Skip to main content

Umbrella menu

  • SfN.org
  • eNeuro
  • The Journal of Neuroscience
  • Neuronline
  • BrainFacts.org

Main menu

  • HOME
  • CONTENT
    • Early Release
    • Featured
    • Current Issue
    • Issue Archive
    • Collections
  • ALERTS
  • FOR AUTHORS
    • Preparing a Manuscript
    • Submission Guidelines
    • Fees
    • Journal Club
    • eLetters
    • Submit
  • EDITORIAL BOARD
  • ABOUT
    • Overview
    • Advertise
    • For the Media
    • Rights and Permissions
    • Privacy Policy
    • Feedback
  • SUBSCRIBE
  • SfN.org
  • eNeuro
  • The Journal of Neuroscience
  • Neuronline
  • BrainFacts.org

User menu

  • Log in
  • Subscribe
  • My alerts
  • My Cart

Search

  • Advanced search
Journal of Neuroscience
  • Log in
  • Subscribe
  • My alerts
  • My Cart
Journal of Neuroscience

Advanced Search

Submit a Manuscript
  • HOME
  • CONTENT
    • Early Release
    • Featured
    • Current Issue
    • Issue Archive
    • Collections
  • ALERTS
  • FOR AUTHORS
    • Preparing a Manuscript
    • Submission Guidelines
    • Fees
    • Journal Club
    • eLetters
    • Submit
  • EDITORIAL BOARD
  • ABOUT
    • Overview
    • Advertise
    • For the Media
    • Rights and Permissions
    • Privacy Policy
    • Feedback
  • SUBSCRIBE
PreviousNext
Research Articles, Development/Plasticity/Repair

Monocytic Infiltrates Contribute to Autistic-like Behaviors in a Two-Hit Model of Neurodevelopmental Defects

Hong-Ru Chen, Ching-Wen Chen, Nandita Mandhani, Jonah C. Short-Miller, Marchelle R. Smucker, Yu-Yo Sun and Chia-Yi Kuan
Journal of Neuroscience 2 December 2020, 40 (49) 9386-9400; DOI: https://doi.org/10.1523/JNEUROSCI.1171-20.2020
Hong-Ru Chen
1Department of Neuroscience, Center for Brain Immunology and Glia, University of Virginia School of Medicine, Charlottesville, Virginia 22908
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ching-Wen Chen
1Department of Neuroscience, Center for Brain Immunology and Glia, University of Virginia School of Medicine, Charlottesville, Virginia 22908
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Nandita Mandhani
2Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia 30322
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jonah C. Short-Miller
1Department of Neuroscience, Center for Brain Immunology and Glia, University of Virginia School of Medicine, Charlottesville, Virginia 22908
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Marchelle R. Smucker
1Department of Neuroscience, Center for Brain Immunology and Glia, University of Virginia School of Medicine, Charlottesville, Virginia 22908
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Yu-Yo Sun
1Department of Neuroscience, Center for Brain Immunology and Glia, University of Virginia School of Medicine, Charlottesville, Virginia 22908
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Chia-Yi Kuan
1Department of Neuroscience, Center for Brain Immunology and Glia, University of Virginia School of Medicine, Charlottesville, Virginia 22908
2Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia 30322
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF
Loading

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 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.

  • autism
  • hypoxia ischemia
  • maternal immune activation
  • monocytes
  • neurodevelopmental defects
  • neuroimmune interactions

SfN exclusive license.

View Full Text

Member Log In

Log in using your username and password

Enter your Journal of Neuroscience username.
Enter the password that accompanies your username.
Forgot your user name or password?

Purchase access

You may purchase access to this article. This will require you to create an account if you don't already have one.
Back to top

In this issue

The Journal of Neuroscience: 40 (49)
Journal of Neuroscience
Vol. 40, Issue 49
2 Dec 2020
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by author
  • Advertising (PDF)
  • Ed Board (PDF)
Email

Thank you for sharing this Journal of Neuroscience article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
Monocytic Infiltrates Contribute to Autistic-like Behaviors in a Two-Hit Model of Neurodevelopmental Defects
(Your Name) has forwarded a page to you from Journal of Neuroscience
(Your Name) thought you would be interested in this article in Journal of Neuroscience.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Print
View Full Page PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Citation Tools
Monocytic Infiltrates Contribute to Autistic-like Behaviors in a Two-Hit Model of Neurodevelopmental Defects
Hong-Ru Chen, Ching-Wen Chen, Nandita Mandhani, Jonah C. Short-Miller, Marchelle R. Smucker, Yu-Yo Sun, Chia-Yi Kuan
Journal of Neuroscience 2 December 2020, 40 (49) 9386-9400; DOI: 10.1523/JNEUROSCI.1171-20.2020

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Respond to this article
Request Permissions
Share
Monocytic Infiltrates Contribute to Autistic-like Behaviors in a Two-Hit Model of Neurodevelopmental Defects
Hong-Ru Chen, Ching-Wen Chen, Nandita Mandhani, Jonah C. Short-Miller, Marchelle R. Smucker, Yu-Yo Sun, Chia-Yi Kuan
Journal of Neuroscience 2 December 2020, 40 (49) 9386-9400; DOI: 10.1523/JNEUROSCI.1171-20.2020
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Introduction
    • Materials and Methods
    • Results
    • Discussion
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Keywords

  • autism
  • hypoxia ischemia
  • maternal immune activation
  • monocytes
  • neurodevelopmental defects
  • neuroimmune interactions

Responses to this article

Respond to this article

Jump to comment:

No eLetters have been published for this article.

Related Articles

Cited By...

More in this TOC Section

Research Articles

  • The phosphoprotein Synapsin Ia regulates the kinetics of dense-core vesicle release
  • Tuba Activates Cdc42 during Neuronal Polarization Downstream of the Small GTPase Rab8a
  • Frontotemporal Regulation of Subjective Value to Suppress Impulsivity in Intertemporal Choices
Show more Research Articles

Development/Plasticity/Repair

  • The Wnt Effector TCF7l2 Promotes Oligodendroglial Differentiation by Repressing Autocrine BMP4-Mediated Signaling
  • Loss of coiled-coil protein Cep55 impairs neural stem cell abscission and results in p53-dependent apoptosis in developing cortex
  • Evidence for Subcortical Plasticity after Paired Stimulation from a Wearable Device
Show more Development/Plasticity/Repair
  • Home
  • Alerts
  • Visit Society for Neuroscience on Facebook
  • Follow Society for Neuroscience on Twitter
  • Follow Society for Neuroscience on LinkedIn
  • Visit Society for Neuroscience on Youtube
  • Follow our RSS feeds

Content

  • Early Release
  • Current Issue
  • Issue Archive
  • Collections

Information

  • For Authors
  • For Advertisers
  • For the Media
  • For Subscribers

About

  • About the Journal
  • Editorial Board
  • Privacy Policy
  • Contact
  • Feedback
(JNeurosci logo)
(SfN logo)

Copyright © 2021 by the Society for Neuroscience.
JNeurosci Online ISSN: 1529-2401

The ideas and opinions expressed in JNeurosci do not necessarily reflect those of SfN or the JNeurosci Editorial Board. Publication of an advertisement or other product mention in JNeurosci should not be construed as an endorsement of the manufacturer’s claims. SfN does not assume any responsibility for any injury and/or damage to persons or property arising from or related to any use of any material contained in JNeurosci.