970 (2017).
O’Loughlin, E., Pakan, J. M. P., Yilmazer-Hanke, D. & McDermott, K. W. Acute in utero exposure to lipopolysaccharide induces inflammation in the pre- and postnatal brain and alters the glial cytoarchitecture in the developing amygdala. J. Neuroinflammation 14, 212 (2017).
Hu, X. et al. Microglia/macrophage polarization dynamics reveal novel mechanism of injury expansion after focal cerebral ischemia. Stroke 43, 3063–3070 (2012).
Thored, P. et al. Long-term accumulation of microglia with proneurogenic phenotype concomitant with persistent neurogenesis in adult subventricular zone after stroke. Glia 57, 835–849 (2009).
Ohgidani, M. et al. Microglial Cd206 gene has potential as a state marker of bipolar disorder. Front. Immunol. 7, 676 (2016).
Grajchen, E. et al. Cd36-mediated uptake of myelin debris by macrophages and microglia reduces neuroinflammation. J. Neuroinflammation 17, 224 (2020).
Hendrickx, D. A. et al. Selective upregulation of scavenger receptors in and around demyelinating areas in multiple sclerosis. J. Neuropathol. Exp. Neurol. 72, 106–118 (2013).
Xie, Y. et al. Biglycan regulates neuroinflammation by promoting M1 microglial activation in early brain injury after experimental subarachnoid hemorrhage. J. Neurochem 152, 368–380 (2020).
Duan, W., Zou, J., Chen, X., Xiao, C. & Jiang, W. Biglycan expression promotes beta-amyloid-induced microglial activation via TLR2 in mouse cell culture model. Clin. Lab. https://doi.org/10.7754/Clin.Lab.2020.200252 (2021).
Li, Y. et al. Osteopontin is a blood biomarker for microglial activation and brain injury in experimental hypoxic-ischemic encephalopathy. eNeuro https://doi.org/10.1523/ENEURO.0253-16.2016 (2017).
Rentsendorj, A. et al. A novel role for osteopontin in macrophage-mediated amyloid-beta clearance in Alzheimer’s models. Brain Behav. Immun. 67, 163–180 (2018).
De Simone, R. et al. The costimulatory molecule B7 is expressed on human microglia in culture and in multiple sclerosis acute lesions. J. Neuropathol. Exp. Neurol. 54, 175–187 (1995).
Wong, H. & Hoeffer, C. Maternal IL-17a in autism. Exp. Neurol. 299, 228–240 (2018).
Choi, G. B. et al. The maternal interleukin-17a pathway in mice promotes autism-like phenotypes in offspring. Science 351, 933–939 (2016).
Pang, Y. et al. Early postnatal lipopolysaccharide exposure leads to enhanced neurogenesis and impaired communicative functions in rats. PLoS ONE 11, e0164403 (2016).
Garay, P. A., Hsiao, E. Y., Patterson, P. H. & McAllister, A. K. Maternal immune activation causes age- and region-specific changes in brain cytokines in offspring throughout development. Brain Behav. Immun. 31, 54–68 (2013).
Gupta, S. et al. Transcriptome analysis reveals dysregulation of innate immune response genes and neuronal activity-dependent genes in autism. Nat. Commun. 5, 5748 (2014).
Estes, M. L. & McAllister, A. K. Immune mediators in the brain and peripheral tissues in autism spectrum disorder. Nat. Rev. Neurosci. 16, 469–486 (2015).
Cui, K., Ashdown, H., Luheshi, G. N. & Boksa, P. Effects of prenatal immune activation on hippocampal neurogenesis in the rat. Schizophr. Res. 113, 288–297 (2009).
Hester, M. S., Tulina, N., Brown, A., Barila, G. & Elovitz, M. A. Intrauterine inflammation reduces postnatal neurogenesis in the hippocampal subgranular zone and leads to accumulation of hilar ectopic granule cells. Brain Res. 1685, 51–59 (2018).
Lin, Y. L. & Wang, S. Prenatal lipopolysaccharide exposure increases depression-like behaviors and reduces hippocampal neurogenesis in adult rats. Behav. Brain Res. 259, 24–34 (2014).
Depino, A. M. Early prenatal exposure to lps results in anxiety- and depression-related behaviors in adulthood. Neuroscience 299, 56–65 (2015).
Tsukada, T., Sakata-Haga, H., Shimada, H., Shoji, H. & Hatta, T. Mid-pregnancy maternal immune activation increases Pax6-positive and Tbr2-positive neural progenitor cells and causes integrated stress response in the fetal brain in a mouse model of maternal viral infection. IBRO Neurosci. Rep. 11, 73–80 (2021).
Cherry, J. D., Olschowka, J. A. & O’Banion, M. K. Neuroinflammation and M2 microglia: the good, the bad, and the inflamed. J. Neuroinflammation 11, 98 (2014).
Hu, X. et al. Microglial and macrophage polarization-new prospects for brain repair. Nat. Rev. Neurol. 11, 56–64 (2015).
Ribeiro Xavier, A. L., Kress, B. T., Goldman, S. A., Lacerda de Menezes, J. R. & Nedergaard, M. A distinct population of microglia supports adult neurogenesis in the subventricular zone. J. Neurosci. 35, 11848–11861 (2015).
Wischhof, L., Irrsack, E., Osorio, C. & Koch, M. Prenatal LPS-exposure–a neurodevelopmental rat model of schizophrenia–differentially affects cognitive functions, myelination and parvalbumin expression in male and female offspring. Prog. Neuropsychopharmacol. Biol. Psychiatry 57, 17–30 (2015).
Basta-Kaim, A. et al. Prenatal administration of lipopolysaccharide induces sex-dependent changes in glutamic acid decarboxylase and parvalbumin in the adult rat brain. Neuroscience 287, 78–92 (2015).
Giovanoli, S., Weber, L. & Meyer, U. Single and combined effects of prenatal immune activation and peripubertal stress on Parvalbumin and Reelin expression in the hippocampal formation. Brain Behav. Immun. 40, 48–54 (2014).
Harvey, L. & Boksa, P. A stereological comparison of Gad67 and Reelin expression in the hippocampal stratum oriens of offspring from two mouse models of maternal inflammation during pregnancy. Neuropharmacology 62, 1767–1776 (2012).
Acknowledgements
Flow cytometry experiments were performed at the UMMC Cancer Center and Research Institute Flow Cytometry Core Facility, which is supported in part through the UMMC Mississippi Center of Excellence in Perinatal Research (MS-CEPR)-COBRE (P20GM121334). We would like to thank Dr. Ava Bengten, Dr. Melanie Wilson, and Dr. Jon Person for their advice and technical assistance in FACS experiments. Research reported in this publication was supported by the National Institute of General Medical Sciences of the National Institutes of Health under Award Number P20GM121334. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Author information
Authors and Affiliations
Contributions
Y.P. and A.B. conceived the study. M.L., A.B., and Y.P. contributed to the study design and drafted the manuscript. M.L., S.L., K.C., S.R., and Y.P. performed experiments. M.L., N.O., L.-W.F., and Y.P. contributed to data analysis.
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing interests.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Rights and permissions
Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Loayza, M., Lin, S., Carter, K. et al. Maternal immune activation alters fetal and neonatal microglia phenotype and disrupts neurogenesis in mice. Pediatr Res 93, 1216–1225 (2023). https://doi.org/10.1038/s41390-022-02239-w
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41390-022-02239-w