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Functions of ERK/MAPK Signaling in GABAergic Circuit Development

ERK/MAPK 信号在 GABAergic 电路开发中的功能

基本信息

批准号：
9923769
负责人：
Jason Marshall Newbern
金额：
$ 34.07万
依托单位：
ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9923769
关键词：
Behavior Behavioral Brain Cells Clinical Cognitive Confocal Microscopy Cues Data Defect Dependence Development Discipline Electrophysiology (science)Equilibrium Exhibits Family Functional disorder Gene Expression Generations Genes Genetic Genetic Models High-Throughput Nucleotide Sequencing Human Hyperactive behavior Impairment Intellectual functioning disability Label Lead Learning Link MAP Kinase Gene MAP2K1 gene MAPK3 gene Mediating Mediator of activation protein Modeling Molecular Morphology Mus Mutant Strains Mice Mutate Mutation NF1 gene Neonatal Neurodevelopmental Disorder Neurologic Neurons Parvalbumins Pathogenesis Pathologic Pathology Pathway interactions Patients Pharmacology Phosphotransferases Play RNA Regulation Resolution Rett Syndrome RiboTag Rodent Model Role Schizophrenia Seizures Signal Transduction Stimulus Synapses Syndrome System Traumatic Brain Injury autism spectrum disorder biocytin cellular development childhood epilepsy critical developmental period designer receptors exclusively activated by designer drugs excitatory neuron extracellular gamma-Aminobutyric Acid in vivo inhibitor/antagonist insight interest mutant mouse model neonatal hypoxic-ischemic brain injury nervous system development neural circuit neuron development neuron loss novel therapeutic intervention patch clamp pediatric traumatic brain injury relating to nervous system repaired response therapeutic target tool

项目摘要

Project Summary/Abstract The ERK/MAPK intracellular signal transduction cascade is activated by extracellular stimuli that play important roles in nervous system development and plasticity. Genetic disruption of ERK/MAPK signaling has been implicated in neurodevelopmental syndromes that involve intellectual disability, learning abnormalities, neurodevelopmental delay, and seizures. Perturbations in ERK/MAPK activity have also been observed in genetic models of autism spectrum disorders, pediatric traumatic brain injury, neonatal hypoxia-ischemia, and childhood epilepsy. GABAergic circuit dysfunction is thought to contribute to the pathogenesis of many of these conditions. However, our understanding of the functions of ERK/MAPK in the initial development of the GABAergic system is poorly understood. This proposal brings together an interdisciplinary team to define the precise role of ERK/MAPK in GABAergic circuit formation and function using a combination of unique genetically modified rodent models, high-resolution confocal microscopy, patch-clamp electrophysiology, high-throughput sequencing, chemogenetic tools, and behavioral analyses. We will delineate changes in cellular development, synaptic strength, activity dependent gene expression, and behavior in ERK/MAPK mutant mouse models that exhibits specific deficits in GABAergic circuits. Finally, we will begin to explore pharmacological and activity- modulating approaches to reverse GABAergic defects in ERK/MAPK mutant mice. These data will provide unique insight into the pathophysiology of conditions resulting from perturbation of ERK/MAPK in the brain and help guide the development of new therapeutic strategies.

项目概要/摘要 ERK/MAPK 细胞内信号转导级联由细胞外刺激激活，发挥作用在神经系统发育和可塑性中发挥重要作用。 ERK/MAPK 信号传导的基因破坏与涉及智力障碍、学习异常的神经发育综合征有关，神经发育迟缓和癫痫发作。还观察到 ERK/MAPK 活性的扰动自闭症谱系障碍、小儿创伤性脑损伤、新生儿缺氧缺血的遗传模型儿童癫痫症。 GABA 能回路功能障碍被认为是导致许多这些疾病的发病机制的原因状况。然而，我们对 ERK/MAPK 功能的理解在最初的开发过程中还很有限。人们对 GABA 能系统知之甚少。该提案汇集了一个跨学科团队来定义利用独特的遗传组合，ERK/MAPK 在 GABA 能回路形成和功能中的精确作用改良啮齿动物模型、高分辨率共聚焦显微镜、膜片钳电生理学、高通量测序、化学遗传学工具和行为分析。我们将描述细胞发育的变化， ERK/MAPK 突变小鼠模型中的突触强度、活动依赖性基因表达和行为 GABA 能回路表现出特定的缺陷。最后，我们将开始探索药理和活性—— 逆转 ERK/MAPK 突变小鼠 GABA 能缺陷的调节方法。这些数据将提供对大脑中 ERK/MAPK 扰动引起的病症的病理生理学有独特的见解帮助指导新治疗策略的开发。