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http://purl.uniprot.org/citations/33127853http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/33127853http://www.w3.org/2000/01/rdf-schema#comment"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 NFκB 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 TNFα. 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.SIGNIFICANCE STATEMENT In autism spectrum disorders (ASDs), prenatal infection or maternal immune activation (MIA) may act as a primer for multiple genetic and environmental factors to impair neurodevelopment. This study examined whether MIA cooperates with neonatal cerebral hypoxia ischemia to promote ASD-like aberrations in mice using a novel two-hit model. It was shown that the combination of MIA and neonatal hypoxia ischemia produces autistic-like behaviors in the offspring, and has synergistic effects in inducing neuroinflammation, monocytic infiltrates, synaptic defects, and perineuronal nets. Furthermore, genetic or pharmacological intervention of the MCP1-CCR2 chemoattractant pathway markedly reduced monocytic infiltrates, perineuronal nets, and autistic-like behaviors. These results suggest reciprocal escalation of immune and neonatal brain injury in a subset of ASD that may benefit from monocyte-targeted treatments."xsd:string
http://purl.uniprot.org/citations/33127853http://purl.org/dc/terms/identifier"doi:10.1523/jneurosci.1171-20.2020"xsd:string
http://purl.uniprot.org/citations/33127853http://purl.uniprot.org/core/author"Chen C.W."xsd:string
http://purl.uniprot.org/citations/33127853http://purl.uniprot.org/core/author"Chen H.R."xsd:string
http://purl.uniprot.org/citations/33127853http://purl.uniprot.org/core/author"Kuan C.Y."xsd:string
http://purl.uniprot.org/citations/33127853http://purl.uniprot.org/core/author"Sun Y.Y."xsd:string
http://purl.uniprot.org/citations/33127853http://purl.uniprot.org/core/author"Short-Miller J.C."xsd:string
http://purl.uniprot.org/citations/33127853http://purl.uniprot.org/core/author"Smucker M.R."xsd:string
http://purl.uniprot.org/citations/33127853http://purl.uniprot.org/core/author"Mandhani N."xsd:string
http://purl.uniprot.org/citations/33127853http://purl.uniprot.org/core/date"2020"xsd:gYear
http://purl.uniprot.org/citations/33127853http://purl.uniprot.org/core/name"J Neurosci"xsd:string
http://purl.uniprot.org/citations/33127853http://purl.uniprot.org/core/pages"9386-9400"xsd:string
http://purl.uniprot.org/citations/33127853http://purl.uniprot.org/core/title"Monocytic Infiltrates Contribute to Autistic-like Behaviors in a Two-Hit Model of Neurodevelopmental Defects."xsd:string
http://purl.uniprot.org/citations/33127853http://purl.uniprot.org/core/volume"40"xsd:string
http://purl.uniprot.org/citations/33127853http://www.w3.org/2004/02/skos/core#exactMatchhttp://purl.uniprot.org/pubmed/33127853
http://purl.uniprot.org/citations/33127853http://xmlns.com/foaf/0.1/primaryTopicOfhttps://pubmed.ncbi.nlm.nih.gov/33127853
http://purl.uniprot.org/uniprot/#_P51683-mappedCitation-33127853http://www.w3.org/1999/02/22-rdf-syntax-ns#objecthttp://purl.uniprot.org/citations/33127853
http://purl.uniprot.org/uniprot/#_Q8BR50-mappedCitation-33127853http://www.w3.org/1999/02/22-rdf-syntax-ns#objecthttp://purl.uniprot.org/citations/33127853
http://purl.uniprot.org/uniprot/#_Q3TRK1-mappedCitation-33127853http://www.w3.org/1999/02/22-rdf-syntax-ns#objecthttp://purl.uniprot.org/citations/33127853
http://purl.uniprot.org/uniprot/#_Q543X3-mappedCitation-33127853http://www.w3.org/1999/02/22-rdf-syntax-ns#objecthttp://purl.uniprot.org/citations/33127853
http://purl.uniprot.org/uniprot/#_Q8CBJ0-mappedCitation-33127853http://www.w3.org/1999/02/22-rdf-syntax-ns#objecthttp://purl.uniprot.org/citations/33127853
http://purl.uniprot.org/uniprot/#_Q3U3U0-mappedCitation-33127853http://www.w3.org/1999/02/22-rdf-syntax-ns#objecthttp://purl.uniprot.org/citations/33127853
http://purl.uniprot.org/uniprot/#_Q543S8-mappedCitation-33127853http://www.w3.org/1999/02/22-rdf-syntax-ns#objecthttp://purl.uniprot.org/citations/33127853
http://purl.uniprot.org/uniprot/#_Q9Z0D9-mappedCitation-33127853http://www.w3.org/1999/02/22-rdf-syntax-ns#objecthttp://purl.uniprot.org/citations/33127853
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