Maternal immune activation by LPS selectively alters specific gene expression profiles of interneuron migration and oxidative stress in the fetus without triggering a fetal immune response

Abstract

Maternal immune activation (MIA) is a risk factor for the development of schizophrenia and autism. Infections during pregnancy activate the mother’s immune system and alter the fetal environment, with consequential effects on CNS function and behavior in the offspring, but the cellular and molecular links between infection-induced altered fetal development and risk for neuropsychiatric disorders are unknown. We investigated the immunological, molecular, and behavioral effects of MIA in the offspring of pregnant Sprague-Dawley rats given an intraperitoneal (0.25 mg/kg) injection of lipopolysaccharide (LPS) on gestational day 15. LPS significantly elevated pro-inflammatory cytokine levels in maternal serum, amniotic fluid, and fetal brain at 4 h, and levels decreased but remained elevated at 24 h. Offspring born to LPS-treated dams exhibited reduced social preference and exploration behaviors as juveniles and young adults. Whole genome microarray analysis of the fetal brain at 4 h post maternal LPS was performed to elucidate the possible molecular mechanisms by which MIA affects the fetal brain. We observed dysregulation of 3,285 genes in restricted functional categories, with increased mRNA expression of cellular stress and cell death genes and reduced expression of developmentally-regulated and brain-specific genes, specifically those that regulate neuronal migration of GABAergic interneurons, including the Distal-less (Dlx) family of transcription factors required for tangential migration from progenitor pools within the ganglionic eminences into the cerebral cortex. Our results provide a novel mechanism by which MIA induces the widespread down-regulation of critical neurodevelopmental genes, including those previously associated with autism.

Immune Involvement in Autism Spectrum Disorder as a Basis for Animal Models

“…This is consistent with findings that placental size correlates with the risk for several adultonset diseases [49][50][51][52]. Acute transcriptional changes and cytokine effects in the fetal brain may serve as an underlying basis for several of the neurodevelopmental impairments observed in MIA offspring (reviewed in [15][16][17][18] [16]. At the same time, the information garnered from diverse MIA studies raises the intriguing question of whether differences in the severity, timing and type of MIA can produce distinct forms of neurodevelopmental disorders.…”

“…Consistent with this notion, poly (I:C) offspring exhibit dynamic age-and regionspecific changes in brain cytokines throughout postnatal development [45,46]. In response to maternal LPS, fetal brains exhibit altered gene expression profiles, with upregulation of genes related to oxidative stress and down regulation of genes related to GABAergic interneuron migration [15]. After maternal influenza infection, embryos exhibit altered brain expression of many genes relevant to autism and schizophrenia, including Sema3a, Foxp2 and Vldlr [47].…”

“…MIA by any of these inflammatory stimuli leads to autism-and schizophreniarelated behavioral abnormalities in the offspring (reviewed in [15][16][17][18]). Intranasal inoculation of pregnant mice with influenza virus, for example, yields offspring with heightened anxiety, deficient sensorimotor gating and reduced social interaction, and a localized reduction in Purkinje cell number [19], all features of autism.…”

N-acetyl-cysteine prevents pyramidal cell disarray and reelin-immunoreactive neuron deficiency in CA3 after prenatal immune challenge in rats

“…Prenatal LPS may affect both mechanisms. Indeed, a decreased expression of transcription factors regulating neuronal migration was observed 4 h after LPS injection to pregnant dams, supporting the hypothesis of a migration disorder (28). On the other hand, prenatal immune challenge may also alter neurogenesis in the fetal and young offspring's brain (29).…”

“…In the present study, we found an early (P10) deficit in reelin-expressing neurons after prenatal LPS, most prominent in the CA3 area. This deficit was transient and might support the hypothesis of migration disorders (28). There is a general consensus for a progressive decrease of the number of reelin-producing cells during postnatal development (34,35).…”