Department of Neurology, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.
Interdepartmental Neuroscience Program, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.
Brain. 2024 Feb 1;147(2):680-697. doi: 10.1093/brain/awad326.
Migraine is a common and disabling neurological disorder. The headache and sensory amplifications of migraine are attributed to hyperexcitable sensory circuits, but a detailed understanding remains elusive. A mutation in casein kinase 1 delta (CK1δ) was identified in non-hemiplegic familial migraine with aura and advanced sleep phase syndrome. Mice carrying the CK1δT44A mutation were more susceptible to spreading depolarization (the phenomenon that underlies migraine aura), but mechanisms underlying this migraine-relevant phenotype were not known. We used a combination of whole-cell electrophysiology and multiphoton imaging, in vivo and in brain slices, to compare CK1δT44A mice (adult males) to their wild-type littermates. We found that despite comparable synaptic activity at rest, CK1δT44A neurons were more excitable upon repetitive stimulation than wild-type, with a reduction in presynaptic adaptation at excitatory but not inhibitory synapses. The mechanism of this adaptation deficit was a calcium-dependent enhancement of the size of the readily releasable pool of synaptic vesicles, and a resultant increase in glutamate release, in CK1δT44A compared to wild-type synapses. Consistent with this mechanism, CK1δT44A neurons showed an increase in the cumulative amplitude of excitatory post-synaptic currents, and a higher excitation-to-inhibition ratio during sustained activity compared to wild-type. At a local circuit level, action potential bursts elicited in CK1δT44A neurons triggered an increase in recurrent excitation compared to wild-type, and at a network level, CK1δT44A mice showed a longer duration of 'up state' activity, which is dependent on recurrent excitation. Finally, we demonstrated that the spreading depolarization susceptibility of CK1δT44A mice could be returned to wild-type levels with the same intervention (reduced extracellular calcium) that normalized presynaptic adaptation. Taken together, these findings show a stimulus-dependent presynaptic gain of function at glutamatergic synapses in a genetic model of migraine, that accounts for the increased spreading depolarization susceptibility and may also explain the sensory amplifications that are associated with the disease.
偏头痛是一种常见的、使人丧失能力的神经系统疾病。偏头痛的头痛和感觉放大归因于超兴奋性感觉回路，但对其详细的理解仍难以捉摸。在非偏瘫性家族性偏头痛伴先兆和睡眠相位提前综合征中发现了酪蛋白激酶 1 德尔塔（CK1δ）的突变。携带 CK1δT44A 突变的小鼠更容易发生扩布性去极化（偏头痛先兆的现象基础），但与这种偏头痛相关表型相关的机制尚不清楚。我们使用全细胞电生理学和多光子成像技术，在体内和脑片中，比较 CK1δT44A 小鼠（成年雄性）与其野生型同窝仔鼠。我们发现，尽管在静息状态下突触活动相当，但 CK1δT44A 神经元在重复刺激下比野生型更易兴奋，兴奋性突触前适应减少，但抑制性突触前适应没有减少。这种适应缺陷的机制是钙依赖性地增加了突触小泡的易释放池的大小，导致 CK1δT44A 突触中谷氨酸释放增加，与野生型相比。与这种机制一致，CK1δT44A 神经元在持续活动期间表现出兴奋性突触后电流的累积幅度增加，以及兴奋与抑制的比率增加。在局部回路水平上，CK1δT44A 神经元中的动作电位爆发引发的兴奋后兴奋比野生型增加，在网络水平上，CK1δT44A 小鼠显示出更长的“上状态”活动持续时间，这依赖于兴奋后兴奋。最后，我们证明 CK1δT44A 小鼠的扩布性去极化易感性可以通过相同的干预（降低细胞外钙）恢复到野生型水平，这种干预恢复了突触前适应。综上所述，这些发现表明，在偏头痛的遗传模型中，谷氨酸能突触存在一种刺激依赖性的突触前功能获得，这可以解释增加的扩布性去极化易感性，也可以解释与疾病相关的感觉放大。
