A novel inhibitory target for temporal lobe epilepsy

摘要 颞叶癫痫是成人最常见的癫痫形式，新的治疗方案是 需要。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表达 NOS 的抑制性神经元的独特亚群（称为 在本提案中称为“NPIN”），我们的初步数据表明这可能是极好的目标 颞叶癫痫的干预。本提案中概述的实验提供了基本的 健康和癫痫动物中 NPIN 的表征，并检验按需假设 NPIN 的光遗传学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提高了我们对 包括癫痫在内的神经系统疾病，并允许明智地设计新的治疗方案。 我们的初步数据表明，NPIN 在海马体内提供抑制作用，并具有 海马外投射，包括额叶皮层。在海马体内，我们初步 数据显示，NPIN 提供了强大、广泛且持久的抑制作用，使 NPIN 处于理想的状态。 改变网络活动的位置。振荡活动，包括 theta，在 海马生理学和相干振荡对于协调信息传递很重要 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 会增加 theta 的相干性 健康动物的海马体内以及海马体和额叶皮层之间。 重要的是，NPIN 提供广泛而强烈的抑制作用的明显能力也表明， NPIN 的需求光遗传学激活可能是抑制慢性癫痫发作的有效策略 癫痫动物。我们的初步数据进一步支持了这一策略，表明长期来看 尽管总体数量有所减少，但癫痫动物 NPIN 仍然存在，并继续提供强大的 抑制。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 准备对海马活动产生重大影响。通过探索 NPIN 在健康和癫痫方面的作用， 该提案中概述的实验将提供对海马细胞类型和 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 NPIN 能够提供广泛而强烈的抑制作用， 作为颞叶癫痫的可能治疗目标令人兴奋。

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.