Hamilton D J, White C M, Rees C L, Wheeler D W, Ascoli G A
Krasnow Institute for Advanced Study, George Mason University, Fairfax, VA, United States.
Krasnow Institute for Advanced Study, George Mason University, Fairfax, VA, United States.
J Pharm Biomed Anal. 2017 Sep 10;144:269-278. doi: 10.1016/j.jpba.2017.03.062. Epub 2017 Apr 29.
Neurons are often classified by their morphological and molecular properties. The online knowledge base Hippocampome.org primarily defines neuron types from the rodent hippocampal formation based on their main neurotransmitter (glutamate or GABA) and the spatial distributions of their axons and dendrites. For each neuron type, this open-access resource reports any and all published information regarding the presence or absence of known molecular markers, including calcium-binding proteins, neuropeptides, receptors, channels, transcription factors, and other molecules of biomedical relevance. The resulting chemical profile is relatively sparse: even for the best studied neuron types, the expression or lack thereof of fewer than 70 molecules has been firmly established to date. The mouse genome-wide in situ hybridization mapping of the Allen Brain Atlas provides a wealth of data that, when appropriately analyzed, can substantially augment the molecular marker knowledge in Hippocampome.org. Here we focus on the principal cell layers of dentate gyrus (DG), CA3, CA2, and CA1, which together contain approximately 90% of hippocampal neurons. These four anatomical parcels are densely packed with somata of mostly excitatory projection neurons. Thus, gene expression data for those layers can be justifiably linked to the respective principal neuron types: granule cells in DG and pyramidal cells in CA3, CA2, and CA1. In order to enable consistent interpretation across genes and regions, we screened the whole-genome dataset against known molecular markers of those neuron types. The resulting threshold values allow over 6000 very-high confidence (>99.5%) expressed/not-expressed assignments, expanding the biochemical information content of Hippocampome.org more than five-fold. Many of these newly identified molecular markers are potential pharmacological targets for major neurological and psychiatric conditions. Furthermore, our approach yields reasonable expression/non-expression estimates for every single gene in each of these four neuron types with >90% average confidence, providing a considerably complete genetic characterization of hippocampal principal neurons.
神经元通常根据其形态和分子特性进行分类。在线知识库Hippocampome.org主要根据啮齿动物海马结构中神经元的主要神经递质（谷氨酸或GABA）及其轴突和树突的空间分布来定义神经元类型。对于每种神经元类型，这个开放获取资源会报告所有已发表的关于已知分子标记物存在与否的信息，包括钙结合蛋白、神经肽、受体、通道、转录因子以及其他具有生物医学相关性的分子。所得的化学图谱相对稀疏：即使对于研究最深入的神经元类型，迄今为止确定表达或未表达的分子也不到70种。艾伦脑图谱的小鼠全基因组原位杂交图谱提供了大量数据，经过适当分析后，可以大幅增加Hippocampome.org中的分子标记知识。在这里，我们重点关注齿状回（DG）、CA3、CA2和CA1的主要细胞层，它们总共包含约90%的海马神经元。这四个解剖区域密集分布着主要为兴奋性投射神经元的胞体。因此，这些层的基因表达数据可以合理地与各自的主要神经元类型相关联：DG中的颗粒细胞以及CA3、CA2和CA1中的锥体细胞。为了实现跨基因和区域的一致解读，我们针对这些神经元类型的已知分子标记物筛选了全基因组数据集。所得的阈值允许进行超过6000个非常高置信度（>99.5%）的表达/未表达赋值，将Hippocampome.org的生化信息内容扩展了五倍多。许多这些新鉴定的分子标记物是主要神经和精神疾病的潜在药理学靶点。此外，我们的方法对这四种神经元类型中每个基因的表达/未表达估计都具有平均>90%的置信度，为海马主要神经元提供了相当完整的遗传特征描述。
