TY - JOUR
T1 - Inhibition of colony stimulating factor 1 receptor corrects maternal inflammation-induced microglial and synaptic dysfunction and behavioral abnormalities
AU - Ikezu, Seiko
AU - Yeh, Hana
AU - Delpech, Jean Christophe
AU - Woodbury, Maya E.
AU - Van Enoo, Alicia A.
AU - Ruan, Zhi
AU - Sivakumaran, Sudhir
AU - You, Yang
AU - Holland, Carl
AU - Guillamon-Vivancos, Teresa
AU - Yoshii-Kitahara, Asuka
AU - Botros, Mina B.
AU - Madore, Charlotte
AU - Chao, Pin Hao
AU - Desani, Ankita
AU - Manimaran, Solaiappan
AU - Kalavai, Srinidhi Venkatesan
AU - Johnson, W. Evan
AU - Butovsky, Oleg
AU - Medalla, Maria
AU - Luebke, Jennifer I.
AU - Ikezu, Tsuneya
N1 - Publisher Copyright:
© 2020, The Author(s).
PY - 2021/6
Y1 - 2021/6
N2 - 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.
AB - 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.
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U2 - 10.1038/s41380-020-0671-2
DO - 10.1038/s41380-020-0671-2
M3 - Article
C2 - 32071385
AN - SCOPUS:85079780271
SN - 1359-4184
VL - 26
SP - 1808
EP - 1831
JO - Molecular Psychiatry
JF - Molecular Psychiatry
IS - 6
ER -