Inhibition of colony stimulating factor 1 receptor corrects maternal inflammation-induced microglial and synaptic dysfunction and behavioral abnormalities.
Mol Psychiatry. 2020-02-18; :
DOI: 10.1038/s41380-020-0671-2
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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.