Departments of Neurology and Neuroscience, Center for Learning and Memory, Dell Medical School, University of Texas at Austin, Austin, Texas 78712.
Departments of Neurology and Neuroscience, Center for Learning and Memory, Dell Medical School, University of Texas at Austin, Austin, Texas 78712
J Neurosci. 2023 Dec 6;43(49):8562-8577. doi: 10.1523/JNEUROSCI.0786-23.2023.
Pathogenic variants in have been linked to severe developmental epileptic encephalopathies including Dravet syndrome. knock-out (KO) mice model loss-of-function (LOF) disorders, demonstrating seizures, developmental delays, and early death. 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 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 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 KO pyramidal neurons, resulting in fundamentally altered cellular information processing in the hippocampus that likely contributes to the complex phenotypes of -linked epileptic encephalopathies. 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. is a gene linked to Dravet syndrome and other developmental epileptic encephalopathies, and 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 , including intrinsic excitability, synaptic properties, and synaptic integration, resulting in greatly enhanced input/output functions of the hippocampus. Our study shows that loss of results in a complex array of cellular and network changes that fundamentally alters information processing in the hippocampus.
在 中发现的致病变异与包括德拉维特综合征在内的严重发育性癫痫性脑病有关。 敲除 (KO) 小鼠模型表现出癫痫发作、发育迟缓以及早逝等功能丧失 (LOF) 障碍。 编码β1 蛋白，这是一种离子通道辅助亚基，在细胞黏附、神经突生长和基因表达中也具有作用。该项目的目标是更好地了解 缺失如何改变大脑中的信息处理，导致癫痫发作和相关认知功能障碍。通过对雄性和雌性 KO 小鼠及其野生型 (WT) 同窝仔鼠海马 CA1 区的切片电生理学研究，我们发现，对生理相关模式化沙费尔侧支 (SC) 刺激的处理会导致 KO 神经元产生更大、更长时间的去极化和更多的尖峰放电，与 WT 相比。KO 神经元表现出增强的内在兴奋性，在电流注入时产生更多的动作电位。有趣的是，SC 刺激在 KO 锥体神经元中产生更小、更易化的兴奋性和 IPSC，但相同刺激下产生更大的突触后电位 (PSP)。我们还发现，模式化突触刺激时，表达 Parvalbumin (PV) 的中间神经元的内在放电减少，表达 Parvalbumin 和 Somatostatin (SST) 的中间神经元的募集受到破坏。神经元信息处理依赖于突触特性、放大或抑制传入突触信号的内在特性以及产生细胞输出的放电特性之间的相互作用。我们在 KO 锥体神经元的这些水平上都发现了变化，导致海马体中基本改变的细胞信息处理，这可能导致与 相关的癫痫性脑病的复杂表型。遗传性发育性癫痫性脑病的治疗选择有限，部分原因是我们对遗传变化如何导致细胞和电路水平功能障碍的了解有限。 是与德拉维特综合征和其他发育性癫痫性脑病相关的基因， KO 小鼠模拟人类疾病，使我们能够研究潜在的神经生理变化。在这里，我们发现缺乏 的大脑在神经元信息处理的所有水平上都发生了变化，包括内在兴奋性、突触特性和突触整合，从而极大地增强了海马体的输入/输出功能。我们的研究表明， 的缺失导致了一系列复杂的细胞和网络变化，从根本上改变了海马体的信息处理。
