Gestational diabetes induces behavioral and brain gene transcription dysregulation in adult offspring

Abstract

The etiology of Autism Spectrum Disorders (ASD) includes a strong genetic component and a complicated environmental component. Recent evidence indicates that maternal diabetes, including gestational diabetes, is associated with an increased prevalence of ASD. While previous studies have looked into possible roles for maternal diabetes in neurodevelopment, there are few studies into how gestational diabetes, with no previous diabetic or metabolic phenotype, may affect neurodevelopment. In this study, we have specifically induced gestational diabetes in mice, followed by behavioral and molecular phenotyping of the mice offspring. Pregnant mice were injected with STZ a day after initiation of pregnancy. Glucose levels increased to diabetic levels between E7 and E14 in pregnancy in a subset of the pregnant animals. Male offspring of Gestational Diabetic mothers displayed increased repetitive behaviors with no dysregulation in the three-chambered social interaction test. RNA-seq analysis revealed a dysregulation in genes related to forebrain development in the frontal cortex and a dysregulation of a network of neurodevelopment and immune related genes in the striatum. Together, these results give evidence that gestational diabetes can induce changes in adulthood behavior and gene transcription in the brain.

Prenatal exposure of diabetes and progestin‐mediated autistic biomarker in peripheral blood mononuclear cells

“…Our results showed that prenatal exposure to either specific hormones (NET and DHT) or diabetes (STZ) in mouse induces oxidative stress (Bjorklund et al, 2020) and mitochondrial dysfunction with suppression of SOD2 and ERRα in the amygdala, in which ERRα modulates mitochondrial function and lipids metabolism, while SOD2 modulates redox situation (Kong et al, 2016;Zhan et al, 2016), consistent with previous reports (Aviel-Shekler et al, 2020;Wang et al, 2019;Xiang et al, 2020;Zou et al, 2017). Furthermore, we found that prenatal factor exposure suppresses gene expression of ERRα and SOD2 in PBMC in autism-like offspring, indicating that oxidative stress (Chen et al, 2021;Liu et al, 2020;Waligora et al, 2019) and mitochondrial dysfunction (Frye, 2020;Gevezova et al, 2020) in PBMC may be the potential biomarkers for ASD screening; this is consistent with recent findings (El-Ansary et al, 2020;Needham et al, 2021).…”

Association of Gestational Diabetes Mellitus and Perinatal Maternal Depression with Early Childhood Behavioral Problems: An Environmental Influences on Child Health Outcomes (ECHO) Study

“…Although ASD, externalizing problems, and diagnoses associated with externalizing problems, such as ADHD, are all more prevalent among males (Santos et al, 2022), it is also possible that GDM affects child neurobehavior in a sexually dimorphic manner. Animal models of GDM have demonstrated male, but not female, offspring display increased repetitive behaviors, but no differences in sociability (Aviel‐Shekler et al, 2020), significantly increased HPA axis stress responses, and impaired sensorimotor gating (Bronson et al, 2017), and memory impairment (Zou et al, 2021). While not directly comparable, an animal model of prenatal maternal overweight or obesity demonstrated maternal high‐fat diet resulted in decreased fetal and adult brain serotonin (5‐HT) availability in males only via a feedback loop where increased inflammation dependent on macrophage Toll‐like receptor 4 signaling resulted in excess microglial phagocytosis of 5‐HT neurons in the dorsal raphe nucleus of males only (Ceasrine et al, 2022).…”

Novel Murine models of Mania and Depression

“…When the righting reflex disappears for more than 30 seconds the mouse was considered asleep. The sleep latency (the time spent between injection of pentobarbital sodium and disappearance of the righting reflex) and sleep duration (the time spent between the mice asleep and appearance of the righting reflex) were recorded [19].…”