Age-Related Gene Expression in the Frontal Cortex Suggests Synaptic Function Changes in Specific Inhibitory Neuron Subtypes.
Age-Related Gene Expression in the Frontal Cortex Suggests Synaptic Function Changes in Specific Inhibitory Neuron Subtypes.
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DOI：
10.3389/fnagi.2017.00162
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发表时间：
2017
影响因子：
4.8
通讯作者：
Sibille E
中科院分区：
文献类型：
--
作者：
French L;Ma T;Oh H;Tseng GC;Sibille E
人类大脑的全基因组表达谱揭示了在整个生命周期中差异表达的基因。表征这些基因有助于我们了解正常功能和病理状况。此外，导致衰老过程中运动、感觉和认知能力下降的具体细胞类型尚不清楚。在这里，我们测试与年龄相关的基因是否在特定的神经细胞类型中表现出更高的表达。我们的研究利用了来自小鼠单细胞表达数据的两个来源的数据和来自死后人类大脑的大基因表达研究的两个年龄关联来源的数据。我们使用非参数基因集分析来测试与特定细胞类型相关的基因的年龄相关富集；我们还将我们的分析限制在特定的基因本体组上。我们的分析重点是来自小鼠视觉皮层的一对主要单细胞表达数据和来自眶额皮层的与年龄相关的人类死后基因表达信息。使用来自海马体、前额叶皮层、体感皮层和血液的数据进行的其他配对被用来验证和测试我们研究结果的特异性。我们发现在少突胶质细胞和星形胶质细胞中高表达的基因与年龄相关的强烈上调，而在2/3层谷氨酸能神经元中高表达的基因随着年龄的增长而下调。不特定于任何神经细胞类型的基因也被下调，可能是由于年龄相关基因的大量组织来源。对细胞类型富集基因的基因本体驱动解剖强调了表达细胞周期蛋白依赖性激酶 6 (Cdk6) 的生长抑素 (Sst) 神经元亚型和表达肌球蛋白结合蛋白的血管活性肠肽 (Vip) 神经元亚型中参与突触传递和细胞间信号转导的基因的强烈下调 C、慢速型（Mybpc1）。这些发现为细胞对正常衰老的特异性易感性提供了新的见解，并表明特定抑制性神经元亚型中与年龄相关的突触变化。
Genome-wide expression profiling of the human brain has revealed genes that are differentially expressed across the lifespan. Characterizing these genes adds to our understanding of both normal functions and pathological conditions. Additionally, the specific cell-types that contribute to the motor, sensory and cognitive declines during aging are unclear. Here we test if age-related genes show higher expression in specific neural cell types. Our study leverages data from two sources of murine single-cell expression data and two sources of age-associations from large gene expression studies of postmortem human brain. We used nonparametric gene set analysis to test for age-related enrichment of genes associated with specific cell-types; we also restricted our analyses to specific gene ontology groups. Our analyses focused on a primary pair of single-cell expression data from the mouse visual cortex and age-related human post-mortem gene expression information from the orbitofrontal cortex. Additional pairings that used data from the hippocampus, prefrontal cortex, somatosensory cortex and blood were used to validate and test specificity of our findings. We found robust age-related up-regulation of genes that are highly expressed in oligodendrocytes and astrocytes, while genes highly expressed in layer 2/3 glutamatergic neurons were down-regulated across age. Genes not specific to any neural cell type were also down-regulated, possibly due to the bulk tissue source of the age-related genes. A gene ontology-driven dissection of the cell-type enriched genes highlighted the strong down-regulation of genes involved in synaptic transmission and cell-cell signaling in the Somatostatin (Sst) neuron subtype that expresses the cyclin dependent kinase 6 (Cdk6) and in the vasoactive intestinal peptide (Vip) neuron subtype expressing myosin binding protein C, slow type (Mybpc1). These findings provide new insights into cell specific susceptibility to normal aging, and suggest age-related synaptic changes in specific inhibitory neuron subtypes.