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Updated: May 22, 2025
Induction of Maternal Immune Activation in Mice at Mid-gestation Stage with Viral Mimic PolyI:C
Published on: March 25, 2016
IFN-γ signaling links ventriculomegaly to choroid plexus and ependyma dysfunction following maternal immune
Yu-Qin Sun1, Xin-Xin Huang1,2, Wei Guo1
1Neuroprotective Drug Discovery Key Laboratory, Jiangsu Key Laboratory of Neurodegeneration, State key laboratory of reproductive medicine and offspring health, Nanjing Medical University, Nanjing, Jiangsu, 211166, China.
Insights
Maternal immune activation (MIA) causes ventriculomegaly in offspring by enhancing interferon-gamma (IFN-γ) signaling, impacting brain development and autism spectrum disorder (ASD) risk. Blocking IFN-γ signaling mitigates these effects.
Area of Science:
- Neuroscience
- Developmental Biology
- Immunology
Background:
- Maternal immune activation (MIA) is a significant environmental risk factor for autism spectrum disorder (ASD).
- MIA is linked to abnormal fetal brain development and neurological conditions in offspring.
Purpose of the Study:
- To investigate the mechanisms by which MIA affects offspring brain development, specifically focusing on ventriculomegaly.
- To identify the role of interferon-gamma (IFN-γ) signaling in MIA-induced developmental abnormalities.
Main Methods:
- Utilized poly (I:C) injection to induce MIA in pregnant dams.
- Assessed offspring for ventriculomegaly, choroid plexus (Chp) and ependymal cell dysfunction.
- Measured IFN-γ signaling pathways and macrophage activation in MIA offspring.
- Administered IFNGR-blocking antibodies and exogenous IFN-γ to dams to evaluate therapeutic and causative effects.
Main Results:
- MIA induced ventriculomegaly in offspring, linked to Chp and ependymal cell dysfunction.
- Sustained elevation of IFN-γ signaling was observed in the brain and serum of MIA offspring.
- IFN-γ signaling disrupted Chp barrier function and suppressed ependymal cell differentiation via STAT1/3 pathways.
- IFNGR-blocking antibody treatment mitigated MIA effects, while maternal IFN-γ administration mimicked MIA.
Conclusions:
- IFN-γ signaling is a key mediator of MIA-induced ventriculomegaly and subsequent compromised fetal brain development in ASD models.
- This study provides a mechanistic link between maternal inflammation, IFN-γ signaling, and abnormal ventricular development in offspring.
- Targeting IFN-γ signaling presents a potential therapeutic strategy for mitigating MIA-associated neurodevelopmental risks.
Abstract:
Maternal immune activation (MIA) is a principal environmental risk factor contributing to autism spectrum disorder (ASD) and can be causally linked to ASD symptoms. In our study, we found that MIA triggered by poly (I: C) injection caused ventriculomegaly in offspring due to the dysfunction of the choroid plexus (Chp) and ependyma. We subsequently identified a sustained enhancement of interferon-γ (IFN-γ) signaling in the brain and serum of MIA offspring. Further study revealed that increased IFN-γ signaling could disrupt the barrier function of Chp epithelial cells by activating macrophages, and suppress the differentiation of primary ependymal cells via the signal transducer and activator of transcription 1/3 signaling. The effects of MIA on the offspring were mitigated by administration of IFNGR-blocking antibody in pregnant dams, while systemic maternal administration of IFN-γ was sufficient to mimic the effect of MIA. Overall, our findings revealed that ventriculomegaly caused by IFN-γ signaling could be a critical factor in compromising fetal brain development in MIA-induced ASD and provide a mechanistic framework for the association between maternal inflammation and abnormal development of ventricles in the offspring.
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