A Cacna1a knockin migraine mouse model with increased susceptibility to cortical spreading depression
A Cacna1a knockin migraine mouse model with increased susceptibility to cortical spreading depression
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DOI：
10.1016/s0896-6273(04)00085-6
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发表时间：
2004-03-04
期刊：
影响因子：
16.2
通讯作者：
Ferrari, MD
中科院分区：
文献类型：
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作者：
van den Maagdenberg, AMJM;Pietrobon, D;Ferrari, MD
偏头痛是一种常见、致残、多因素、阵发性神经血管疾病，病因不明。家族性偏瘫型偏头痛 1 型 (FHM-1) 是一种先兆偏头痛的孟德尔亚型，由编码神经元 Ca(v)2.1 Ca2+ 通道的 alpha(1) 亚基的 CACNA1A 基因错义突变引起。我们构建了携带人类纯 FHM-1 R192Q 突变的敲入小鼠模型，并发现了多种功能获得效应。这些包括小脑神经元中 Ca(v)2.1 电流密度的增加、神经肌肉接头处神经传递的增强，以及在完整动物中，皮质扩散抑制（CSD；偏头痛先兆的可能机制）的阈值降低和速度增加。我们的数据表明，偏头痛中 CSD 和先兆的易感性增加可能是由于皮质过度兴奋。 R192Q FHM-1 小鼠是研究偏头痛机制和治疗的有前途的动物模型。
Migraine is a common, disabling, multifactorial, episodic neurovascular disorder of unknown etiology. Familial hemiplegic migraine type 1 (FHM-1) is a Mendelian subtype of migraine with aura that is caused by missense mutations in the CACNA1A gene that encodes the alpha(1) subunit of neuronal Ca(v)2.1 Ca2+ channels. We generated a knockin mouse model carrying the human pure FHM-1 R192Q mutation and found multiple gain-of-function effects. These include increased Ca(v)2.1 current density in cerebellar neurons, enhanced neurotransmission at the neuromuscular junction, and, in the intact animal, a reduced threshold and increased velocity of cortical spreading depression (CSD; the likely mechanism for the migraine aura). Our data show that the increased susceptibility for CSD and aura in migraine may be due to cortical hyperexcitability. The R192Q FHM-1 mouse is a promising animal model to study migraine mechanisms and treatments.