Astrocytic mechanisms in a new genetic model of migraine

偏头痛影响世界人口的12%，并且是世界范围内残疾的主要原因之一。然而 令人惊讶的是，人们对这种疾病的基本特征知之甚少。我们帮助开发了一种新的老鼠基因， 偏头痛的模型，我们现在建议检查其机制。酪蛋白激酶1 δ（CK 1d）小鼠 来自一个有先兆的遗传性偏头痛家族。我们发现CK 1d小鼠有两个关键点， 与偏头痛相关的表型：对偏头痛触发的感觉网络反应增加， 增加对皮质扩散性抑制（CSD）的敏感性，这是偏头痛先兆的基础。虽然我们的 最初的努力集中在潜在的神经元机制，这种网络的兴奋性，我们已经能够 排除这些，现在专注于越来越多的证据表明CK 1d突变通过以下方式发挥作用： 星形胶质细胞-特别是通过受损的摄取谷氨酸和钾。我们的第一个目标是直接检查 在CK 1d动物和野生型同窝仔中，使用体内两种方法的组合， 光子显微镜和全细胞电生理记录。我们的假设是，由于其对 星形胶质细胞合胞体功能，CK 1d突变减缓谷氨酸和K+再摄取。我们将与 CK 1d抑制和过度表达，以及直接抑制CK 1d靶点连接蛋白43（Cx43）。的 第二个目标将采取类似的方法，同时检查CSD，第三个目标将检查感觉网络 功能我们的假设是，受损的星形胶质细胞摄取是共同的机制， 表型如果成功，我们将能够评估CK 1d突变是否是必要的和足够的， 偏头痛表型，以及通过何种特定机制发挥其作用。这项工作可能很重要 因为这将大大增加证据表明，星形胶质细胞的再摄取，像神经元的兴奋性，是一个可行的， 诱发偏头痛的途径第二个重要方面是，尽管CK 1d突变无疑是罕见的， 它与所有其他单基因偏头痛模型的区别在于突变携带者有正常的偏头痛发作， (as反对与偏瘫相关的攻击），因此可能与大多数 偏头痛患者

Migraine affects 12% of the world population, and is one of the leading causes of disability worldwide. Yet surprisingly little is known about the basic features of this disease. We helped develop a new mouse genetic model of migraine, and we now propose to examine its mechanisms. The casein kinase 1 delta (CK1d) mouse expresses a mutation from a family with inherited migraine with aura. We found that CK1d mice had two key phenotypes relevant to migraine: an increased sensory network response to a migraine trigger, and an increased susceptibility to cortical spreading depression (CSD), which underlies the migraine aura. While our initial efforts focused on potential neuronal mechanisms underlying this network excitability, we have been able to rule those out, and now focus on increasing evidence that the CK1d mutation exerts its effects through astrocytes - specifically through impaired uptake of glutamate and potassium. Our first aim will directly examine glutamate and K+ reuptake on CK1d animals and wild type littermates, using a combination of in vivo two photon microscopy and whole cell electrophysiological recordings. Our hypothesis is that due to its effects on astrocyte syncitial function, the CK1d mutation slows glutamate and K+ reuptake. We will confirm this with CK1d inhibition and overexpression, and direct inhibition of the connexin43 protein (Cx43), a CK1d target. The second aim will take a similar approach while examining CSD, and the third aim will examine sensory network function. Our hypothesis is that impaired astrocytic uptake is the common mechanism that links both phenotypes. If successful we will be able to assess whether the CK1d mutation is necessary and sufficient for the migraine phenotype, and by what specific mechanism(s) it exerts its effects. This work could be important because it would add significantly to evidence that astrocytic reuptake, like neuronal excitability, is a viable path to migraine induction. A second important aspect is that, although the CK1d mutation is undoubtedly rare, it contrasts with all other monogenic migraine models in that mutation carriers have normal migraine attacks (as opposed to attacks associated with hemiplegia), and thus could be more relevant to the majority of migraine sufferers.