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Abstract：
Dravet Syndrome (DS) is a genetic neurodevelopmental disease. Recurrent severe seizures begin in infancy and co-morbidities follow, including developmental delay, cognitive and behavioral dysfunction. A majority of DS patients have an SCN1A heterozygous gene mutation. This mutation causes a loss-of-function in inhibitory neurons, initiating seizure onset. We have investigated whether the sodium channelopathy may result in structural changes in the DS model independent of seizures. Morphometric analyses of axons within the corpus callosum were completed at P16 and P50 in Scn1a heterozygote KO male mice and their age-matched wild-type littermates. Trainable machine learning algorithms were used to examine electron microscopy images of ~400 myelinated axons per animal, per genotype, including myelinated axon cross-section area, frequency distribution and g-ratios. Pilot data for Scn1a heterozygote KO mice demonstrate the average axon caliber was reduced in developing and adult mice. Qualitative analysis also shows micro-features marking altered myelination at P16 in the DS model, with myelin out-folding and myelin debris within phagocytic cells. The data has indicated, in the absence of behavioral seizures, factors that governed a shift toward small calibre axons at P16 have persisted in adult Scn1a heterozygote KO corpus callosum. The pilot study provides a basis for future meta-analysis that will enable robust estimates of the effects of the sodium channelopathy on axon architecture. We propose that early therapeutic strategies in DS could help minimize the effect of sodium channelopathies, beyond the impact of overt seizures, and therefore achieve better long-term treatment outcomes.
摘要：
Dravet综合征（DS）是一种遗传性神经发育疾病。反复发作的严重癫痫发作始于婴儿期，合并症随之而来，包括发育迟缓,认知和行为功能障碍。大多数DS患者具有SCN1A杂合基因突变。这种突变导致抑制性神经元的功能丧失，开始癫痫发作。我们已经研究了钠通道作用是否可能导致DS模型的结构变化，而与癫痫发作无关。在Scn1a杂合子KO雄性小鼠及其年龄匹配的野生型同窝中，在P16和P50处完成了call体内轴突的形态测量分析。可训练的机器学习算法用于检查每只动物约400个有髓鞘轴突的电子显微镜图像，每个基因型，包括有髓鞘的轴突横截面面积，频率分布和G比。Scn1a杂合子KO小鼠的试验数据表明，发育中和成年小鼠的平均轴突口径降低。定性分析还显示，在DS模型中，在P16处标记髓鞘形成改变的微观特征，吞噬细胞内髓磷脂折叠和髓磷脂碎片。数据表明，在没有行为癫痫发作的情况下，在成年Scn1a杂合子KOcall体中，控制P16向小口径轴突转移的因素仍然存在。该初步研究为未来的荟萃分析提供了基础，该分析将能够可靠地估计钠通道作用对轴突结构的影响。我们建议DS的早期治疗策略可以帮助最小化钠通道病的影响，除了公开缉获的影响，并因此获得更好的长期治疗结果。
