Abstract
Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders characterized by impaired skills in social interaction and communication in addition to restricted and repetitive behaviors. Many different factors may contribute to ASD development; in particular, oxytocin receptor (OXTR) deficiency has been reported to be associated with ASD, although the detailed mechanism has remained largely unknown. Epidemiological study has shown that maternal diabetes is associated with ASD development. In this study, we aim to investigate the potential role of OXTR on maternal diabetes-mediated social deficits in offspring. Our in vitro study of human neuron progenitor cells showed that hyperglycemia induces OXTR suppression and that this suppression remains during subsequent normoglycemia. Further investigation showed that OXTR suppression is due to hyperglycemia-induced persistent oxidative stress and epigenetic methylation in addition to the subsequent dissociation of estrogen receptor β (ERβ) from the OXTR promoter. Furthermore, our in vivo mouse study showed that maternal diabetes induces OXTR suppression; prenatal OXTR deficiency mimics and potentiates maternal diabetes-mediated anxiety-like behaviors, while there is less of an effect on autism-like behaviors. Additionally, postnatal infusion of OXTR partly, while infusion of ERβ completely, reverses maternal diabetes-induced social deficits. We conclude that OXTR may be an important factor for ASD development and that maternal diabetes-induced suppression of oxytocin receptor contributes to social deficits in offspring.
Highlights
Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders characterized by deficits in social interaction and communication in addition to restricted and repetitive behaviors (Rossignol and Frye, 2012; Baron-Cohen et al, 2019)
The results showed that 4-day high glucose treatment significantly suppressed the gene expression of both oxytocin receptor (OXTR) and OXT; when the cells switched into low glucose, OXTR expression remained low, while OXT expression returned to normal; superoxide dismutase 2 (SOD2) expression (↑SOD2) on day 5 completely reversed the HG-mediated effect; and SOD2 knockdown on day 5 mimicked the HG-mediated effect
The results showed that the binding ability of Estrogen receptor β (ERβ) on the OXTR promoter was significantly decreased in the HG(4d) + LG(4d)/CTL group compared to the LG(4d) + LG(4d)/CTL group, and this effect was completely restored by infection of SOD2 in HG(4d) + LG(4d)/↑SOD2 group; on the other hand, other transcription factors, including estrogen receptor α (ERα), showed no significant difference, indicating that ERβ is responsible for hyperglycemia-induced OXTR suppression
Summary
Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders characterized by deficits in social interaction and communication in addition to restricted and repetitive behaviors (Rossignol and Frye, 2012; Baron-Cohen et al, 2019). Many factors, including genetics/epigenetics, sex and environmental factors have been reported to be associated with ASD development (Rossignol and Frye, 2012; Bralten et al, 2018). In conjunction with OXT, OXTR has been reported to regulate diverse social behaviors (Maejima et al, 2018; Gulliver et al, 2019; Resendez et al, 2020; Soltys et al, 2020) and play a role in ASD etiology (Jacob et al, 2007; LoParo and Waldman, 2015; Uzefovsky et al, 2019), there has been some controversy with these conclusions (Tansey et al, 2010). Epigenetic modification of OXTR has been widely reported to be associated with ASD development (Jack et al, 2012; Maud et al, 2018; Krol et al, 2019; Tops et al, 2019), the detailed mechanism remains unclear
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
