Inflammatory, synaptic, motor, and behavioral alterations induced by gestational sepsis on the offspring at different stages of life

Granja, Marcelo Gomes and Alves, Letícia Pires and Leardini-Tristão, Marina and Saul, Michelle Edelman and Bortoni, Letícia Coelho and de Moraes, Flávia Maciel and Ferreira, Erica Camila and de Moraes, Bianca Portugal Tavares and da Silva, Victória Zerboni and Dos Santos, Adrielle Ferreira Ribeiro and Silva, Adriana Ribeiro and Gonçalves-de-Albuquerque, Cassiano Felippe and Bambini-Junior, Victorio and Weyrich, Andrew S and Rondina, Matthew T and Zimmerman, Guy A and de Castro-Faria-Neto, Hugo Caire (2021) Inflammatory, synaptic, motor, and behavioral alterations induced by gestational sepsis on the offspring at different stages of life. Journal of neuroinflammation, 18 (1): 60. ISSN 1742-2094

Abstract

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.