Uncovering True Cellular Phenotypes: Using Induced Pluripotent Stem Cell-Derived Neurons to Study Early Insults in Neurodevelopmental Disorders.
Uncovering True Cellular Phenotypes: Using Induced Pluripotent Stem Cell-Derived Neurons to Study Early Insults in Neurodevelopmental Disorders.
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DOI：
10.3389/fneur.2018.00237
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发表时间：
2018
影响因子：
3.4
通讯作者：
Levine ES
中科院分区：
文献类型：
--
作者：
Fink JJ;Levine ES
神经发育障碍的动物模型为与过多的遗传中断相关的分子、细胞和电路水平的缺陷提供了宝贵的见解。在许多情况下，这些缺陷与疾病相关行为的变化有关，但这些发现很少被转化为人类疾病的治疗。这可能是由于显著的物种差异和对涉及多个基因缺失或复制的疾病建模的困难。在这些模型中，由于成熟神经系统中继发性疾病表型的积累以及潜在的代偿机制，对主要潜在的病理生理学的识别是混乱的。诱导多能干细胞技术的发现现在为准确模拟复杂的遗传性神经遗传疾病提供了一种工具。使用这项技术，可以产生患者特定的细胞系，并将其分化为特定的神经元亚型，这些亚型可以用于鉴定初级细胞和分子表型。很明显，突触结构和功能的损害是神经发育障碍的常见病理生理学，而在神经元发育的最早阶段进行电生理分析对于确定导致突触功能障碍的活性和兴奋性变化以及确定疾病修改治疗的靶点至关重要。
Animal models of neurodevelopmental disorders have provided invaluable insights into the molecular-, cellular-, and circuit-level defects associated with a plethora of genetic disruptions. In many cases, these deficits have been linked to changes in disease-relevant behaviors, but very few of these findings have been translated to treatments for human disease. This may be due to significant species differences and the difficulty in modeling disorders that involve deletion or duplication of multiple genes. The identification of primary underlying pathophysiology in these models is confounded by the accumulation of secondary disease phenotypes in the mature nervous system, as well as potential compensatory mechanisms. The discovery of induced pluripotent stem cell technology now provides a tool to accurately model complex genetic neurogenetic disorders. Using this technique, patient-specific cell lines can be generated and differentiated into specific subtypes of neurons that can be used to identify primary cellular and molecular phenotypes. It is clear that impairments in synaptic structure and function are a common pathophysiology across neurodevelopmental disorders, and electrophysiological analysis at the earliest stages of neuronal development is critical for identifying changes in activity and excitability that can contribute to synaptic dysfunction and identify targets for disease-modifying therapies.
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影响因子：
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作者：
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