Monocytic infiltrates contribute to autistic-like behaviors in a two-hit model of neurodevelopmental defects

• Type of Material: Article
• Authors: Hong-Ru Chen, University of Virginia School of Medicine; Ching-Wen Chen, University of Virginia School of Medicine; Nandita Mandhani, Emory University School of Medicine; Jonah C Short-Miller, University of Virginia School of Medicine; Marchelle R Smucker, University of Virginia School of Medicine; Yu-Yo Sun, Emory University; Chia-Yi Kuan, Emory University
• Language: English
• Date: 2020-12-02
• Publisher: Emory University Libraries
• Publication Version: Final Published Version
• Copyright Statement: © 2020 the authors
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1523/JNEUROSCI.1171-20.2020
• Title of Journal or Parent Work: Journal of Neuroscience
• Volume: 40
• Issue: 49
• Start Page: 9386
• End Page: 9400
• Grant/Funding Information: This work was supported by the National Institute of Health Grants NS095064, NS100419, and NS108763 to C.-Y.K. and NS106592 to Y.-Y.S., and American Heart Association Postdoctoral Fellowship 18POST34080334 to H.-R.C.
• Keywords: Autistic Disorder; Male; autism; maternal immune activation; Macrophage Activation; Developmental Disabilities; neurodevelopmental defects; Post-Synaptic Density; Mice, Inbred C57BL; Social Behavior; NF-kappa B; Parvalbumins; Mice; Monocytes; Female; Animals; monocytes; Microglia; Signal Transduction; Poly I-C; Pregnancy; neuroimmune interactions; Behavior, Animal; hypoxia ischemia; Brain Ischemia
• Research Categories: Health Sciences, Immunology; Health Sciences, Medicine and Surgery

Abstract

Growing evidence suggests that early-life interactions among genetic, immune, and environment factors may modulate neurodevelopment and cause psycho-cognitive deficits. Maternal immune activation (MIA) induces autism-like behaviors in offspring, but how it interplays with perinatal brain injury (especially birth asphyxia or hypoxia ischemia [HI]) is unclear. Herein we compared the effects of MIA (injection of poly[I:C] to dam at gestational day 12.5), HI at postnatal day 10, and the combined MIA/HI insult in murine offspring of both sexes. We found that MIA induced autistic-like behaviors without microglial activation but amplified post-HI NFjB signaling, pro-inflammatory responses, and brain injury in offspring. Conversely, HI neither provoked autistic-like behaviors nor concealed them in the MIA offspring. Instead, the dual MIA/HI insult added autistic-like behaviors with diminished synaptic density and reduction of autism-related PSD-95 and Homer-1 in the hippocampus, which were missing in the singular MIA or HI insult. Further, the dual MIA/HI insult enhanced the brain influx of Otx2-positive monocytes that are associated with an increase of perineuronal net-enwrapped parvalbumin neurons. Using CCR2-CreER mice to distinguish monocytes from the resident microglia, we found that the monocytic infiltrates gradually adopted a ramified morphology and expressed the microglial signature genes (Tmem119, P2RY12, and Sall1) in post-MIA/HI brains, with some continuing to express the proinflammatory cytokine TNFa. Finally, genetic or pharmacological obstruction of monocytic influx significantly reduced perineuronal net-enwrapped parvalbumin neurons and autistic-like behaviors in MIA/HI offspring. Together, these results suggest a pathologic role of monocytes in the two-hit (immune plus neonatal HI) model of neurodevelopmental defects.