Prenatal stress changes the glycoprotein GPM6A gene expression and induces epigenetic changes in rat offspring brain

Abstract

Prenatal stress (PS) exerts strong impact on fetal brain development and on adult offspring brain functions. Previous work demonstrated that chronic stress alters the mRNA expression of GPM6A, a neuronal glycoprotein involved in filopodium extension. In this work, we analyzed the effect of PS on gpm6a expression and the epigenetic mechanisms involved. Pregnant Wistar rats received restraint stress during the last week of gestation. Male offspring were sacrificed on postnatal days 28 and 60. Hippocampus and prefrontal cortex samples were analyzed for gene expression (qPCR for mRNAs and microRNAs), methylation status (bisulfite conversion) and protein levels. Hippocampal neurons in culture were used to analyze microRNA overexpression effects. Prenatal stress induced changes in gpm6a levels in both tissues and at both ages analyzed, indicating a persistent effect. Two CpG islands in the gpm6a gene were identified. Variations in the methylation pattern at three specific CpGs were found in hippocampus, but not in PFC samples from PS offspring. microRNAs predicted to target gpm6a were identified in silico. qPCR measurements showed that PS modified the expression of several microRNAs in both tissues, being microRNA-133b the most significantly altered. Further studies overexpressing this microRNA in neuronal cultures showed a reduction in gmp6a mRNA and protein level. Moreover filopodium density was also reduced, suggesting that GPM6A function was affected. Gestational stress affected gpm6a gene expression in offspring likely through changes in methylation status and in posttranscriptional regulation by microRNAs. Thus, our findings propose gpm6a as a novel target for epigenetic regulation during prenatal stress.

Altered expression of neuroplasticity-related genes in the brain of depressed suicides

“…Epigenetic mechanisms could be a possible explanation since GPM6A has been identified as a novel target for epigenetic regulation during prenatal stress through changes in methylation status and in posttranscriptional regulation by microRNAs. GPM6A mRNA expression has been shown to be modulated by miR-133b (Monteleone et al, 2014) and by miR-124 (El-Kordi et al, 2013). Interestingly, miR-133b expression is modulated by prenatal stress exposure in rats both in the hippocampus and PFC (Monteleone et al, 2014).…”

“…The neuronal membrane glycoprotein M6a (GPM6A), a member of the myelin proteolipid protein (PLP/DM20) family, has been shown to play a role in stress response in different animal models (Alfonso et al, 2004a,b; Cooper et al, 2009; Monteleone et al, 2014). For example, chronic social and physical stress decreases Gpm6a mRNA levels in the hippocampus, and this downregulation is prevented by administration of antidepressants (Alfonso et al, 2004b, 2006).…”

Epigenetic Signaling in Psychiatric Disorders

“…Targets of these miRNAs include genes implicated in neurotransmission, stress response, and disorders such as schizophrenia and bipolar disorder. For example, prenatal stress increases levels of GPM6A, a neuronal glycoprotein involved in filopodium extension, in the HPC and PFC of male mice at both PN28 and PN60 119 . This is accompanied by enhanced miR-133b, Dnmt3a , and Mecp2 levels and with alterations in methylation patterns within two CpG islands of the Gpm6a gene 119 .…”

“…For example, prenatal stress increases levels of GPM6A, a neuronal glycoprotein involved in filopodium extension, in the HPC and PFC of male mice at both PN28 and PN60 119 . This is accompanied by enhanced miR-133b, Dnmt3a , and Mecp2 levels and with alterations in methylation patterns within two CpG islands of the Gpm6a gene 119 . Furthermore, miR-133b downregulated Gpm6a levels and reduced neurite extensions in cultured HPC neurons, demonstrating functional consequences of miR-133b dysregulation by prenatal stress.…”

Women's posttraumatic stress symptoms and autism spectrum disorder in their children

“…It has been hypothesized that maternal stress affects several biological systems that in turn negatively impact the development of the fetus’ brain. Hypothesized mechanisms include effects of maternal cortisol, reduced blood flow (Van den Bergh, et al, 2005) and immune function (Parker & Douglas, 2010) on the development of the fetus’ limbic system, prefrontal cortex, hypothalamic-pituitary-adrenal (HPA) axis (Talge, Neal, & Glover, 2007), and immune system (Parker & Douglas, 2010), possibly in part through epigenetic alterations (Gurnot et al, 2013; Monteleone et al, 2014; Oberlander et al, 2008). …”