Identification of genetic pathways that regulate neuronal circuits in C. elegans

描述（由申请人提供）：许多神经系统疾病与影响神经元活动和突触功能的基因突变有关。了解这些基因如何调节正常的电路功能将对此类疾病的管理产生深远的影响。除了神经元，大脑还含有近十倍于神经元的非神经胶质细胞，它们支持神经元功能并调节兴奋/抑制平衡。哺乳动物模型系统的研究受到哺乳动物大脑细胞和遗传复杂性的阻碍。使用简单的、完整的生物体模型系统具有降低细胞复杂性的优点，同时在生理条件下保持神经元和非神经元的连接。该项目的总体目标是揭示非神经元细胞调节神经元兴奋/抑制平衡的机制。线虫，秀丽隐杆线虫，将被用作模型系统，主要有四个原因：1）它的神经元网络是通过人类保守的机制形成和维持的，2）它有一个简单的，完全映射的神经系统，3）它很容易通过遗传技术操纵，4）它与自闭症谱系障碍和癫痫中突变的基因有很好的保守同源物。本研究的目标将通过以下具体目标来实现：目标1：使用RNA干扰筛选来鉴定调节神经元兴奋/抑制失衡的非神经元细胞中的遗传途径。目标二：利用荧光标记细胞相互作用的遗传方法，表征在兴奋/抑制不平衡条件下神经元和非神经元细胞之间的物理相互作用。目标3：确定非神经元细胞的调节是否可以防止自闭症谱系障碍基因突变引起的兴奋/抑制失衡。本申请的完成将使我们更深入地了解生理和病理条件下神经元与周围非神经元细胞之间的相互作用。此外，这项研究将揭示影响突触功能的神经系统疾病的致病机制，如自闭症谱系障碍或癫痫。最后，该项目将为治疗自闭症谱系障碍、癫痫和相关神经系统疾病的新疗法提供潜在靶点。

DESCRIPTION (provided by applicant): Many neurological disorders are associated with genetic mutations that affect neuronal activity and synapse function. Understanding how these genes regulate normal circuit function will have profound impact on the management of such diseases. In addition to neurons, the brain contains nearly ten times as many non-neuronal glial cells, which support neuronal function and regulate excitation/inhibition balance. The studies of mammalian model systems are hindered by this cellular and genetic complexity of the mammalian brain. The use of a simple, whole organism model system has the advantages of reducing the cellular complexity, while maintaining the neuronal and non-neuronal connectivity under physiological conditions. The overall goal of this project is to uncover the mechanisms by which non-neuronal cells modulate neuronal excitation/inhibition balance. The roundworm, Caenorhabditis elegans, will be utilized as a model system for four main reasons: 1) its neuronal networks are formed and maintained through mechanisms that are conserved in humans, 2) it has a simple, fully mapped nervous system, 3) it is easy to manipulate through genetic techniques, and 4) it has well-conserved homologs to genes mutated in autism spectrum disorders and epilepsy. The goals of this study will be accomplished through the following specific aims: Aim 1: Identify genetic pathways in non-neuronal cells that regulate neuronal excitation/inhibition imbalance using an RNA- interference screen. Aim 2: Characterize the physical interactions between neurons and non-neuronal cells under excitation/inhibition imbalanced conditions utilizing a genetic approach to fluorescently tag cellular interactions. Aim 3: Determine whether modulation of non-neuronal cells can prevent excitation/inhibition imbalance caused by mutations in autism spectrum disorder genes. The completion of this application will provide a deeper understanding of the interactions between neurons and the surrounding non-neuronal cells under physiological and pathological conditions. Additionally, this study will uncover the pathogenic mechanism(s) of neurological disorders that affect synaptic functions, such as autism spectrum disorders or epilepsy. Finally, this project will provide potential targets for novel therapies for the treatment of autism spectrum disorders, epilepsy, and related neurological diseases.