Glycine receptor mouse mutants: model systems for human hyperekplexia
Glycine receptor mouse mutants: model systems for human hyperekplexia
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DOI：
10.1111/bph.12335
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发表时间：
2013-11
影响因子：
7.3
通讯作者：
Natascha Schaefer;G. Langlhofer;Christoph J. Kluck;C. Villmann
中科院分区：
文献类型：
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作者：
Natascha Schaefer;G. Langlhofer;Christoph J. Kluck;C. Villmann
人类高丛症是一种由抑制性甘氨酸介导的神经传递紊乱引起的神经运动障碍。编码甘氨酸受体亚基或相关蛋白的基因突变，如GLRA1、GLRB、GPHN和ARHGEF9，已在高丛症患者中被检测到。典型的症状是对意外的声音或触觉刺激的惊吓发作，剧烈震颤，在惊吓和呼吸暂停期间失去姿势控制。通常患者用氯硝西泮治疗，这可能通过上调gaba能反应来帮助减轻严重症状。然而，其机制尚不完全清楚。在携带甘氨酸受体突变的小鼠模型中观察到类似的神经运动表型。这些小鼠模型是分析潜在病理机制的绝佳工具。然而，在突变小鼠中通过GABAA受体数量上调寻找甘氨酸能功能障碍突触后代偿的研究失败了，因为表达水平与野生型小鼠相似。然而，已经观察到突触前适应机制从混合GABA/甘氨酸能到GABA能突触前终端的不寻常转换。是否这种突触前适应解释了症状的改善或存在其他补偿机制仍在研究中。在自发甘氨酸受体小鼠突变体、敲入和敲出研究的帮助下，有可能将行为变化与甘氨酸能抑制的药理学差异联系起来。这篇综述的重点是各种小鼠模型的结构和功能特征，用于阐明潜在的信号转导途径和适应过程，并描述了一种利用突变受体的基因治疗调节来克服功能突变损失的新途径。
Human hyperekplexia is a neuromotor disorder caused by disturbances in inhibitory glycine‐mediated neurotransmission. Mutations in genes encoding for glycine receptor subunits or associated proteins, such as GLRA1, GLRB, GPHN and ARHGEF9, have been detected in patients suffering from hyperekplexia. Classical symptoms are exaggerated startle attacks upon unexpected acoustic or tactile stimuli, massive tremor, loss of postural control during startle and apnoea. Usually patients are treated with clonazepam, this helps to dampen the severe symptoms most probably by up‐regulating GABAergic responses. However, the mechanism is not completely understood. Similar neuromotor phenotypes have been observed in mouse models that carry glycine receptor mutations. These mouse models serve as excellent tools for analysing the underlying pathomechanisms. Yet, studies in mutant mice looking for postsynaptic compensation of glycinergic dysfunction via an up‐regulation in GABAA receptor numbers have failed, as expression levels were similar to those in wild‐type mice. However, presynaptic adaptation mechanisms with an unusual switch from mixed GABA/glycinergic to GABAergic presynaptic terminals have been observed. Whether this presynaptic adaptation explains the improvement in symptoms or other compensation mechanisms exist is still under investigation. With the help of spontaneous glycine receptor mouse mutants, knock‐in and knock‐out studies, it is possible to associate behavioural changes with pharmacological differences in glycinergic inhibition. This review focuses on the structural and functional characteristics of the various mouse models used to elucidate the underlying signal transduction pathways and adaptation processes and describes a novel route that uses gene‐therapeutic modulation of mutated receptors to overcome loss of function mutations.