Glial KCNQ channels.

胶质 KCNQ 通道。

• 批准号: 10436561
• 负责人: Laura Bianchi
• 金额: $ 38.38万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-15 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10436561
• 关键词: Affect; Afferent Neurons; Alzheimer' s Disease; Animal Model; Astrocytes; Behavioral; Behavioral Assay; Bipolar Disorder; Caenorhabditis elegans; Cells; Complex; Consumption; Data; Electrophysiology (science); Encapsulated; Epilepsy; Familial benign neonatal epilepsy; Family; Functional Imaging; Genes; Goals; Heart; Homologous Gene; Human; Huntington Disease; Image; Individual; Knock-out; Light; Link; Mammals; Membrane Potentials; Mutate; Mutation; Neonatal; Nervous System Physiology; Nervous system structure; Neuroglia; Neurologic; Neurons; Octanols; Odors; Organ; Output; Parkinson Disease; Pathogenicity; Pathology; Pharmacology; Phenotype; Phosphatidylinositol 4,5-Diphosphate; Physiological; Potassium Channel; Property; Regulation; Rest; Role; Sensory; Structure; Testing; Time; Voltage-Gated Potassium Channel; Work; autism spectrum disorder; cell type; epileptic encephalopathies; experimental study; gain of function; gamma-Aminobutyric Acid; genetic approach; genetic manipulation; in vivo; knock-down; loss of function mutation; member; mutant; neuronal excitability; neuropsychiatry; response; transcriptome sequencing

Project Summary/Abstract KCNQ channels are members of a conserved family of voltage-gated potassium channels. KCNQ2 through KCNQ5 subunits are expressed in the nervous system, where they regulate neuronal excitability. Epilepsy, autism, and other neurological conditions have been associated with mutations in the KCNQ channel genes expressed in the nervous system. Although evidence supports the expression of KCNQ channels both in neurons and in glia, the role of these channels in glial cells is still unknown. In this study, we use C. elegans to investigate the physiological function of KCNQ channels in glia and the consequences of glial KCNQ pathogenic mutations. Using RNA sequencing we have found that the amphid glia, a pair of glial cells that encapsulate sensory neurons in the amphid sensory organ, express KCNQ worm homolog kqt- 2. Preliminary behavioral and Ca2+ imaging experiments suggest reduced GABA release from glia of kqt-2 knockout and glial knock down worms. Importantly, expression in amphid glia of human KCNQ2 and KCNQ3 genes rescue the kqt-2 knockout phenotype, supporting conservation of function across species. Thus, our preliminary results suggest that glial KCNQ channels may be needed in glia to dampen neuronal activity via GABA release. In this application we will test this hypothesis through the following 3 specific aims: 1) To establish to what extent the function of glia and neurons is altered in kqt-2 knockout; 2) To determine the physiological properties of KCNQ channels in glia; and 3) To establish the consequences of glial KCNQ pathogenic mutations on glial and neuronal structure and function. Our findings suggest a paradigm shift: neuronal output is regulated not only by neuronal KCNQ channels but also by glial KCNQs. Our work will shed light on the underlying mechanism of this regulation and will determine the contribution of pathogenic glial KCNQ mutation to the expression of the phenotype.

项目摘要/摘要 KCNQ通道是电压门控钾通道家族的成员。 KCNQ2通过 KCNQ5亚基在神经系统中表达，它们调节神经元兴奋性。癫痫， 自闭症和其他神经系统状况与KCNQ通道基因中的突变有关 在神经系统中表达。尽管证据支持KCNQ通道的表达 神经元和神经胶质中，这些通道在神经胶质细胞中的作用仍然未知。在这项研究中，我们使用C。 秀丽隐杆线虫研究胶质中KCNQ通道的生理功能和神经胶质的后果 KCNQ致病突变。使用RNA测序，我们发现了两对胶质细胞的胶质细胞 这将感觉神经元封装在两栖动物器官中 2。初步行为和Ca2+成像实验表明，KQT-2的Glia释放了GABA 敲除和神经胶质敲除蠕虫。重要的是，在人类KCNQ2和KCNQ3的两栖神经胶质中的表达 基因营救了KQT-2敲除表型，支持跨物种的功能保护。因此，我们的 初步结果表明，在神经胶质中可能需要使用神经胶质KCNQ通道，以使神经元活性通过 GABA发布。在此应用中，我们将通过以下3个特定目的来检验该假设：1） 在KQT-2基因敲除中改变了神经胶质和神经元的功能在多大程度上； 2）确定 GLIA中KCNQ通道的生理特性； 3）建立神经胶质KCNQ的后果 神经胶质和神经元结构和功能的致病突变。我们的发现表明范式转变： 神经元输出不仅受神经元KCNQ通道调节，而且还受神经胶质KCNQ的调节。我们的工作将 阐明该调节的基本机制，并将确定致病性的贡献 神经胶质KCNQ突变对表型的表达。