Cellular and Molecular Neuroscience Laboratory, National Brain Research Centre, Manesar, Gurgaon 122 050, India.
Hum Mol Genet. 2012 Apr 15;21(8):1824-34. doi: 10.1093/hmg/ddr614. Epub 2012 Jan 3.
Angelman syndrome (AS) is a neurodevelopmental disorder caused due to deletions or loss-of-function mutations in maternally inherited UBE3A. Ube3a functions as an ubiquitin ligase as well as a transcriptional coactivator of steroid hormone receptors. However, the mechanisms by which maternal Ube3a deficiency gives rise to phenotypic features of AS are not clear. We report here that Ube3a regulates glucocorticoid receptor (GR) transactivation and GR signaling pathway is disrupted in Ube3a-maternal-deficient mice brain. The expression of several GR-dependent genes is down-regulated in multiple brain regions of Ube3a-maternal-deficient mice. AS mice show significantly higher level of blood corticosterone, selective loss of GR and reduced number of parvalbumin-positive inhibitory interneurons in their hippocampus that could ultimately lead to increased stress. These mice also exhibit increased anxiety-like behavior, which could be due to chronic stress. Altogether, our findings suggest that chronic stress due to altered GR signaling might lead to anxiety-like behavior in a mouse of model of AS.
天使综合征（AS）是一种神经发育障碍，由母系遗传的UBE3A 缺失或功能丧失突变引起。UBE3A 作为一种泛素连接酶以及甾体激素受体的转录共激活因子发挥作用。然而，母系UBE3A 缺乏导致 AS 表型特征的机制尚不清楚。我们在此报告，UBE3A 调节糖皮质激素受体（GR）的转录激活，并且在 Ube3a-母系缺陷小鼠的大脑中，GR 信号通路被破坏。在 Ube3a-母系缺陷小鼠的多个脑区中，几种 GR 依赖性基因的表达下调。AS 小鼠的血液皮质酮水平显著升高，其海马中的 GR 选择性缺失和数量减少，而抑制性中间神经元的数量减少，这可能最终导致应激增加。这些小鼠还表现出焦虑样行为增加，这可能是由于慢性应激。总之，我们的研究结果表明，由于 GR 信号改变导致的慢性应激可能导致 AS 模型小鼠出现焦虑样行为。
