The Synaptic Dysregulation in Adolescent Rats Exposed to Maternal Immune Activation.

Magdalena Cieślik,Aleksandra Zawadzka,Grzegorz A Czapski,Agata Adamczyk,Magdalena Gassowska-Dobrowolska,Agnieszka Dominiak,Małgorzata Frontczak-Baniewicz,Magdalena Gewartowska

doi:10.3389/fnmol.2020.555290

Abstract

Maternal immune activation (MIA) is a risk factor for neurodevelopmental disorders in offspring, but the pathomechanism is largely unknown. The aim of our study was to analyse the molecular mechanisms contributing to synaptic alterations in hippocampi of adolescent rats exposed prenatally to MIA. MIA was evoked in pregnant female rats by i.p. administration of lipopolysaccharide at gestation day 9.5. Hippocampi of offspring (52–53-days-old rats) were analysed using transmission electron microscopy (TEM), qPCR and Western blotting. Moreover, mitochondrial membrane potential, activity of respiratory complexes, and changes in glutathione system were measured. It was found that MIA induced changes in hippocampi morphology, especially in the ultrastructure of synapses, including synaptic mitochondria, which were accompanied by impairment of mitochondrial electron transport chain and decreased mitochondrial membrane potential. These phenomena were in agreement with increased generation of reactive oxygen species, which was evidenced by a decreased reduced/oxidised glutathione ratio and an increased level of dichlorofluorescein (DCF) oxidation. Activation of cyclin-dependent kinase 5, and phosphorylation of glycogen synthase kinase 3β on Ser9 occurred, leading to its inhibition and, accordingly, to hypophosphorylation of microtubule associated protein tau (MAPT). Abnormal phosphorylation and dysfunction of MAPT, the manager of the neuronal cytoskeleton, harmonised with changes in synaptic proteins. In conclusion, this is the first study demonstrating widespread synaptic changes in hippocampi of adolescent offspring prenatally exposed to MIA.

Highlights

Many environmental factors impact the brain during the key stages of prenatal development (Kern et al, 2017)
LPS evoked in foetuses and placenta an increase in the expression of some inflammation-related genes as well as an increase in the level of Iba1-a marker of microglia (Supplementary Figure 1)
Our results demonstrate that the level of nitrotyrosine is not changed in the hippocampi of maternal immune activation (MIA)-affected offspring (Figure 5D), suggesting that oxidative stress might be not evoked by cytotoxic mechanisms of activated microglia

Summary

Introduction

Many environmental factors impact the brain during the key stages of prenatal development (Kern et al, 2017). Some infectious agents may evoke specific neurological complications, such as Zika virus infection causing microcephaly and other serious brain anomalies (Rasmussen et al, 2016). It seems that activation of the immune system and fever in general, not a specific pathogen, is responsible for early impairment of neurodevelopmental processes in offspring leading to long-term consequences in adult life. Animals exposed to MIA during pregnancy develop alterations in neuronal migration and density leading in consequence to changes in the volume of several brain structures (Bergdolt and Dunaevsky, 2019). The nature of MIA-evoked developmental changes in the central nervous system (CNS) is strictly dependent on the time of MIA (Bergdolt and Dunaevsky, 2019)

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