1 Florey Institute for Neuroscience and Mental Health, The University of Melbourne, Parkville, 3010, Australia.
2 Department of Neurology and Epileptology, Hertie Institute of Clinical Brain Research, University of Tübingen, Germany3 Neurological Clinic and Institute of Applied Physiology, University of Ulm, D-89081 Germany.
Brain. 2014 Jun;137(Pt 6):1701-15. doi: 10.1093/brain/awu077. Epub 2014 Apr 17.
Epileptic encephalopathies, including Dravet syndrome, are severe treatment-resistant epilepsies with developmental regression. We examined a mouse model based on a human β1 sodium channel subunit (Scn1b) mutation. Homozygous mutant mice shared phenotypic features and pharmaco-sensitivity with Dravet syndrome. Patch-clamp analysis showed that mutant subicular and layer 2/3 pyramidal neurons had increased action potential firing rates, presumably as a consequence of their increased input resistance. These changes were not seen in L5 or CA1 pyramidal neurons. This raised the concept of a regional seizure mechanism that was supported by data showing increased spontaneous synaptic activity in the subiculum but not CA1. Importantly, no changes in firing or synaptic properties of gamma-aminobutyric acidergic interneurons from mutant mice were observed, which is in contrast with Scn1a-based models of Dravet syndrome. Morphological analysis of subicular pyramidal neurons revealed reduced dendritic arborization. The antiepileptic drug retigabine, a K+ channel opener that reduces input resistance, dampened action potential firing and protected mutant mice from thermal seizures. These results suggest a novel mechanism of disease genesis in genetic epilepsy and demonstrate an effective mechanism-based treatment of the disease.
癫痫性脑病，包括德拉维特综合征，是一种严重的耐药性癫痫，伴有发育倒退。我们研究了一种基于人类β1 钠通道亚基（Scn1b）突变的小鼠模型。杂合突变小鼠表现出与德拉维特综合征相似的表型特征和药物敏感性。膜片钳分析显示，突变的海马锥体细胞和 2/3 层的锥体细胞的动作电位发放率增加，推测是由于其输入电阻增加所致。这些变化在 L5 或 CA1 锥体细胞中未观察到。这提出了一种区域性癫痫发作机制的概念，该概念得到了以下数据的支持：在海马体中观察到自发性突触活动增加，但在 CA1 中没有观察到增加。重要的是，从突变小鼠中观察到γ-氨基丁酸能中间神经元的放电或突触特性没有变化，这与基于 Scn1a 的德拉维特综合征模型相反。海马锥体细胞的形态分析显示树突分支减少。抗癫痫药物瑞替加滨是一种 K+通道开放剂，可降低输入电阻，抑制动作电位发放，并保护突变小鼠免受热性惊厥。这些结果表明遗传性癫痫的一种新的疾病发病机制，并证明了一种有效的基于机制的疾病治疗方法。
