Abstract
Maternal immune activation (MIA) disrupts the central innate immune system during a critical neurodevelopmental period. Microglia are primary innate immune cells in the brain although their direct influence on the MIA phenotype is largely unknown. Here we show that MIA alters microglial gene expression with upregulation of cellular protrusion/neuritogenic pathways, concurrently causing repetitive behavior, social deficits, and synaptic dysfunction to layer V intrinsically bursting pyramidal neurons in the prefrontal cortex of mice. MIA increases plastic dendritic spines of the intrinsically bursting neurons and their interaction with hyper-ramified microglia. Treating MIA offspring by colony stimulating factor 1 receptor inhibitors induces depletion and repopulation of microglia, and corrects protein expression of the newly identified MIA-associated neuritogenic molecules in microglia, which coalesces with correction of MIA-associated synaptic, neurophysiological, and behavioral abnormalities. Our study demonstrates that maternal immune insults perturb microglial phenotypes and influence neuronal functions throughout adulthood, and reveals a potent effect of colony stimulating factor 1 receptor inhibitors on the correction of MIA-associated microglial, synaptic, and neurobehavioral dysfunctions.
Highlights
These authors contributed : Seiko Ikezu, Hana Yeh, Jean-Christophe Delpech, Maya E
In order to determine the effect of PLX on microglia, we evaluated microglial number of male offspring by immunohistochemistry against phagocyte marker ionized calcium biding adapter molecule 1 (IBA1) in the medial prefrontal cortex, the area implicated in aberrant neuronal circuitry and synchrony in main factors being poly(I:C) (MIA) [21] (Fig. 1b)
MIA increased microglial density in the medial prefrontal cortex (mPFC) compared with CTRL offspring at P42, which was not observed at P60 (Fig. 1c), suggesting the transient increase of microglia by MIA, which is in line with the previous studies [22, 23]
Summary
These authors contributed : Seiko Ikezu, Hana Yeh, Jean-Christophe Delpech, Maya E. Microglial transcriptome analyses revealed that poly(I:C) injected MIA offspring showed shifting of early microglia to more developmental stage at P1 [10] or reduced expression of sensome molecules related to phagocytosis at P120, which was prevented by the administration of minocycline, an anti-inflammatory drug [13]. Those results indicate that early immune insults may change the course of microglial development and phenotype, thereby dysregulate their physiological function to support neuronal development and plasticity. CSF1R inhibitor treatment corrected microglial phenotypic changes and aberrant interactions with neurons, accompanied by normalized synaptic properties and spine morphologies
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