Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, University College London, London, UK.
San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milan, Italy.
Neurobiol Dis. 2024 Oct 15;201:106688. doi: 10.1016/j.nbd.2024.106688. Epub 2024 Oct 3.
Dravet Syndrome (DS) is most often caused by heterozygous loss-of-function mutations in the voltage-gated sodium channel gene SCN1A (Na1.1), resulting in severe epilepsy and neurodevelopmental impairment thought to be cause by reduced interneuron excitability. However, recent studies in mouse models suggest that interneuron dysfunction alone does not completely explain all the cellular and network impairments seen in DS. Here, we investigated the development of the intrinsic, synaptic, and network properties of CA1 pyramidal cells in a DS model prior to the appearance of overt seizures. We report that CA1 pyramidal cell development is altered by heterozygous reduction of Scn1a, and propose that this is explained by a period of reduced intrinsic excitability in early postnatal life, during which Scn1a is normally expressed in hippocampal pyramidal cells. We also use a novel ex vivo model of homeostatic plasticity to show an instability in homeostatic response during DS epileptogenesis. This study provides evidence for the early effects of Scn1a haploinsufficiency in pyramidal cells in contributing to the pathophysiology of DS.
德拉维特综合征（DS）通常是由电压门控钠离子通道基因 SCN1A（Na1.1）的杂合功能丧失突变引起的，导致严重的癫痫和神经发育障碍，据认为这是由于中间神经元兴奋性降低所致。然而，最近的小鼠模型研究表明，中间神经元功能障碍本身并不能完全解释 DS 中观察到的所有细胞和网络损伤。在这里，我们在明显癫痫发作之前研究了 DS 模型中 CA1 锥体神经元的内在、突触和网络特性的发育。我们报告说，Scn1a 的杂合性减少改变了 CA1 锥体神经元的发育，并且提出这可以解释为正常表达于海马锥体神经元中的 Scn1a 在出生后早期生命中存在一段内在兴奋性降低的时期。我们还使用了一种新的体外同源性可塑性模型，显示了 DS 癫痫发生过程中同源性反应的不稳定性。这项研究为 Scn1a 单倍不足在锥体神经元中对 DS 病理生理学的早期影响提供了证据。
