Astrocytic mechanisms in a new genetic model of migraine

偏头痛影响着世界12%的人口，是全世界导致残疾的主要原因之一。还没有 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小鼠基因 偏头痛的模型，我们现在建议研究它的机制。酪蛋白激酶1增量(CK1d)小鼠 表达一个遗传性偏头痛先兆家族的突变。我们发现CK1d小鼠有两把钥匙 与偏头痛相关的表型：对偏头痛触发的感觉网络反应增强，以及 增加对皮质扩散性抑制(CSD)的易感性，这是偏头痛先兆的基础。而我们的 最初的努力集中在这种网络兴奋性潜在的神经元机制上，我们已经能够 排除这些，现在专注于越来越多的证据表明CK1d突变通过 星形胶质细胞--特别是通过谷氨酸和钾的摄取受损。我们的第一个目标将直接检查 CK1d动物和野生型仔鼠体内谷氨酸和K+的再吸收 光子显微镜和全细胞电生理记录。我们的假设是，由于它对 星形胶质细胞的联会功能，CK1d突变减慢谷氨酸和K+的重新摄取。我们将与您确认这一点 CK1d的抑制和过度表达，以及连接蛋白43(Cx43)的直接抑制，是CK1d的靶点。这个 第二个目标将在检查CSD时采取类似的方法，第三个目标将检查感觉网络 功能。我们的假设是，星形胶质细胞摄取受损是连接两者的共同机制 表型。如果成功，我们将能够评估CK1d突变是否是必要的和充分的 偏头痛的表型，以及它是通过什么具体机制发挥作用的(S)。这项工作可能很重要 因为这将大大增加星形细胞再摄取的证据，就像神经元兴奋性一样，是一种可行的 引发偏头痛的途径。第二个重要的方面是，尽管CK1d突变无疑是罕见的， 它与所有其他单基因偏头痛模型的对比在于，突变携带者有正常的偏头痛发作 (相对于与偏瘫相关的攻击)，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.