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Inflammatory, synaptic, motor, and behavioral alterations induced by gestational sepsis on the offspring at different
Marcelo Gomes Granja1,2, Letícia Pires Alves1,2, Marina Leardini-Tristão1
1Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz - Fiocruz, Rio de Janeiro, Brazil.
Insights
Maternal sepsis during pregnancy impacts offspring neurodevelopment, causing lasting cognitive and behavioral issues. This study reveals how gestational infection affects brain immunity and synaptic function, leading to motor and memory impairments.
Area of Science:
- Neuroscience
- Immunology
- Developmental Biology
Background:
- Sepsis is a systemic inflammatory condition with potential adverse effects on fetal development.
- Gestational sepsis can lead to neurodevelopmental impairments and lasting behavioral alterations in offspring.
- Understanding the impact of maternal sepsis on the developing brain is crucial for identifying long-term health risks.
Purpose of the Study:
- To investigate the effects of maternal sepsis on inflammatory cytokine levels and synaptic protein expression in the brains of neonatal, young, and adult mice.
- To analyze motor development, behavioral changes, and cognitive impairments in offspring exposed to maternal sepsis.
- To establish a link between gestational sepsis and neurodevelopmental outcomes in offspring.
Main Methods:
- Pregnant mice were exposed to Klebsiella spp. (sepsis group) or saline (control group) at embryonic day 14.
- Offspring were assessed at various postnatal days (P2, P8, P30, P60) for cytokine levels (TNF-α, IL-1β, IL-6) and synaptic proteins (synaptophysin, PSD95, β-tubulin).
- Motor function tests and behavioral/cognitive assessments were conducted at different developmental stages.
Main Results:
- Gestational sepsis induced a systemic pro-inflammatory response in neonates and altered brain immunity in the hippocampus, neocortex, frontal cortex, and cerebellum across all ages.
- Reduced levels of synaptic proteins synaptophysin and PSD95 were observed in the brains of offspring exposed to maternal sepsis.
- Offspring exhibited motor impairments, depressive-like behavior, impaired fear-conditioned and spatial memory, and learning deficits.
Conclusions:
- Maternal sepsis during gestation can lead to significant neurodevelopmental deficits in offspring.
- The observed brain inflammation and synaptic protein alterations correlate with long-term behavioral and cognitive impairments.
- Gestational sepsis may be a contributing factor to the development of depression, learning, and memory deficits in offspring.
Background:
The term sepsis is used to designate a systemic condition of infection and inflammation associated with hemodynamic changes that result in organic dysfunction. Gestational sepsis can impair the development of the central nervous system and may promote permanent behavior alterations in the offspring. The aim of our work was to evaluate the effects of maternal sepsis on inflammatory cytokine levels and synaptic proteins in the hippocampus, neocortex, frontal cortex, and cerebellum of neonatal, young, and adult mice. Additionally, we analyzed the motor development, behavioral features, and cognitive impairments in neonatal, young and adult offspring.
Methods:
Pregnant mice at the 14th embryonic day (E14) were intratracheally instilled with saline 0.9% solution (control group) or Klebsiella spp. (3 × 108 CFU) (sepsis group) and started on meropenem after 5 h. The offspring was sacrificed at postnatal day (P) 2, P8, P30, and P60 and samples of liver, lung, and brain were collected for TNF-α, IL-1β, and IL-6 measurements by ELISA. Synaptophysin, PSD95, and β-tubulin levels were analyzed by Western blot. Motor tests were performed at all analyzed ages and behavioral assessments were performed in offspring at P30 and P60.
Results:
Gestational sepsis induces a systemic pro-inflammatory response in neonates at P2 and P8 characterized by an increase in cytokine levels. Maternal sepsis induced systemic downregulation of pro-inflammatory cytokines, while in the hippocampus, neocortex, frontal cortex, and cerebellum an inflammatory response was detected. These changes in the brain immunity were accompanied by a reduction of synaptophysin and PSD95 levels in the hippocampus, neocortex, frontal cortex, and cerebellum, in all ages. Behavioral tests demonstrated motor impairment in neonates, and depressive-like behavior, fear-conditioned memory, and learning impairments in animals at P30 and P60, while spatial memory abilities were affected only at P60, indicating that gestational sepsis not only induces an inflammatory response in neonatal mouse brains, but also affects neurodevelopment, and leads to a plethora of behavioral alterations and cognitive impairments in the offspring.
Conclusion:
These data suggest that maternal sepsis may be causatively related to the development of depression, learning, and memory impairments in the litter.
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