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

• Published in: Molecular psychiatry Vol. 26; no. 6; pp. 1808 - 1831
• Main Authors: Ikezu, Seiko, Yeh, Hana, Delpech, Jean-Christophe, Woodbury, Maya E., Van Enoo, Alicia A., Ruan, Zhi, Sivakumaran, Sudhir, You, Yang, Holland, Carl, Guillamon-Vivancos, Teresa, Yoshii-Kitahara, Asuka, Botros, Mina B., Madore, Charlotte, Chao, Pin-Hao, Desani, Ankita, Manimaran, Solaiappan, Kalavai, Srinidhi Venkatesan, Johnson, W. Evan, Butovsky, Oleg, Medalla, Maria, Luebke, Jennifer I., Ikezu, Tsuneya
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.06.2021; Nature Publishing Group
• Subjects: 13/1; 13/106; 13/51; 14/19; 14/32; 14/63; 14/69; 38/91; 631/337; 631/378; 64/60; 692/699/476/1373; 96/31; Animals; Axonogenesis; Behavior, Animal; Behavioral Sciences; Biological Psychology; Brain; Cell receptors; Child development deviations; Colonies; Colony-stimulating factor; Colony-stimulating factors (Physiology); Complications and side effects; Dendritic spines; Development and progression; Developmental disabilities; Disease Models, Animal; Female; Fetus; Gene expression; Growth; Health aspects; Immune response; Immune system; Inflammation; Innate immunity; Life Sciences; Macrophage Colony-Stimulating Factor; Medicine; Medicine & Public Health; Mental illness; Mice; Microglia; Neurons; Neurons and Cognition; Neurosciences; Perinatal infection; Pharmacotherapy; Phenotypes; Physiological aspects; Prefrontal cortex; Pregnancy; Prenatal Exposure Delayed Effects; Prenatal influences; Psychiatry; Pyramidal cells; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; Risk factors; Social behavior; United States
• ISSN: 1359-4184; 1476-5578; 1476-5578
• DOI: 10.1038/s41380-020-0671-2

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.