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

• DOI: 10.1038/s41380-020-0671-2
• Publication Date: 2020-02-18T16:14:29Z
• Authors: Seiko Ikezu; Hana Yeh; Jean-Christophe D...; Maya E. Woodbury; Alicia A. Van Enoo; Zhi Ruan; Sudhir Sivakumaran; Yang You; Carl Holland; Teresa Guillamon-...; Asuka Yoshii-Kita...; Mina B. Botros; Charlotte Madore; Pin-Hao Chao; Ankita Desani; Solaiappan Manimaran; Srinidhi Venkates...; W. Evan Johnson; Oleg Butovsky; Maria Medalla; Jennifer I. Luebke; Tsuneya Ikezu
• Keywords: Inflammation; Neurons; 0303 health sciences; Behavior, Animal; [SDV]Life Sciences [q-bio]; Macrophage Colony-Stimulating Factor; Brain; Article; [SDV] Life Sciences [q-bio]; Disease Models, Animal; Mice; 03 medical and health sciences; Pregnancy; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; Prenatal Exposure Delayed Effects; 616; Animals; [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]; Female; [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]; Microglia

AbstractMaternal 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.