Pioglitazone alleviates maternal sleep deprivation-induced cognitive deficits in male rat offspring by enhancing microglia-mediated neurogenesis.

Maternal sleep disturbance in pregnancy causes cognitive impairments and emotional disorders in offspring. Microglia-mediated inflammatory processes contribute to prenatal stress-induced neurodevelopmental deficits. Peroxisome proliferator-activated receptor gamma (PPARγ) activation underlies the switching of microglial activation phenotypes, which has emerged as a pharmacological target for regulating neuroinflammatory responses in the treatment of neuropsychiatric disorders. Here we investigated the effects of PPARγ-dependent microglial activation on neurogenesis and cognitive behavioral outcomes in male rat offspring exposed to maternal sleep deprivation (MSD) for 72 h from days 18-21 of pregnancy. In the Morris water maze test, male MSD rat offspring needed more time than control offspring to escape to the hidden platform and spent less time in the target quadrant when the hidden platform was removed. In MSD rat offspring, microglial density as determined by immunofluorescence was higher, microglia showed fewer and shorter processes, and neurogenesis in the hippocampus was significantly reduced. Levels of mRNA encoding pro-inflammatory markers IL-6, TNFα, and IL-1ß were higher in male MSD offspring, whereas levels of anti-inflammatory markers Arg1, IL-4, and IL-10 were lower, as was PPARγ expression in the hippocampus. PPARγ activation by pioglitazone (30 mg/kg/day, i.p., 7 d) mitigated these negative effects of MSD, rescuing hippocampal neurogenesis and improving cognitive function. The PPARγ inhibitor GW9662 (1 mg/kg/day, i.p., 7 d) eliminated the effects of pioglitazone. Conditioned medium from pioglitazone-treated microglia promoted proliferation and differentiation of neural progenitor cells. These results suggest that MSD-induced deficits in spatial learning and memory can be ameliorated through PPARγ-dependent modulation of microglial phenotypes.

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

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.