Neurobiol Dis. 2019 May;125:1-13. doi: 10.1016/j.nbd.2019.01.005.

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

Zhao Q1, Wang Q2, Wang J1, Tang M1, Huang S1, Peng K2, Han Y1, Zhang J1, Liu G2, Fang Q3, You Z4.
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. Copyright © 2019 Elsevier Inc.

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

PMID:  30659984

 

Supplement:

Maternal infection during pregnancy contributes to neurodevelopmental abnormalities, which are associated with an increased frequency of cognitive deficits in the offspring (Estes and McAllister 2016). Since the innate immune system has important functions in brain development, it has been hypothesized that their abnormal activation can lead to a variety of central nervous system disorders (Salter and Stevens 2017; Tiwari and Pal 2017). In particular, microglia, as the immune cells of the central nervous system, have been proposed to contribute to the pathogenesis of neurodevelopmental disorders (Hanamsagar and Bilbo 2017). Several studies suggest that peroxisome proliferator-activated receptor gamma (PPARγ), a ligand-dependent transcription factor of the nuclear hormone receptor family, mediates immune inflammatory responses and induces monocyte and microglia activation (Bouhlel, Derudas et al. 2007; Zhao, Sun et al. 2007). In this mouse study, we investigated whether targeting PPARγ could mitigate neurodevelopmental and neurobehavioral problems in offspring exposed to maternal immune activation (MIA).

MIA was induced by a single viral-mimetic intraperitoneal injection of polyriboinosinic-polyribocytidilic acid (polyI:C, 10 mg/kg) on embryonic day 18. MIA increased inflammatory responses in the maternal serum and fetal hippocampus at 12 h post-injection. MIA-induced abnormal postnatal behaviors strongly correlated with neurogenesis impairment in the hippocampus. Hippocampal microglia in MIA offspring were more dense than in control offspring and exhibited a classical M1 activated phenotype. Prepubertal MIA offspring showed impaired spatial learning and memory and elevated anxiety-like behaviors. Injecting prepubertal MIA offspring with the commercial PPARγ agonist pioglitazone reduced microglia density and caused a switch towards the M2 activated phenotype. These changes were associated with improvements in hippocampus-dependent spatial learning, memory, anxiety-like behaviors and neurogenesis.

In order to understand the role of microglia-derived PPARγ in neurogenesis, cultures of neural precursor cells (NPCs) with microglial conditioned medium were incubated ex vivo. PolyI:C-treated microglial cells exhibited an M1 phenotype and switched to the M2 phenotype after piogliotazone incubation. GW9662-treated cells maintained their M1 phenotype. Treating NPCs cultures with conditioned medium from microglia incubated with polyI:C and/or GW9662 reduced neurogenesis, and this effect was reversed by incubating the cultures with conditioned medium from microglia treated with pioglitazone. These results show that PPARγ-mediated activation of M2 microglia stimulates neurogenesis (Figure 1).

Our results suggest the following model (Figure 1). MIA markedly reduces PPARγ expression in the hippocampus of offspring, which drives microglia to adopt an M1 phenotype. A PPARγ agonist can reprogram the microglia to switch from an M1 to M2 phenotype, helping to ameliorate neurodevelopmental and cognitive disorders.

 

 

Figure 1. The beneficial effect of proliferator-activated receptor gamma (PPARγ) activation on the neurodevelopment of offspring exposed to maternal immune activation. Maternal immune activation during pregnancy induces resting microglia to adopt an M1 phenotype, impairing hippocampal neurogenesis. This contributes to neurobehavioral abnormalities in the offspring. Pioglitazone activates PPARγ and switches microglial phenotype from M1 to M2, which increases hippocampal neurogenesis and mitigates neurobehavioral abnormalities.

 

 

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