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体内电穿孔作为一种活体基因操作工具,用于研究精神疾病:从基因到回路再到行为。

In utero electroporation as a tool for genetic manipulation in vivo to study psychiatric disorders: from genes to circuits and behaviors.

机构信息

Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.

出版信息

Neuroscientist. 2012 Apr;18(2):169-79. doi: 10.1177/1073858411399925. Epub 2011 May 5.

Abstract

Many genetic risk factors for major mental disorders have key roles in brain development. Thus, exploring the roles for these genetic factors for brain development at the molecular, cellular, and neuronal circuit level is crucial for discovering how genetic disturbances affect high brain functions, which ultimately lead to disease pathologies. However, it is a tremendously difficult task, given that most mental disorders have genetic complexities in which many genetic risk factors have multiple roles in different cell types and brain regions over a time-course dependent manner. Furthermore, some genetic risk factors are likely to act epistatically in common molecular pathways. For this reason, a technique for spatial and temporal manipulation of multiple genes is necessary for understanding how genetic disturbances contribute to disease etiology. Here, the authors will review the said technique, in utero electroporation, which investigates the molecular disease pathways in rodent models for major mental disorders. This technique is also useful to examine the effect of genetic risks at the behavioral level. Furthermore, the authors will discuss the recent progress of this technology, such as inducible and cell type-specific targeting, as well as nonepisomal genetic manipulation, which provide further availability of this technique for research on major mental disorders.

摘要

许多主要精神障碍的遗传风险因素在大脑发育中起着关键作用。因此,探索这些遗传因素在分子、细胞和神经元回路水平上对大脑发育的作用对于发现遗传紊乱如何影响高级大脑功能至关重要,而高级大脑功能最终会导致疾病病理。然而,这是一项极其艰巨的任务,因为大多数精神障碍的遗传复杂性在于,许多遗传风险因素以时间依赖的方式在不同的细胞类型和脑区中发挥多种作用。此外,一些遗传风险因素可能在常见的分子途径中表现出上位性。出于这个原因,需要一种用于时空操纵多个基因的技术,以了解遗传紊乱如何导致疾病病因。在这里,作者将回顾上述技术,即体内电穿孔技术,该技术用于研究主要精神障碍的啮齿动物模型中的分子疾病途径。该技术还可用于在行为水平上检查遗传风险的影响。此外,作者还将讨论该技术的最新进展,如诱导和细胞类型特异性靶向以及非连锁遗传操作,这为主要精神障碍的研究提供了该技术的进一步应用。

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