A novel inhibitory target for temporal lobe epilepsy

摘要 颞叶癫痫是成人癫痫最常见的形式，新的治疗选择是 needed.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（参考文献2005年10月27日， 我们的初步数据表明，这些国家可能是 颞叶癫痫的治疗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表征，并测试按需 NPIN的光遗传学激活将抑制颞叶癫痫小鼠模型中的癫痫发作。 对神经元回路及其组成细胞类型的研究提高了我们对神经元回路的理解。 该系统可用于治疗包括癫痫在内的神经系统疾病，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在海马内提供抑制作用， 海马体外投射，包括额叶皮质。在海马体中，我们初步的 数据显示，NPIN提供了强、宽和持久的抑制作用，使NPIN处于理想的 改变网络活动。振荡活动，包括θ，在 海马生理学和相干振荡对于协调的信息传递是重要的 并预测任务表现。我们的初步数据表明，NPIN能够诱导θ 振荡优先，我们进一步假设，NPIN将增加相干的θ 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提供广泛和强抑制的明显能力也表明， 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持续存在，尽管总数减少，并继续提供强有力的 抑制作用总之，我们的初步数据表明，NPIN是一个独特的神经元群体 准备对海马体的活动产生重大影响通过探索健康和癫痫中的NPIN， 本提案中概述的实验将提供海马细胞类型的更全面的说明， 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。鉴于其提供广泛和强抑制的能力，NPIN是 作为颞叶癫痫可能的治疗靶点令人兴奋。

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.