Murine adult neural progenitor cells alter their proliferative behavior and gene expression after the activation of toll-like-receptor 3

Abstract

Viral infections during pregnancy significantly increase the risk for psychological pathologies like schizophrenia in the offspring. One of the main morphological hallmarks of schizophrenia is a reduced size of the hippocampus. Since new neurons are produced in this particular brain compartment throughout life, it might be possible that low neurogenesis levels triggered by a maternal viral infection contribute to developmental deficits of the hippocampus. We injected polyinosinic:polycytidylic acid (Poly I:C) in pregnant C57Bl/6 mice to stimulate an anti-viral response through TLR3 and examined gene expressions in the neuronal progenitor cells (NPCs) of the offspring at different ages. Additionally, we treated adult NPC lines with Poly I:C to investigate its direct effect. We could show for the first time that TLR3 and its downstream effector molecule IRF3 are expressed in adult NPCs. Poly I:C treatment in vitro and in vivo led to the regulation of proliferation and genes involved in antiviral response, migration, and survival. These findings indicate that NPCs of the fetus are able to react towards an in utero immune response, and thus, changes in the neuronal stem cell pool can contribute to the development of neurological diseases like schizophrenia.

Maternal immune activation in neurodevelopmental disorders

“…A reduction in the number of reelin-positive cells was observed in the same animals, however, suggesting a potential defect in cell migration and morphogenesis of the DG (Depino, 2015). In vitro assays using DG neural progenitor cells treated with Poly(I:C) showed that direct TLR3 activation in these cells could increase proliferation; however, a decrease in the number of cells immunoreactive for the proliferation marker Ki67 was observed in the DG of adult MIA animals (Melnik et al, 2012). Further in vitro evidence suggests that IL-1ß signaling may contribute to the decrease in proliferation of neural progenitor cells isolated from ventral mesencephalon (Crampton et al, 2012).…”

“…on GD18-19) caused a reduction of proliferative cells labeled with BrdU in the dentate gyrus (DG) during fetal development and in the early postnatal stage (P14) (Cui et al, 2009). In vitro assays using DG neural progenitor cells treated with Poly(I:C) showed that direct TLR3 activation in these cells could increase proliferation; however, a decrease in the number of cells immunoreactive for the proliferation marker Ki67 was observed in the DG of adult MIA animals (Melnik et al, 2012). However, treatment with LPS earlier in gestation (25 mg/kg on GD9) did not affect neurogenesis in the mouse DG (Depino, 2015).…”

Genes in immune pathways associated with abnormal white matter integrity in first-episode and treatment-naïve patients with schizophrenia

“…37 Melnik et al reported that IRF3 might be critical in regulating the development of neuronal progenitor cells. 38 The analysis of protein-protein interaction networks showed that IRF3 interacts with other schizophrenia susceptibility genes, such as CREB1, AKT1 and ESR1. 39 Furthermore, several studies identified that AKT1 and CREB1 were associated with synaptic plasticity in the hippocampus.…”

“…The interferon regulatory factor 3 gene (IRF3), located on chromosome 19q13, plays a key role in the innate immune system through the response to viral infection 37 . Melnik et al reported that IRF3 might be critical in regulating the development of neuronal progenitor cells 38 . The analysis of protein–protein interaction networks showed that IRF3 interacts with other schizophrenia susceptibility genes, such as CREB1, AKT1 and ESR1 39 …”

Predicting Epigenomic Functions of Genetic Variants in the Context of Neurodevelopment via Deep Transfer Learning

“…IRF3 is a key regulator of the innate immune system and is a plausible SCZ risk gene [88]. Recent studies show that it may be important in regulating the development of neuronal progenitor cells [48], and physically interacts with other schizophrenia susceptibility genes, such as CREB1, AKT1 and ESR1 [88]. We performed additional in-depth study of a region containing rs1080500, which is highlighted as possible causal variant by MetaChrom.…”