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Inhibition of colony stimulating factor 1 receptor corrects maternal inflammation-induced microglial and synaptic dysfunction and behavioral abnormalities.

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.

SUBMITTER: Ikezu S

PROVIDER: S-EPMC7431382 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Inhibition of colony stimulating factor 1 receptor corrects maternal inflammation-induced microglial and synaptic dysfunction and behavioral abnormalities.

Ikezu Seiko S Yeh Hana H Delpech Jean-Christophe JC Woodbury Maya E ME Van Enoo Alicia A AA Ruan Zhi Z Sivakumaran Sudhir S You Yang Y Holland Carl C Guillamon-Vivancos Teresa T Yoshii-Kitahara Asuka A Botros Mina B MB Madore Charlotte C Chao Pin-Hao PH Desani Ankita A Manimaran Solaiappan S Kalavai Srinidhi Venkatesan SV Johnson W Evan WE Butovsky Oleg O Medalla Maria M Luebke Jennifer I JI Ikezu Tsuneya T

Molecular psychiatry 20200218 6

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 neur ...[more]

PMID: 32071385

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Project description:Endotoxin tolerance (ET) is a reduced responsiveness of innate immune cells like macrophages/monocytes to an endotoxin challenge following a previous encounter with the endotoxin. Although ET in peripheral systems has been well studied, little is known about ET in the brain. The present study showed that brain immune cells, microglia, being different from peripheral macrophages, displayed non-cell autonomous mechanisms in ET formation. Specifically, neurons and astroglia were indispensable for microglial ET. Macrophage colony-stimulating factor (M-CSF) secreted from these non-immune cells was essential for governing microglial ET. Neutralization of M-CSF deprived the neuron-glia conditioned medium of its ability to enable microglia to form ET when microglia encountered two lipopolysaccharide (LPS) treatments. Recombinant M-CSF protein rendered enriched microglia refractory to the second LPS challenge leading to microglial ET. Activation of microglial M-CSF receptor (M-CSFR; also known as CSF1R) and the downstream ERK1/2 signals was responsible for M-CSF-mediated microglial ET. Endotoxin-tolerant microglia in neuron-glia cultures displayed M2-like polarized phenotypes, as shown by upregulation of M2 marker Arg-1, elevated production of anti-inflammatory cytokine interleukin 10, and decreased secretion of pro-inflammatory mediators (tumor necrosis factor α, nitric oxide, prostaglandin E2 and interleukin 1β). Endotoxin-tolerant microglia protected neurons against LPS-elicited inflammatory insults, as shown by reduced neuronal damages in LPS pre-treatment group compared with the group without LPS pre-treatment. Moreover, while neurons and astroglia became injured during chronic neuroinflammation, microglia failed to form ET. Thus, this study identified a distinct non-cell autonomous mechanism of microglial ET. Interactions of M-CSF secreted by neurons and astroglia with microglial M-CSFR programed microglial ET. Loss of microglial ET could be an important pathogenetic mechanism of inflammation-associated neuronal damages.

Dataset Information

Inhibition of colony stimulating factor 1 receptor corrects maternal inflammation-induced microglial and synaptic dysfunction and behavioral abnormalities.

Publications

Inhibition of colony stimulating factor 1 receptor corrects maternal inflammation-induced microglial and synaptic dysfunction and behavioral abnormalities.

Similar Datasets

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