Abstract
Background: Altered white matter connectivity, as evidenced by pervasive microstructural changes in myelination and axonal integrity in neuroimaging studies, has been implicated in the development of autism spectrum disorder (ASD) and related neurodevelopmental conditions such as schizophrenia. Despite an increasing appreciation that such white matter disconnectivity is linked to social behavior deficits, virtually no etiologically meaningful myelin-related genes have been identified in oligodendrocytes, the key myelinating cells in the CNS, to furnish an account on the causes. The impact of neurodevelopmental perturbations during pregnancy such as maternal immune activation (MIA) on these genes in memory-related neural networks has not been experimentally scrutinized.Methods: In this study, a mouse model of MIA by the viral dsRNA analog poly(I:C) was employed to mimic the effects of inflammation during pregnancy. Transcriptional expression levels of selected myelin- or oligodendroglia-related genes implicated in schizophrenia or ASD development were analyzed by in situ hybridization (ISH) and quantitative real-time PCR (qRT-PCR) with brain samples from MIA and control groups. The analysis focused on SOX-10 (SRY-related HMG-box 10), MAG (myelin-associated glycoprotein), and Tf (transferrin) expression in the hippocampus and the surrounding memory-related cortical regions in either hemisphere.Results: Specifically, ISH reveals that in the brain of prenatal poly(I:C)-exposed mouse offspring in the MIA model (gestation day 9), mRNA expression of the genes SOX10, MAG and Tf were generally reduced in the limbic system including the hippocampus, retrosplenial cortex and parahippocampal gyrus on either side of the hemispheres. qRT-PCR further confirms the reduction of SOX10, MAG, and Tf expression in the medial prefrontal cortex, sensory cortex, amygdala, and hippocampus.Conclusions: Our present results provide direct evidence that prenatal exposure to poly(I:C) elicits profound and long-term changes in transcript level and spatial distribution of myelin-related genes in multiple neocortical and limbic regions, notably the hippocampus and its surrounding memory-related neural networks. Our work demonstrates the potential utility of oligodendroglia-related genes as biomarkers for modeling neurodevelopmental disorders, in agreement with the hypothesis that MIA during pregnancy could lead to compromised white matter connectivity in ASD.
Highlights
Altered white matter connectivity, as evidenced by pervasive microstructural changes in myelination and axonal integrity in neuroimaging studies, has been implicated in the development of autism spectrum disorder (ASD) and related neurodevelopmental conditions such as schizophrenia
SOX10, L-myelin associated glycoprotein (MAG), and Tf transcript expression was generally reduced in several brain regions including the hippocampus, retrosplenial granular cortex (RSG), and retrosplenial dysgranular cortex (RSD), in the prenatal poly(I:C)-exposed group relative to saline-exposed control
SOX10 signals were observed in the left caudate-putamen (CPu; Figure 1G), but no SOX10 signals were detected on the right side of CPu (Figure 1H) in saline control mice
Summary
As evidenced by pervasive microstructural changes in myelination and axonal integrity in neuroimaging studies, has been implicated in the development of autism spectrum disorder (ASD) and related neurodevelopmental conditions such as schizophrenia. Altered expression patterns of myelin- or oligodendroglia-related genes reported in schizophrenia patients include the oligodendrocyte markers SRY-related HMG-box 10 (SOX10, Iwamoto et al, 2005; Jones et al, 2007; Maeno et al, 2007; Kato and Iwamoto, 2014), myelin-associated glycoprotein (MAG, Fujita et al, 1998; Yin et al, 1998; Felsky et al, 2012) and transferrin (Escobar Cabrera et al, 1994; Guardia Clausi et al, 2010), which are critically involved in myelination and oligodendrocyte progenitor differentiation (Baumann and Pham-Dinh, 2001) Both clinical and experimental studies have proposed a variety of potential diagnostic or prognostic biomarkers for ASD based on biological samples from peripheral tissues or body fluids such as serum and urine (Bridgemohan et al, 2019; Salloum-Asfar et al, 2019; Swanson and Hazlett, 2019; Shen et al, 2020). There has been no consensus as to which of the molecular markers should be profiled toward a systematic understanding of oligodendroglial abnormality in animal models for ASD or schizophrenia, including the MIA (maternal immune activation) models (Estes and McAllister, 2016)
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