Mouse models of rare monogenic forms of migraine provide a unique experimental system to study the cellular and circuit mechanisms of the primary brain dysfunctions causing a migraine disorder. Here, we discuss the migraine-relevant phenotypes and the migraine-relevant functional alterations in the brain of five genetic mouse models of migraine, four of which carry mutations derived from patients with familial hemiplegic migraine (FHM) and the fifth carry a mutation from patients with both phenotypically normal MA and familial advanced sleep phase syndrome (FASPS). We focus on the latter mouse model, in which a ubiquitous serine-threonine kinase is mutated, and on two mouse models of pure FHM, in which a voltage-gated calcium channel controlling neurotransmitter release at most brain synapses and a Na/K ATPase that is expressed mainly in astrocytes in the adult brain are mutated, respectively. First, we describe the behavioral phenotypes of the genetic animal models and review the evidence that an increased susceptibility to experimentally induced cortical spreading depression (CSD) is a key migraine-relevant phenotype common to the five models. Second, we review the synaptic alterations in the cerebral cortex of the genetic models of migraine and discuss the mechanisms underlying their increased susceptibility to CSD. Third, we review the alterations in the trigeminovascular pain pathway and discuss possible implications for migraine pain mechanisms. Finally, we discuss the insights into migraine pathophysiology obtained from the genetic models of migraine, in particular regarding the mechanisms that make the brain of migraineurs susceptible to the ignition of “spontaneous” CSDs. Although the reviewed functional studies support the view of migraine as a disorder of the brain characterized by dysfunctional regulation of the excitatory/inhibitory balance in specific neuronal circuits, much work remains to be done in the genetic mouse models e.g. to identfy the relevant dysfunctional circuits and to establish whether and how the alterations in the function of specific circuits (in the cerebral cortex and/or other brain areas) are state-dependent and may, in certain conditions, favor CSD ignition and the migraine attack.

中文翻译：

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偏头痛的遗传小鼠模型

罕见的单基因偏头痛小鼠模型提供了一个独特的实验系统来研究导致偏头痛疾病的原发性脑功能障碍的细胞和电路机制。在这里，我们讨论了五种偏头痛遗传小鼠模型的大脑中与偏头痛相关的表型和与偏头痛相关的功能改变，其中四种携带来自家族性偏瘫偏头痛 (FHM) 患者的突变，第五种携带来自患者的突变表型正常的 MA 和家族性晚期睡眠期综合征 (FASPS)。我们关注后一种小鼠模型，其中普遍存在的丝氨酸-苏氨酸激酶发生突变，以及两种纯 FHM 小鼠模型，其中控制大多数脑突触神经递质释放的电压门控钙通道和主要在成人大脑星形胶质细胞中表达的 Na/K ATPase 分别发生突变。首先，我们描述了遗传动物模型的行为表型，并回顾了对实验诱导的皮质扩散性抑制 (CSD) 的易感性增加是五种模型常见的关键偏头痛相关表型的证据。其次，我们回顾了偏头痛遗传模型大脑皮层的突触改变，并讨论了它们对 CSD 易感性增加的潜在机制。第三，我们回顾了三叉神经血管疼痛通路的改变，并讨论了对偏头痛机制的可能影响。最后，我们讨论了从偏头痛的遗传模型中获得的对偏头痛病理生理学的见解，特别是关于使偏头痛患者的大脑容易受到“自发”CSD 点燃的机制。尽管所审查的功能研究支持将偏头痛视为一种以特定神经元回路中兴奋/抑制平衡的功能失调调节为特征的大脑疾病的观点，但在遗传小鼠模型中仍有许多工作要做，例如识别相关功能失调的回路和确定特定回路（在大脑皮层和/或其他大脑区域）功能的改变是否以及如何依赖于状态，并且在某些情况下可能有利于 CSD 点火和偏头痛发作。特别是关于使偏头痛患者的大脑容易受到“自发”CSD 点燃的机制。尽管所审查的功能研究支持将偏头痛视为一种以特定神经元回路中兴奋/抑制平衡的功能失调调节为特征的大脑疾病的观点，但在遗传小鼠模型中仍有许多工作要做，例如识别相关功能失调的回路和确定特定回路（在大脑皮层和/或其他大脑区域）功能的改变是否以及如何依赖于状态，并且在某些情况下可能有利于 CSD 点火和偏头痛发作。特别是关于使偏头痛患者的大脑容易受到“自发”CSD 点燃的机制。尽管所审查的功能研究支持将偏头痛视为一种以特定神经元回路中兴奋/抑制平衡的功能失调调节为特征的大脑疾病的观点，但在遗传小鼠模型中仍有许多工作要做，例如识别相关功能失调的回路和确定特定回路（在大脑皮层和/或其他大脑区域）功能的改变是否以及如何依赖于状态，并且在某些情况下可能有利于 CSD 点火和偏头痛发作。