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首页> 外文期刊>Neurobiology of disease >Loss of cortical GABA terminals in Unverricht-Lundborg disease
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Loss of cortical GABA terminals in Unverricht-Lundborg disease

机译：Unverricht-Lundborg病中皮质GABA末端的丢失

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Unverricht-Lundborg disease (ULD) is the most common progressive myoclonic epilepsy. Its etiology has been identified in a defect of a protease inhibitor, cystatin B (CSTB), but the mechanism(s) by which this defect translates in the clinical manifestations of the disease are still obscure. We tested the hypothesis that ULD is accompanied by a loss of cortical GABA inhibition in a murine model (the CSTB knockout mouse) and in a human case. Cortical GABA signaling has been investigated measuring VGAT immunohistochemistry (a histological marker of the density of GABA terminals), GABA release from synaptosomes and paired-pulse stimulation. In CSTB knockout mice, a progressive decrease in neocortex thickness was found, associated with a prevalent loss of GABA interneurons. A marked reduction in VGAT labeling was found in the cortex of both CSTB knockout mice and an ULD patient. This implicates a reduction in GABA synaptic transmission, which was confirmed in the mouse model as reduction in GABA release from isolated nerve terminals and as loss of electrophysiologically measured GABA inhibition. The alterations in VGAT immunolabeling progressed in time, paralleling the worsening of myoclonus. These results provide direct evidence that loss of cortical GABA input occurs in a relevant animal model and in a case of human ULD, leading to a condition of latent hyperexcitability that favors myoclonus and seizures. These findings contribute to the understanding of the pathogenic mechanism of ULD and of the neurobiological basis of the effect of currently employed drugs.
机译：Unverricht-Lundborg病（ULD）是最常见的进行性肌阵挛性癫痫。已经在蛋白酶抑制剂胱抑素B（CSTB）的缺陷中发现了其病因，但是该缺陷在疾病临床表现中转化的机制仍然不清楚。我们在小鼠模型（CSTB基因敲除小鼠）和人类病例中检验了ULD伴随着皮质GABA抑制作用丧失的假设。已经研究了皮质GABA信号传导，通过测量VGAT免疫组织化学（GABA末端密度的组织学标记），突触小体释放GABA和成对脉冲刺激来进行研究。在CSTB基因敲除小鼠中，发现新皮层厚度逐渐减少，与GABA中间神经元的普遍丢失有关。在CSTB基因敲除小鼠和ULD患者的皮质中均发现VGAT标记显着减少。这暗示了GABA突触传递的减少，这在小鼠模型中被确认为从孤立的神经末梢释放的GABA减少以及电生理学测量的GABA抑制作用的丧失。 VGAT免疫标记的变化随时间进展，与肌阵挛的恶化并行。这些结果提供了直接的证据，即在相关的动物模型中以及在人类ULD的情况下发生了皮质GABA输入的损失，导致了潜在的过度兴奋状态，有利于肌阵挛和癫痫发作。这些发现有助于人们了解ULD的致病机理以及目前使用药物的神经生物学基础。

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