Moon Anna L, Mawson Eleanor R, Gasalla Patricia, Wilkinson Lawrence S, Dwyer Dominic M, Hall Jeremy, Thomas Kerrie L
Neuroscience and Mental Health Innovation Institute, School of Medicine, Cardiff University, Cardiff CF24 4HQ, UK.
Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff CF24 4HQ, UK.
Int J Mol Sci. 2025 Jun 10;26(12):5547. doi: 10.3390/ijms26125547.
Common and rare variation in gene expression has been consistently associated with neuropsychiatric disorders such as schizophrenia, bipolar disorder, and major depression. However, the underlying biological pathways that cause this association have yet to be fully determined. In this study, we present evidence that rats with a reduced gene dosage of have increased basal corticosterone levels in the periphery and reduced the expression of encoding the glucocorticoid receptor in the hippocampus and hypothalamus. These results are consistent, with an effect of dosage on hypothalamus-pituitary-adrenal (HPA) axis function. Heterozygous rats had lower levels of the histone markers H3K4me3 and H3K27acat exon 1 of the gene. These histone modifications are typically linked to increased gene expression, but here were not associated with changes in the expression of exon 1 variants under non-stress conditions. Heterozygous rats additionally show increased anxiety behaviours. These results support an association of heterozygosity with the altered activity of the HPA axis and function in the resting state, and this may be a predisposing mechanism that contributes to the increased risk of psychiatric disorders with stress.
基因表达中的常见和罕见变异一直与精神分裂症、双相情感障碍和重度抑郁症等神经精神疾病有关。然而，导致这种关联的潜在生物学途径尚未完全确定。在本研究中，我们提供证据表明，基因剂量减少的大鼠外周基础皮质酮水平升高，海马体和下丘脑中编码糖皮质激素受体的基因表达降低。这些结果与基因剂量对下丘脑-垂体-肾上腺（HPA）轴功能的影响一致。杂合基因大鼠基因外显子1的组蛋白标记H3K4me3和H3K27ac水平较低。这些组蛋白修饰通常与基因表达增加有关，但在非应激条件下，此处与外显子1变体的表达变化无关。杂合基因大鼠还表现出焦虑行为增加。这些结果支持基因杂合性与HPA轴活性改变及静息状态下功能的关联，这可能是一种易患机制，导致应激时精神疾病风险增加。
