Genome-Wide Analysis of Differential Gene Expression and Splicing in Excitatory Neurons and Interneuron Subtypes
Genome-Wide Analysis of Differential Gene Expression and Splicing in Excitatory Neurons and Interneuron Subtypes
复制标题
兴奋性神经元和中间神经元亚型差异基因表达和剪接的全基因组分析
DOI：
10.1523/jneurosci.1615-19.2019
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发表时间：
2020-01-29
影响因子：
5.3
通讯作者：
Hanson, Jesse E.
中科院分区：
文献类型：
--
作者：
Huntley, Melanie A.;Srinivasan, Karpagam;Hanson, Jesse E.
皮层回路活动由抑制主兴奋性（EXC）神经元的小白蛋白（PV）和生长抑素（SST）中间神经元和抑制其他中间神经元激活的血管活性肠肽（VIP）中间神经元形成。为了了解功能专门化的分子遗传学基础，并确定每种神经元亚型特异性的潜在药物靶点，我们对雄性和雌性小鼠大脑中EXC、PV、SST和VIP神经元的基因表达和剪接进行了全基因组评估。这些结果揭示了许多神经元亚型特异性基因表达的例子，以及剪接异构体的使用，可以解释神经元亚型之间的功能差异，包括突触前可塑性，突触后受体功能和突触连接规范。我们提供了一个可搜索的网络资源，用于探索兴奋性、PV、SST和VIP神经元之间mRNA表达和剪接形式的差异（http://research-pub.gene.com/NeuronSubtypeTranscriptomes）。该资源结合了独特的新数据集和对多个相关数据集的分析方法的新应用，确定了操纵电路功能的许多潜在药物靶点，揭示了疾病相关基因的神经元亚型特异性作用，并有助于理解在人类患者大脑中观察到的基因表达变化。
Cortical circuit activity is shaped by the parvalbumin (PV) and somatostatin (SST) interneurons that inhibit principal excitatory (EXC) neurons and the vasoactive intestinal peptide (VIP) interneurons that suppress activation of other interneurons. To understand the molecular-genetic basis of functional specialization and identify potential drug targets specific to each neuron subtype, we performed a genome wide assessment of both gene expression and splicing across EXC, PV, SST and VIP neurons from male and female mouse brains. These results reveal numerous examples where neuron subtype-specific gene expression, as well as splice-isoform usage, can explain functional differences between neuron subtypes, including in presynaptic plasticity, postsynaptic receptor function, and synaptic connectivity specification. We provide a searchable web resource for exploring differential mRNA expression and splice form usage between excitatory, PV, SST, and VIP neurons (http://research-pub.gene.com/NeuronSubtypeTranscriptomes) . This resource, combining a unique new dataset and novel application of analysis methods to multiple relevant datasets, identifies numerous potential drug targets for manipulating circuit function, reveals neuron subtype-specific roles for disease-linked genes, and is useful for understanding gene expression changes observed in human patient brains.