Department of Neuroscience and Pharmacology, University of Copenhagen, Copenhagen, Denmark.
Departments of Human Genetics and Neurology, Leiden University Medical Center, Leiden, The Netherlands.
Ann Neurol. 2016 Aug;80(2):219-32. doi: 10.1002/ana.24707. Epub 2016 Jul 26.
Familial hemiplegic migraine type 1 (FHM1) is a subtype of migraine with aura caused by a gain-of-function mutation in the pore-forming α1 subunit of CaV 2.1 (P/Q-type) calcium channels. However, the mechanisms underlying how the disease is brought about and the prolonged aura remain incompletely understood.
In the anesthetized FHM1 mouse model in vivo, we used two-photon microscopy to measure calcium changes in neurons and astrocytes during somatosensory stimulations and cortical spreading depression (CSD), the putative mechanism of the migraine aura. We combined it with assessment of local field potentials by electrophysiological recordings, cerebral blood flow by laser Doppler flowmetry, and oxygen consumption with measurement of the oxygen tissue tension.
During spreading depression, the evoked increase in cytosolic Ca(2+) was larger and faster in FHM1 mice than wild-type (WT) mice. It was accompanied by larger increases in oxygen consumption in FHM1 mice, leading to tissue anoxia, but moderate hypoxia, in WT mice. In comparison, before CSD, Ca(2+) and hemodynamic responses to somatosensory stimulations were smaller in FHM1 mice than WT mice and almost abolished after CSD. The CSD-induced Ca(2+) changes were mitigated by the CaV 2.1 gating modifier, tert-butyl dihydroquinone.
Our findings suggest that tissue anoxia might be a mechanism for prolonged aura in FHM1. Reduced Ca(2+) signals during normal network activity in FHM1 as compared to WT mice may explain impaired neurovascular responses in the mutant, and these alterations could contribute to brain frailty in FHM1 patients. Ann Neurol 2016;80:219-232.
家族性偏瘫性偏头痛 1 型（FHM1）是一种有先兆偏头痛的亚型，由钙通道 P/Q 型 α1 亚基（CaV2.1）的功能获得性突变引起。然而，疾病的发病机制和延长的先兆仍不完全清楚。
在体内麻醉的 FHM1 小鼠模型中，我们使用双光子显微镜测量感觉刺激和皮质扩散性抑制（CSD）期间神经元和星形胶质细胞中的钙变化，CSD 是偏头痛先兆的潜在机制。我们将其与电生理记录评估局部场电位、激光多普勒流量测量评估脑血流以及测量氧组织张力评估耗氧量相结合。
在扩散性抑制期间，FHM1 小鼠中的细胞溶质 Ca（2+）增加幅度大于野生型（WT）小鼠，并且速度更快。它伴随着 FHM1 小鼠中耗氧量的增加，导致组织缺氧，但 WT 小鼠中为中度缺氧。相比之下，在 CSD 之前，FHM1 小鼠的 Ca（2+）和对感觉刺激的血液动力学反应小于 WT 小鼠，并且在 CSD 后几乎消除。CSD 诱导的 Ca（2+）变化被 CaV2.1 门控修饰剂叔丁基二氢醌减轻。
我们的发现表明组织缺氧可能是 FHM1 中延长先兆的机制。与 WT 小鼠相比，FHM1 中正常网络活动期间的 Ca（2+）信号减少可能解释了突变体中神经血管反应受损，并且这些改变可能导致 FHM1 患者的大脑脆弱。神经病学杂志 2016；80：219-232。
