Early life stress perturbs the maturation of microglia in the developing hippocampus.
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.
Department of Psychiatry, Yale University School of Medicine, 300 George Street, Suite 901, New Haven, CT 06511, USA.
Jean-Christophe
JC
Delpech
Department of Psychiatry, Yale University School of Medicine, 300 George Street, Suite 901, New Haven, CT 06511, USA.
Lan
L
Wei
Department of Psychiatry, Yale University School of Medicine, 300 George Street, Suite 901, New Haven, CT 06511, USA.
Jin
J
Hao
W.M. Keck Foundation Biotechnology Resource Laboratory, Yale University, New Haven, CT 06511, USA.
Xiaoqing
X
Yu
Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Charlotte
C
Madore
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, Boston, USA.
Oleg
O
Butovsky
Department of Psychiatry, Yale University School of Medicine, 300 George Street, Suite 901, New Haven, CT 06511, USA. Electronic address: arie.kaffman@yale.edu.
Arie
A
Kaffman
D000367:Age Factors; D000818:Animals; D006624:Hippocampus / Q000254:growth & development* / Q000378:metabolism*; D008426:Maternal Deprivation; D051379:Mice; D008807:Mice, Inbred BALB C; D017628:Microglia / Q000378:metabolism*; D013315:Stress, Psychological / Q000378:metabolism*
Creb1; Early life stress; Hippocampus; Microglia; PU.1; Phagocytosis; RelA; Sp1