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.

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在婴儿期开始，随后出现合并症，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功能丧失，引发癫痫发作。我们研究了钠离子通道病是否会导致 DS 模型的结构变化，而与癫痫发作无关。胼胝体内轴突的形态测量分析在Scn1a 的P16 和 P50完成杂合子 KO 雄性小鼠及其年龄匹配的野生型同窝仔。可训练的机器学习算法用于检查每只动物、每种基因型约 400 个有髓鞘轴突的电子显微镜图像，包括有髓鞘轴突横截面积、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。定性分析还显示微特征标记 DS 模型中 P16 处的髓鞘形成改变，髓鞘外折叠和吞噬细胞内的髓鞘碎片。数据表明，在没有行为性癫痫发作的情况下，控制 P16 向小口径轴突转变的因素在成人Scn1a 中持续存在杂合子 KO 胼胝体。该试点研究为未来的荟萃分析奠定了基础，这将使钠离子通道病对轴突结构的影响进行可靠估计。我们建议 DS 的早期治疗策略可以帮助最大限度地减少钠离子通道病的影响，超越明显癫痫发作的影响，从而实现更好的长期治疗结果。