Abstract
BackgroundMaternal immune activation (MIA) is a risk factor for neurodevelopmental disorders such as autism and schizophrenia, as well as seizure development. The amygdala is a brain region involved in the regulation of emotions, and amygdalar maldevelopment due to infection-induced MIA may lead to amygdala-related disorders. MIA priming of glial cells during development has been linked to abnormalities seen in later life; however, little is known about its effects on amygdalar biochemical and cytoarchitecture integrity.MethodsTime-mated C57BL6J mice were administered a single intraperitoneal injection of 50 μg/kg lipopolysaccharide (LPS) on embryonic day 12 (E12), and the effects of MIA were examined at prenatal, neonatal, and postnatal developmental stages using immunohistochemistry, real-time quantitative PCR, and stereological quantification of cytoarchitecture changes.ResultsFetal brain expression of pro-inflammatory cytokines (IL-1β, TNFα, and IL-6) was significantly upregulated at 4 h postinjection (E12) and remained elevated until the day of birth (P0). In offspring from LPS-treated dams, amygdalar expression of pro-inflammatory cytokines was also increased on day 7 (P7) and expression was sustained on day 40 (P40). Toll-like receptor (TLR-2, TLR-4) expression was also upregulated in fetal brains and in the postnatal amygdala in LPS-injected animals. Morphological examination of cells expressing ionized calcium-binding adaptor molecule 1 (Iba-1) and glial fibrillary acidic protein (GFAP) suggested long-term microglial activation and astrogliosis in postnatal amygdalar regions.ConclusionsOur results showed that LPS-induced MIA at E12 induces a pro-inflammatory cytokine profile in the developing fetal brain that continues up to early adulthood in the amygdala. Inflammation elicited by MIA may activate cells in the fetal brain and lead to alterations in glial (microglia and astrocyte) cells observed in the postnatal amygdala. Moreover, increased pro-inflammatory cytokines and their effects on glial subpopulations may in turn have deleterious consequences for neuronal viability. These MIA-induced changes may predispose offspring to amygdala-related disorders such as heightened anxiety and depression and also neurodevelopmental disorders, such as autism spectrum disorders.
Highlights
Maternal immune activation (MIA) is a risk factor for neurodevelopmental disorders such as autism and schizophrenia, as well as seizure development
Bacterial induced MIA increases the production of inflammatory cytokines in the prenatal brain and postnatal amygdala We first investigated the effect MIA on inflammatory cytokine expression at different stages of development
Whole brain lysates were analyzed at embryonic day 12 (E12) (4-h postinjection), E16, E18, and P0 in prenatal/neonatal stages, and the amygdala was dissected under the microscope at postnatal stages P7, postnatal day 14 (P14), and P40 (Fig. 1a)
Summary
Maternal immune activation (MIA) is a risk factor for neurodevelopmental disorders such as autism and schizophrenia, as well as seizure development. Compelling evidence suggests that early life challenge, as a result of maternal immune activation (MIA), can have longlasting, negative effects on neurochemistry, brain excitability, and behavior [4, 5, 22, 43]. Animal models have been developed to study the link between behavioral discrepancies and cellular, molecular, and morphological alterations in the offspring’s brain after prenatal exposure to an immune modulating agents such as polyinosinic:polycytidylic acid (poly I:C) and lipopolysaccharide (LPS) which mimic viral or bacterial infections, respectively [1, 6, 17, 22]. MIA induced with LPS challenge has produced abnormalities such as decreased expression of Reelin (structural marker), increased immunoreactivity for glial fibrillary acidic protein (GFAP), activation of microglial cells, long-term changes in GABAergic function, and decreases in neocortical and hippocampal thickness [12, 15, 26, 32]. The first aim of this study was to investigate the effects of LPS-induced MIA on murine amygdalar development with regard to the cellular, molecular, and cytoarchitectural changes that may occur over key developmental stages
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