Glial KCNQ channels.

胶质 KCNQ 通道。

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

项目概要/摘要 KCNQ 通道是电压门控钾通道保守家族的成员。 KCNQ2通过 KCNQ5 亚基在神经系统中表达，调节神经元的兴奋性。癫痫，自闭症和其他神经系统疾病与 KCNQ 通道基因的突变有关表达于神经系统。尽管有证据支持 KCNQ 通道在在神经元和神经胶质细胞中，这些通道在神经胶质细胞中的作用仍然未知。在本研究中，我们使用 C. 线虫研究神经胶质细胞中 KCNQ 通道的生理功能以及神经胶质细胞的后果 KCNQ致病突变。通过 RNA 测序，我们发现两栖类神经胶质细胞，一对神经胶质细胞包裹两栖动物感觉器官中的感觉神经元，表达 KCNQ 蠕虫同源物 kqt- 2. 初步行为和 Ca2+ 成像实验表明 kqt-2 胶质细胞 GABA 释放减少敲除和神经胶质敲除蠕虫。重要的是，人 KCNQ2 和 KCNQ3 在两栖类神经胶质细胞中的表达基因拯救了 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，神经胶质细胞中可能需要神经胶质细胞 KCNQ 通道来抑制神经元活动 GABA 释放。在此应用中，我们将通过以下 3 个具体目标来检验该假设：1) 确定 kqt-2 敲除中神经胶质细胞和神经元的功能发生多大程度的改变； 2）确定神经胶质细胞中KCNQ通道的生理特性； 3) 确定神经胶质 KCNQ 的后果神经胶质和神经元结构和功能的致病突变。我们的研究结果表明范式转变：神经元输出不仅受神经元 KCNQ 通道调节，还受神经胶质 KCNQ 调节。我们的工作将阐明这种调节的基本机制并将确定致病性的贡献胶质细胞KCNQ突变导致表型的表达。