A novel inhibitory target for temporal lobe epilepsy

颞叶癫痫的新抑制靶点

• 批准号: 10058281
• 负责人: Esther Krook-Magnuson
• 金额: $ 32.99万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-01 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10058281
• 关键词: Adult; Animal Testing; Animals; Anterior; Area; Basic Science; Cell Count; Cells; Chronic; Control Animal; Data; Development; Disease; Dorsal; Electroencephalography; Electrophysiology (science); Epilepsy; Health; Hippocampus (Brain); Interneurons; Intervention; Investigation; Label; Literature; Location; Modeling; Monitor; Morphology; Neurons; Nitric Oxide Synthase; Patients; Physiology; Play; Population; Positioning Attribute; Property; Pyramidal Cells; Research; Role; Seizures; Slice; Synapses; Task Performances; Temporal Lobe; Temporal Lobe Epilepsy; Testing; Transgenic Mice; Viral Vector; Work; axonal sprouting; base; cell type; design; experimental study; frontal lobe; genetic approach; improved; in vivo; inhibitory neuron; kainate; mouse model; nervous system disorder; neuronal circuitry; novel; optogenetics; postsynaptic; public health relevance; therapeutic target; virus genetics

ABSTRACT Temporal lobe epilepsy is the most common form of epilepsy in adults, and new treatment options are needed. Using viral vectors and intersectional genetic approaches in transgenic mice, we are able to selectively label and manipulate a unique subpopulation of NOS-expressing inhibitory neurons (referred to in this proposal as “NPINs”) which our preliminary data indicate may be excellent targets for intervention in temporal lobe epilepsy. The experiments outlined in this proposal provide a basic characterization of NPINs in healthy and epileptic animals, and test the hypothesis that on-demand optogenetic activation of NPINs will inhibit seizures in a mouse model of temporal lobe epilepsy. Investigation of neuronal circuits and their constituent cell-types improves our understanding of neurological disorders including epilepsy, and allows for the informed design of new treatment options. Our preliminary data indicate that NPINs provide inhibition within the hippocampus and have extrahippocampal projections, including to the frontal cortex. Within the hippocampus, our preliminary data shows that NPINs provide strong, broad, and long lasting inhibition, placing NPINs in an ideal position to alter network activity. Oscillatory activity, including theta, plays an important role in hippocampal physiology, and coherent oscillations are important for coordinated information transfer and predict task performance. Our preliminary data indicates that NPINs are able to induce theta oscillations preferentially, and we further hypothesize that NPINs will increase the coherence of theta within the hippocampus and between the hippocampus and frontal cortex in healthy animals. Importantly, NPINs’ apparent ability to provide broad and strong inhibition also suggests that on- demand optogenetic activation of NPINs may be an effective strategy to inhibit seizures in chronically epileptic animals. Further supporting this strategy, our preliminary data demonstrates that in chronically epileptic animals NPINs persist despite a reduction in overall number and continue to provide strong inhibition. Taken together, our preliminary data indicates that NPINs are a unique neuronal population poised to have a major impact on hippocampal activity. By exploring NPINs in health and in epilepsy, the experiments outlined in this proposal will provide a fuller account of hippocampal cell types and circuitry, including GABAergic projection neurons, and improve our understanding and ability to treat disorders including epilepsy. Given their ability to provide broad and strong inhibition, NPINs are exciting as a possible therapeutic target in temporal lobe epilepsy.

摘要 颞叶癫痫是成人中最常见的癫痫形式，新的治疗方案是 需要的。在转基因小鼠中使用病毒载体和交叉遗传方法，我们能够 选择性地标记和操纵一组独特的表达一氧化氮合酶的抑制神经元(参考 我们的初步数据表明，这可能是一个很好的目标 对颞叶癫痫的干预。本提案中概述的实验提供了一个基本的 NPIN在健康和癫痫动物中的特征，并检验按需 NPIN的光遗传激活将抑制颞叶癫痫小鼠模型的癫痫发作。 对神经元回路及其组成细胞类型的研究增进了我们对 包括癫痫在内的神经疾病，并允许在知情的情况下设计新的治疗方案。 我们的初步数据表明，NPIN在海马体内提供抑制作用，并具有 海马区外的投射，包括到额叶皮质。在海马体内，我们的初步研究 数据显示，NPIN提供了强大、广泛和持久的抑制，使NPIN处于理想状态 改变网络活动的位置。振荡活动，包括theta，在以下方面发挥重要作用 海马体生理学和相干振荡对于协调信息传递是重要的 并预测任务绩效。我们的初步数据表明，NPIN能够诱导theta 振荡优先，我们进一步假设NPIN将增加theta的连贯性 在健康动物的海马体内以及海马体和额叶皮质之间。 重要的是，NPIN的明显能力提供广泛和强大的抑制也表明，对- 需求光基因激活NPIN可能是抑制慢性癫痫发作的有效策略 患有癫痫的动物。进一步支持这一战略，我们的初步数据表明，在长期 癫痫动物NPIN在总数减少的情况下仍然存在，并继续提供强大的 抑制力。综上所述，我们的初步数据表明，NPIN是一个独特的神经元群体 准备对海马区的活动产生重大影响。通过探索NPIN在健康和癫痫中的作用， 本提案中概述的实验将提供更全面的海马细胞类型和 电路，包括GABA能投射神经元，并提高我们的理解和治疗能力 包括癫痫在内的疾病。鉴于它们能够提供广泛而强大的抑制作用，NPIN是 兴奋作为治疗颞叶癫痫的一个可能的靶点。