SCN1B的致病变异与包括Dravet综合征在内的严重发育性癫痫性脑病有关。SCN1b基因敲除(KO)小鼠模型SCN1B功能缺失障碍,展示癫痫发作,发育迟缓,和早逝。SCN1B编码蛋白β1,一种离子通道辅助亚基,也在细胞粘附中起作用,神经突生长,和基因表达。该项目的目的是更好地了解Scn1b的丢失如何改变大脑中的信息处理,导致癫痫发作和相关的认知功能障碍。使用雄性和雌性Scn1bKO小鼠和野生型(WT)同窝的海马CA1区域的切片电生理学,我们发现生理相关模式化Schaffer侧支(SC)刺激的处理产生更大的,与WT相比,KO神经元的去极化时间延长,尖峰增加。KO神经元表现出增强的内在兴奋性,用电流注入激发更多的动作电位。有趣的是,SC刺激产生较小,更有利于KO锥体神经元的兴奋性和抑制性突触后电流,但是在相同的刺激下,突触后电位更大。我们还发现,响应于模式化的突触刺激,表达小白蛋白的中间神经元的内在放电减少,并破坏了表达小白蛋白和生长抑素的中间神经元的募集。神经元信息处理依赖于突触特性之间的相互作用,放大或抑制传入突触信号的内在特性,和产生细胞输出的点火特性。我们在Scn1bKO锥体神经元中发现了这些水平的变化,导致海马中细胞信息处理发生根本改变,这可能导致SCN1B相关的癫痫性脑病的复杂表型。重要性陈述遗传性发育性癫痫性脑病的治疗选择有限,部分原因是我们缺乏对遗传变化如何导致细胞和回路水平功能障碍的理解。SCN1B是与Dravet综合征和其他发育性癫痫性脑病相关的基因,和Scn1b基因敲除小鼠表型复制人类疾病,允许我们研究潜在的神经生理变化。在这里,我们发现了缺乏Scn1b的大脑中神经元信息处理的各个层面的变化,包括内在的兴奋性,突触性质,和突触整合,导致海马体的输入/输出功能大大增强。我们的研究表明,Scn1b的丢失会导致一系列复杂的细胞和网络变化,从而从根本上改变海马的信息处理。
Pathogenic variants in
SCN1B have been linked to severe developmental epileptic encephalopathies including Dravet syndrome.
Scn1b knock-out (KO) mice model
SCN1B loss-of-function (LOF) disorders, demonstrating seizures, developmental delays, and early death.
SCN1B encodes the protein β1, an ion channel auxiliary subunit that also has roles in cell adhesion, neurite outgrowth, and gene expression. The goal of this project is to better understand of how loss of
Scn1b alters information processing in the brain, resulting in seizures and associated cognitive dysfunction. Using slice electrophysiology in the CA1 region of the hippocampus from male and female Scn1b KO mice and wild-type (WT) littermates, we found that processing of physiologically relevant patterned Schaffer collateral (SC) stimulation produces larger, prolonged depolarizations and increased spiking in KO neurons compared with WTs. KO neurons exhibit enhanced intrinsic excitability, firing more action potentials with current injection. Interestingly, SC stimulation produces smaller, more facilitating excitatory and IPSCs in KO pyramidal neurons, but larger postsynaptic potentials (PSPs) with the same stimulation. We also found reduced intrinsic firing of parvalbumin (PV)-expressing interneurons and disrupted recruitment of both parvalbumin-expressing and somatostatin (SST)-expressing interneurons in response to patterned synaptic stimulation. Neuronal information processing relies on the interplay between synaptic properties, intrinsic properties that amplify or suppress incoming synaptic signals, and firing properties that produce cellular output. We found changes at each of these levels in Scn1b KO pyramidal neurons, resulting in fundamentally altered cellular information processing in the hippocampus that likely contributes to the complex phenotypes of SCN1B-linked epileptic encephalopathies.SIGNIFICANCE STATEMENT Genetic developmental epileptic encephalopathies have limited treatment options, in part because of our lack of understanding of how genetic changes result in dysfunction at the cellular and circuit levels.
SCN1B is a gene linked to Dravet syndrome and other developmental epileptic encephalopathies, and
Scn1b knock-out (KO) mice phenocopy the human disease, allowing us to study underlying neurophysiological changes. Here, we found changes at all levels of neuronal information processing in brains lacking Scn1b, including intrinsic excitability, synaptic properties, and synaptic integration, resulting in greatly enhanced input/output functions of the hippocampus. Our study shows that loss of Scn1b results in a complex array of cellular and network changes that fundamentally alters information processing in the hippocampus.