Abstract
An increasing number of epidemiological investigations and animal models research suggest that prenatal stress (PS) could cause depression-like behavior in the offspring, which is sex specific. However, the underlying mechanisms remain to be elucidated. This study is to investigate the promoter methylation of metabotropic glutamate receptor 1 (mGluR1) and metabotropic Glutamate Receptor 5 (mGluR5) gene modification on PS induced depression-like behavior in offspring rats (OR). PS models were established, with or without 5-aza-2′-deoxycytidine (5-azaD, decitabine) treatment. Animal behavior was assessed by the sucrose preference test (SPT), forced swimming test (FST), and open field test (OFT). The mRNA and protein expression levels of mGluR1 and mGluR5 in the hippocampus of offspring were detected with quantitative real-time PCR and Western blot analysis, respectively. The promoter methylation in the hippocampus of mGluR1 and mGluR5 OR were also analyzed. SPT showed significantly reduced sucrose preference in PS induced OR. FST showed significantly prolonged immobility time in PS induced OR. OFT showed significantly reduced central residence time in PS induced OR and no significantly influence in rearing as well as in frequency of micturition. Moreover, the mRNA, protein expression levels, and gene promoter methylation level of mGluR1 and mGluR5 in the hippocampus were significantly increased in the PS induced male OR, while no significantly influence in the PS induced female OR. Furthermore, the PS induced effects in male OR could be reversed by the microinjection of 5-azaD. In conclusion, our results showed that the promoter methylation of mGluR1 and mGluR5 gene modification is only involved in PS induced depression-like behavior in male OR in a sex-specific manner. These findings might contribute to the understanding of the disease pathogenesis and clinical treatment in future.
Highlights
The main clinical manifestations of depression, known as depression obstacles, are symptoms related to low sentiment and being low-spirited along with decreased interests for external activities
It is considered as the ability to experience pleasure, which is a fundamental feature displayed in clinical depression [42]
We discovered that the percentages of sugar water preference in progeny were significantly reduced, and that the administration of 5-azaD was able to effectively interfere with this behavior while playing a therapeutic role
Summary
The main clinical manifestations of depression, known as depression obstacles, are symptoms related to low sentiment and being low-spirited along with decreased interests for external activities. As a means to avoid the influence of females in estrus caused by hormonal changes, previous studies conducted regarding the effects of prenatal stress-induced behavior on anxiety and depression were concentrated in the male offspring. Recent studies suggest that prenatal stress may influence the expression of glutamate receptor protein within the hippocampus, prefrontal cortex, and the amygdala of both male and female offspring. Zuena’s laboratory studies have shown that prenatal stress can lead to a decrease in the expression level of mGluR5 in the hippocampus of the male offspring [23]. Whether the metabotropic glutamate receptors 1 and 5 (mGluR1 and mGluR5) promoter region methylated modification involved in the PS induced depression-like behavior in the offspring rats (OR), and the related mechanisms, were explored. The effects of JNJ16259685 (JNJ), a selective mGluR1 antagonist, and MTEP, a metabotropic glutamate receptor subtype 5 Antagonists on the PS induced depression-like behavior in the OR were investigated
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