Maternal Immune Activation Induces Neuroinflammation and Cortical Synaptic Deficits in the Adolescent Rat Offspring.

Magdalena Cieślik,Magdalena Gąssowska-Dobrowolska,Aleksandra Zawadzka,Agata Adamczyk,David Q Beversdorf,Grzegorz A Czapski,Paweł M Boguszewski,Magdalena Gewartowska,Rafał Polowy,Robert K Filipkowski,Anna Wilkaniec,Grace Y Sun,Henryk Jęśko,Małgorzata Frontczak-Baniewicz,Agnieszka Dominiak

doi:10.3390/ijms21114097

Abstract

Maternal immune activation (MIA), induced by infection during pregnancy, is an important risk factor for neuro-developmental disorders, such as autism. Abnormal maternal cytokine signaling may affect fetal brain development and contribute to neurobiological and behavioral changes in the offspring. Here, we examined the effect of lipopolysaccharide-induced MIA on neuro-inflammatory changes, as well as synaptic morphology and key synaptic protein level in cerebral cortex of adolescent male rat offspring. Adolescent MIA offspring showed elevated blood cytokine levels, microglial activation, increased pro-inflammatory cytokines expression and increased oxidative stress in the cerebral cortex. Moreover, pathological changes in synaptic ultrastructure of MIA offspring was detected, along with presynaptic protein deficits and down-regulation of postsynaptic scaffolding proteins. Consequently, ability to unveil MIA-induced long-term alterations in synapses structure and protein level may have consequences on postnatal behavioral changes, associated with, and predisposed to, the development of neuropsychiatric disorders.

Highlights

There is increasing evidence indicating that maternal immune activation (MIA) during pregnancy is an important risk factor for the progeny to develop neuropsychiatric disorders including autism spectrum disorders (ASD)
The body weights of control and MIA offspring, measured on postnatal day (PND) 10 and 50, were not affected by prenatal LPS injection
Our results showed a significant reduction of the levels of key components of the sensitive factor attachment protein receptor (SNARE) complex, i.e., synaptobrevin1/2—VAMP1/2 and syntaxin-1 (Stx-1, p = 0.0153), in the cerebral cortex of MIA rats (Figure 10a,d)

Summary

Introduction

There is increasing evidence indicating that maternal immune activation (MIA) during pregnancy is an important risk factor for the progeny to develop neuropsychiatric disorders including autism spectrum disorders (ASD). Activation of MIA during critical time points of fetal neurogenesis may negatively affect brain structure and function of progeny. The relevance of inflammation in these disorders suggests the correlation between brain dysfunction and alterations in pro-inflammatory cytokines and the number and/or morphology of microglial cells [2]. Preclinical studies on prenatal infection as well as on animal models of MIA demonstrated observable abnormalities in neuronal development of offspring along with an increase in microglia, which is linked to schizophrenia-like behavior [13,14,15]. Current knowledge suggests a combination of genetic, epigenetic, and environmental factors, and their involvement in dysregulation of neurotransmission [6,18]

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