Transcriptomic networks implicate neuronal energetic abnormalities in three mouse models harboring autism and schizophrenia-associated mutations.
Transcriptomic networks implicate neuronal energetic abnormalities in three mouse models harboring autism and schizophrenia-associated mutations.
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DOI：
10.1038/s41380-019-0576-0
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发表时间：
2021-05-01
影响因子：
11
通讯作者：
Geschwind, Daniel H
中科院分区：
文献类型：
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作者：
Gordon, Aaron;Forsingdal, Annika;Geschwind, Daniel H
精神疾病的遗传风险是复杂的，因此识别不同形式的遗传风险可能重合的共享分子途径具有重大意义。越来越多的遗传和基因组研究表明，这种共享的分子途径存在于具有不同临床表现的疾病中，例如精神分裂症和自闭症谱系障碍（ASD）。但这与特定遗传风险因素的关系尚不清楚。此外，在大脑中发现的一些分子变化是否与潜在的混淆生前或死后因素有关很难证明。我们分析了来自三个小鼠品系的皮质和海马的转录组，这些小鼠品系模拟了与精神分裂症和ASD相关的人类拷贝数变体（CNVs）：Df（h15 q13）/+、Df（h22 q11）/+和Df（h1 q21）/+，它们分别携带15q13.3缺失、22q11.2缺失和1q21.1缺失。虽然我们发现在单个基因水平上差异表达的重叠很少，但基因网络分析确定了在所有三种小鼠模型中失调的共表达基因的两个皮质和两个海马模块。一个皮质模块与神经元能量学和放电率相关，并与SCZ和ASD患者死后人脑中发现的变化重叠。这些数据突出了在携带主要风险等位基因的小鼠模型中会聚基因表达的方面，并加强了人类神经元能量学变化与神经精神疾病之间的联系。
Genetic risk for psychiatric illness is complex, so identification of shared molecular pathways where distinct forms of genetic risk might coincide is of substantial interest. A growing body of genetic and genomic studies suggest that such shared molecular pathways exist across disorders with different clinical presentations, such as schizophrenia and autism spectrum disorder (ASD). But how this relates to specific genetic risk factors is unknown. Further, whether some of the molecular changes identified in brain relate to potentially confounding antemortem or postmortem factors are difficult to prove. We analyzed the transcriptome from the cortex and hippocampus of three mouse lines modeling human copy number variants (CNVs) associated with schizophrenia and ASD: Df(h15q13)/+, Df(h22q11)/+, and Df(h1q21)/+ which carry the 15q13.3 deletion, 22q11.2 deletion, and 1q21.1 deletion, respectively. Although we found very little overlap of differential expression at the level of individual genes, gene network analysis identified two cortical and two hippocampal modules of co-expressed genes that were dysregulated across all three mouse models. One cortical module was associated with neuronal energetics and firing rate, and overlapped with changes identified in postmortem human brain from SCZ and ASD patients. These data highlight aspects of convergent gene expression in mouse models harboring major risk alleles, and strengthen the connection between changes inneuronal energetics and neuropsychiatric disorders in humans.