Department of Neurobiology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
Laboratory of Molecular and Developmental Biology, National Institute of Genetics and Department of Genetics, SOKENDAI (The Graduate University for Advanced Studies), Shizuoka, Japan.
J Neurophysiol. 2021 Dec 1;126(6):1934-1942. doi: 10.1152/jn.00343.2021. Epub 2021 Nov 3.
Spreading depolarization (SD) is a slowly propagating wave of neuronal and glial depolarization. A growing number of studies show that SD and SD-like phenomena play a role in neurological disorders such as migraine, stroke, and traumatic brain injury. Despite the clinical importance of SD, its underlying molecular and cellular mechanisms remain elusive, possibly because of insufficient animal model allowing genetic manipulation. Such a model would also allow high-throughput screening for SD-suppressing drug development. To address this, we developed a novel experimental system to study SD using zebrafish. Electrophysiological recordings in the immobilized adult zebrafish revealed that increasing extracellular potassium concentration elicited SD with a large and long-lasting negative shift of direct current (DC) potential in the optic tectum. It also reduced the oscillatory activity in the extracellular field potential and increased the expression of the immediate early gene c-fos. Pharmacological blocking of the -methyl-d-aspartate (NMDA) glutamate receptor attenuated the propagation of SD, suggesting that glutamatergic neurotransmission mediated tectal SD in zebrafish. Our analyses revealed that the zebrafish tectum and rodent cortex had similar SD kinetics. The current study provides electrophysiological and pharmacological evidence that zebrafish SD and mammal SD are comparable. This zebrafish SD model is suitable for genetic manipulation and cost-effective high-throughput screening. It could pave the way to novel diagnostic and therapeutic methods applicable to SD-associated neurological disorders. Previous studies have implicated spreading depolarization (SD) in stroke and migraine. Here, we demonstrate SD, for the first time, in the adult zebrafish tectum showing waveform kinetics, c-fos expression, and attenuation by -methyl-d-aspartate glutamate receptor blocker as observed in the rodent cortex. Since the zebrafish is an animal model amenable to genetic manipulation and chemical screening, this result could pave the way to novel diagnostic and therapeutic methods applicable to SD-associated neurological disorders.
去极化扩散（SD）是一种神经元和神经胶质去极化的缓慢传播波。越来越多的研究表明，SD 和类似 SD 的现象在偏头痛、中风和创伤性脑损伤等神经疾病中发挥作用。尽管 SD 具有临床重要性，但它的潜在分子和细胞机制仍不清楚，这可能是由于缺乏允许遗传操作的动物模型。这样的模型也将允许高通量筛选 SD 抑制药物的开发。为了解决这个问题，我们开发了一种使用斑马鱼研究 SD 的新型实验系统。在固定的成年斑马鱼中进行的电生理记录显示，增加细胞外钾浓度会引起 SD，导致光顶盖的直流（DC）电位出现大而持久的负向偏移。它还降低了细胞外场电位的振荡活动，并增加了即刻早期基因 c-fos 的表达。NMDA 谷氨酸受体的药理学阻断减弱了 SD 的传播，表明在斑马鱼中，谷氨酸能神经传递介导了顶盖的 SD。我们的分析表明，斑马鱼顶盖和啮齿动物皮层具有相似的 SD 动力学。本研究提供了电生理学和药理学证据，表明斑马鱼 SD 和哺乳动物 SD 是可比的。这种斑马鱼 SD 模型适合遗传操作和具有成本效益的高通量筛选。它可以为与 SD 相关的神经疾病开辟新的诊断和治疗方法。先前的研究表明，扩散性去极化（SD）与中风和偏头痛有关。在这里，我们首次在成年斑马鱼顶盖中显示出波形动力学、c-fos 表达和 NMDA 谷氨酸受体阻滞剂的衰减，这与啮齿动物皮层中的观察结果一致。由于斑马鱼是一种可进行遗传操作和化学筛选的动物模型，因此这一结果可能为与 SD 相关的神经疾病开辟新的诊断和治疗方法。
