Early life stress perturbs the maturation of microglia in the developing hippocampus.
Brain, Behavior, and Immunity. 2016-10-01; 57: 79-93
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1. Brain Behav Immun. 2016 Oct;57:79-93. doi: 10.1016/j.bbi.2016.06.006. Epub 2016
Early life stress perturbs the maturation of microglia in the developing
Delpech JC(1), Wei L(1), Hao J(1), Yu X(2), Madore C(3), Butovsky O(4), Kaffman
(1)Department of Psychiatry, Yale University School of Medicine, 300 George
Street, Suite 901, New Haven, CT 06511, USA.
(2)W.M. Keck Foundation Biotechnology Resource Laboratory, Yale University, New
Haven, CT 06511, USA.
(3)Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s
Hospital, Harvard Medical School, Boston, MA 02115, USA.
(4)Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s
Hospital, Harvard Medical School, Boston, MA 02115, USA; Evergrande Center for
Immunologic Diseases, Brigham and Women’s Hospital, Harvard Medical School,
(5)Department of Psychiatry, Yale University School of Medicine, 300 George
Street, Suite 901, New Haven, CT 06511, USA. Electronic address:
Children exposed to abuse or neglect show abnormal hippocampal development and
similar findings have been reported in rodent models. Using brief daily
separation (BDS), a mouse model of early life stress, we previously showed that
exposure to BDS impairs hippocampal function in adulthood and perturbs synaptic
maturation, synaptic pruning, axonal growth and myelination in the developing
hippocampus. Given that microglia are involved in these developmental processes,
we tested whether BDS impairs microglial activity in the hippocampus of 14
(during BDS) and 28-day old mice (one week after BDS). We found that BDS
increased the density and altered the morphology of microglia in the hippocampus
of 14-day old pups, effects that were no longer present on postnatal day (PND)
28. Despite the normal cell number and morphology seen at PND28, the molecular
signature of hippocampal microglia, assessed using the NanoString immune panel,
was altered at both ages. We showed that during normal hippocampal development,
microglia undergo significant changes between PND14 and PND28, including reduced
cell density, decreased ex vivo phagocytic activity, and an increase in the
expression of genes involved in inflammation and cell migration. However,
microglia harvested from the hippocampus of 28-day old BDS mice showed an
increase in phagocytic activity and reduced expression of genes that normally
increase across development. Promoter analysis indicated that alteration in the
transcriptional activity of PU.1, Creb1, Sp1, and RelA accounted for most of the
transcriptional changes seen during normal microglia development and for most of
the BDS-induced changes at PND14 and PND28. These findings are the first to
demonstrate that early life stress dysregulates microglial function in the
developing hippocampus and to identify key transcription factors that are likely
to mediate these changes.
Copyright © 2016. Published by Elsevier Inc.
PMID: 27301858 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflict of interest.