Histidine Decarboxylase Knockout Mice as a Model of the Pathophysiology of Tourette Syndrome and Related Conditions.
Histidine Decarboxylase Knockout Mice as a Model of the Pathophysiology of Tourette Syndrome and Related Conditions.
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DOI：
10.1007/164_2016_127
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发表时间：
2017
影响因子：
--
通讯作者：
Pittenger C
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文献类型：
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作者：
Pittenger C
虽然组胺 (HA) 在中枢神经系统中的正常功能在过去 30 年逐渐受到关注，但神经递质 HA 异常与人类疾病的关系却较慢地被发现。 2010 年，对生物合成酶组氨酸脱羧酶 (Hdc) 中一种罕见的无义突变的描述带来了新的见解，这种突变与抽动秽语综合症 (TS) 以及单一家族谱系中的相关病症有关。随后的基因工作为散发性 TS 中 HA 信号异常提供了进一步的支持。由于这项基因工作的结果，15 多年前产生的 Hdc 基因敲除小鼠已被重新检查为 TS 和相关病症的病理生理学模型。在这些 KO 小鼠和 Hdc 突变人类携带者中进行的平行研究揭示了基底神经节系统的异常及其受多巴胺 (DA) 的调节，并证实了该模型的病因学、表面和预测有效性。因此，Hdc-KO 模型可作为探索 TS 和相关病症的病理生理学的独特平台，并为后续人体测试生成特定假设。本章总结了该模型的开发和验证，并总结了最近和正在进行的工作，使用它来进一步研究可能导致 TS 和相关病症的病理生理变化。
While the normal functions of histamine (HA) in the central nervous system have gradually come into focus over the past 30 years, the relation of abnormalities in neurotransmitter HA to human disease has been slower to emerge. New insight came with the 2010 description of a rare nonsense mutation in the biosynthetic enzyme histidine decarboxylase (Hdc) that was associated with Tourette syndrome (TS) and related conditions in a single family pedigree. Subsequent genetic work has provided further support for abnormalities of HA signaling in sporadic TS. As a result of this genetic work, Hdc knockout mice, which were generated more than 15 years ago, have been reexamined as a model of the pathophysiology of TS and related conditions. Parallel work in these KO mice and in human carriers of the Hdc mutation has revealed abnormalities in the basal ganglia system and its modulation by dopamine (DA) and has confirmed the etiologic, face, and predictive validity of the model. The Hdc-KO model thus serves as a unique platform to probe the pathophysiology of TS and related conditions, and to generate of specific hypotheses for subsequent testing in humans. This chapter summarizes the development and validation of this model and summarize recent and ongoing work using it to further investigate pathophysiological changes that may contribute to TS and related conditions.