Maternal gastrointestinal nematode infection alters hippocampal neuroimmunity, promotes synaptic plasticity, and improves resistance to direct infection in offspring.

The developing brain is vulnerable to maternal bacterial and viral infections which induce strong inflammatory responses in the mother that are mimicked in the offspring brain, resulting in irreversible neurodevelopmental defects, and associated cognitive and behavioural impairments. In contrast, infection during pregnancy and lactation with the immunoregulatory murine intestinal nematode, Heligmosomoides bakeri, upregulates expression of genes associated with long-term potentiation (LTP) of synaptic networks in the brain of neonatal uninfected offspring, and enhances spatial memory in uninfected juvenile offspring. As the hippocampus is involved in spatial navigation and sensitive to immune events during development, here we assessed hippocampal gene expression, LTP, and neuroimmunity in 3-week-old uninfected offspring born to H. bakeri infected mothers. Further, as maternal immunity shapes the developing immune system, we assessed the impact of maternal H. bakeri infection on the ability of offspring to resist direct infection. In response to maternal infection, we found an enhanced propensity to induce LTP at Schaffer collateral synapses, consistent with RNA-seq data indicating accelerated development of glutamatergic synapses in uninfected offspring, relative to those from uninfected mothers. Hippocampal RNA-seq analysis of offspring of infected mothers revealed increased expression of genes associated with neurogenesis, gliogenesis, and myelination. Furthermore, maternal infection improved resistance to direct infection of H. bakeri in offspring, correlated with transfer of parasite-specific IgG1 to their serum. Hippocampal immunohistochemistry and gene expression suggest Th2/Treg biased neuroimmunity in offspring, recapitulating peripheral immunoregulation of H. bakeri infected mothers. These findings indicate maternal H. bakeri infection during pregnancy and lactation alters peripheral and neural immunity in uninfected offspring, in a manner that accelerates neural maturation to promote hippocampal LTP, and upregulates the expression of genes associated with neurogenesis, gliogenesis, and myelination.

Maternal gastrointestinal nematode infection enhances spatial memory of uninfected juvenile mouse pups.

The developing brain is particularly vulnerable to factors including maternal infection during pregnancy. Establishment of neural networks critical for memory and cognition begins during the perinatal period, when Heligmosomoides bakeri, a gastrointestinal (GI) nematode restricted to the maternal mouse intestine, has been shown to upregulate expression of long-term potentiation genes in the young rodent pup brain. We explored the impact of maternal infection during pregnancy and early lactation on the spatial behavior of uninfected male and female juvenile mice. Pre-weaned pups of H. bakeri infected dams exhibited less exploratory behaviour compared to pups of uninfected dams on postnatal day (PD) 16 but not PD 17, possibly reflecting a transient fear of an unfamiliar environment and/or a brief neurodevelopmental delay. Our two spatial memory tests show for the first time an enhancement of spatial memory in response to maternal nematode infection regardless of pup sex. At PD 17, pups of infected dams expressed object location memories after 3 h in the Object Location Test whereas offspring of uninfected mothers did not. In addition, at PD 34, juveniles of infected mothers retained their ability to find the escape hole in the Barnes Maze Test for one week whereas offspring from uninfected mothers did not. This finding is even more striking given that spatial memory was positively associated with pup length, yet this maternal infection impaired linear growth of pups. Thus, the positive impact of maternal infection on spatial memory countered any impairment associated with the shorter length of the pups. Overall, these novel findings indicate that a maternal GI nematode infection during pregnancy and lactation positively influences the spatial memory of uninfected juvenile offspring with potential fitness implications for the next generation.