Format

Send to

Choose Destination
Neurobiol Dis. 2019 May;125:1-13. doi: 10.1016/j.nbd.2019.01.005. Epub 2019 Jan 17.

Maternal immune activation-induced PPARγ-dependent dysfunction of microglia associated with neurogenic impairment and aberrant postnatal behaviors in offspring.

Author information

1
School of Life Science and Technology, Center for Informational Biology, University of Electronic Science and Technology of China, Chengdu, Sichuan 610054, China.
2
Department of Histology and Embryology, School of Basic Medical Sciences, Southwest Medical University, Luzhou, Sichuan 646000, China.
3
Graduate Program in Neuroscience, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
4
School of Life Science and Technology, Center for Informational Biology, University of Electronic Science and Technology of China, Chengdu, Sichuan 610054, China; Department of Histology and Embryology, School of Basic Medical Sciences, Southwest Medical University, Luzhou, Sichuan 646000, China. Electronic address: youzili@uestc.edu.cn.

Abstract

Maternal infection during pregnancy is an important factor involved in the pathogenesis of brain disorders in the offspring. Mounting evidence from maternal immune activation (MIA) animals indicates that microglial priming may contribute to neurodevelopmental abnormalities in the offspring. Because peroxisome proliferator-activated receptor gamma (PPARγ) activation exerts neuroprotective effects by regulating neuroinflammatory response, it is a pharmacological target for treating neurogenic disorders. We investigated the effect of PPARγ-dependent microglial activation on neurogenesis and consequent behavioral outcomes in male MIA-offspring. Pregnant dams on gestation day 18 received Poly(I:C) (1, 5, or 10 mg/kg; i.p.) or the vehicle. The MIA model that received 10 mg/kg Poly(I:C) showed significantly increased inflammatory responses in the maternal serum and fetal hippocampus, followed by cognitive deficits, which were highly correlated with hippocampal neurogenesis impairment in prepubertal male offspring. The microglial population in hippocampus increased, displayed decreased processes and larger soma, and had a higher expression of the CD11b, which is indicative of the M1 phenotype (classical activation). Activation of the PPARγ pathway by pioglitazone in the MIA offspring rescued the imbalance of the microglial activation and ameliorated the MIA-induced suppressed neurogenesis and cognitive impairments and anxiety behaviors. In an in vitro experiment, PPARγ-induced M2 microglia (alternative activation) promoted the proliferation and differentiation of neural precursor cells. These results indicated that the MIA-induced long-term changes in microglia phenotypes were associated with hippocampal neurogenesis and neurobehavioral abnormalities in offspring. Modulation of the microglial phenotypes was associated with a PPARγ-mediated neuroprotective mechanism in the MIA offspring and may serve as a potential therapeutic approach for prenatal immune activation-induced neuropsychiatric disorders.

KEYWORDS:

Maternal immune activation; Microglia activation; Neurogenesis; Offspring; PPARγ

PMID:
30659984
DOI:
10.1016/j.nbd.2019.01.005

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center