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Birth is an inflammatory event for the newborn, characterized by elevations in interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF)-α peripherally and/or centrally, as well as changes in brain microglia. However, the mechanism(s) underlying these responses is unknown. Toll-like receptors (TLRs) play crucial roles in innate immunity and initiate inflammatory cascades upon recognition of endogenous or exogenous antigens. Most TLR signaling depends on the adaptor molecule myeloid differentiation primary response 88 (MyD88). We independently varied MyD88 gene status in mouse dams and their offspring to determine whether the inflammatory response to birth depends on MyD88 signaling and, if so, whether that signaling occurs in the offspring, the mother, or both. We find that the perinatal surges in plasma IL-6 and brain expression of TNF-α depend solely on MyD88 gene status of the offspring, whereas postnatal increases in plasma IL-10 and TNF-α depend on MyD88 in both the pup and dam. Interestingly, MyD88 genotype of the dam primarily drives differences in offspring brain microglial density and has robust effects on developmental neuronal cell death. Milk cytokines were evaluated as a possible source of postnatal maternal influence; although we found high levels of CXCL1/GROα and several other cytokines in ingested post-partum milk, their presence did not require MyD88. Thus, the inflammatory response previously described in the late-term fetus and newborn depends on MyD88 (and, by extension, TLRs), with signaling in both the dam and offspring contributing. Unexpectedly, naturally-occuring neuronal cell death in the newborn is modulated primarily by maternal MyD88 gene status.
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Chd8 haploinsufficiency impacts rearing experience in C57BL/6 mice
Abstract Mutations inCHD8are one of the highest genetic risk factors for autism spectrum disorder. Studies in mice that investigate underlying mechanisms have shownChd8haploinsufficient mice display some trait disruptions that mimic clinical phenotypes, although inconsistencies have been reported in some traits across different models on the same strain background. One source of variation across studies may be the impact ofChd8haploinsufficiency on maternal‐offspring interactions. While differences in maternal care as a function ofChd8genotype have not been studied directly, a previous study showed that pup survival was reduced when reared byChd8heterozygous dams compared with wild‐type (WT) dams, suggesting altered maternal care as a function ofChd8genotype. Through systematic observation of the C57BL/6 strain, we first determined the impact ofChd8haploinsufficiency in the offspring on WT maternal care frequencies across preweaning development. We next determined the impact of maternalChd8haploinsufficiency on pup care. Compared with litters with all WT offspring, WT dams exhibited less frequent maternal behaviors toward litters consisting of offspring with mixedChd8genotypes, particularly during postnatal week 1. DamChd8haploinsufficiency decreased litter survival and increased active maternal care also during postnatal week 1. Determining the impact ofChd8haploinsufficiency on early life experiences provides an important foundation for interpreting offspring outcomes and determining mechanisms that underlie heterogeneous phenotypes.
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- Award ID(s):
- 2011039
- PAR ID:
- 10498325
- Publisher / Repository:
- Wiley-Blackwell
- Date Published:
- Journal Name:
- Genes, Brain and Behavior
- Volume:
- 23
- Issue:
- 2
- ISSN:
- 1601-1848
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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