Astrocytic mechanisms in a new genetic model of migraine

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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.