[Epub ahead of

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

Seiko Ikezu, Hana Yeh, Jean-Christophe Delpech, Maya E. Woodbury, Alicia A. Van Enoo, Zhi Ruan, Sudhir Sivakumaran, Yang You, Carl Holland, Teresa Guillamon-Vivancos, Asuka Yoshii-Kitahara, Mina B. Botros, Charlotte Madore, Pin-Hao Chao, Ankita Desani, Solaiappan Manimaran, Srinidhi Venkatesan Kalavai, W. Evan Johnson, Oleg Butovsky, Maria Medalla, Jennifer I. Luebke, Tsuneya Ikezu
Mol Psychiatry. 2020-02-18; :
DOI: 10.1038/s41380-020-0671-2

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

Ikezu S(1), Yeh H(2)(3), Delpech JC(2), Woodbury ME(2)(3), Van Enoo AA(2), Ruan
Z(2), Sivakumaran S(4), You Y(2), Holland C(4), Guillamon-Vivancos T(4),
Yoshii-Kitahara A(2), Botros MB(2), Madore C(5), Chao PH(2), Desani A(2),
Manimaran S(6), Kalavai SV(2), Johnson WE(6), Butovsky O(5), Medalla M(4), Luebke
JI(4)(7), Ikezu T(8)(9)(10).

Author information:
(1)Departments of Pharmacology and Experimental Therapeutics, Boston University
School of Medicine, Boston, MA, USA. .
(2)Departments of Pharmacology and Experimental Therapeutics, Boston University
School of Medicine, Boston, MA, USA.
(3)Graduate Program in Neuroscience, Boston University, Boston, MA, USA.
(4)Anatomy and Neurobiology, Boston University School of Medicine, Boston, MA,
USA.
(5)Ann Romney Center for Neurologic Diseases, Department of Neurology and
Evergrande Center for Immunologic Diseases, Brigham and Women’s Hospital, Harvard
Medical School, Boston, MA, USA.
(6)Computational Biomedicine, Boston University School of Medicine, Boston, MA,
USA.
(7)Center for Systems Neuroscience, Boston University, Boston, MA, USA.
(8)Departments of Pharmacology and Experimental Therapeutics, Boston University
School of Medicine, Boston, MA, USA. .
(9)Center for Systems Neuroscience, Boston University, Boston, MA, USA.
.
(10)Department of Neurology and Alzheimer’s Disease Center, Boston University
School of Medicine, Boston, MA, USA. .

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.

DOI: 10.1038/s41380-020-0671-2
PMCID: PMC7431382 [Available on 2021-08-18]
PMID: 32071385

Auteurs Bordeaux Neurocampus