Cerebellar Neurogensis

小脑神经发生

基本信息

批准号：
7987191
负责人：
Angelique Bordey
金额：
$ 36.2万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-01 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7987191
关键词：
Abbreviations Accounting Acute Address Affect Astrocytes Attention deficit hyperactivity disorder Axon Brain Brain region Bromodeoxyuridine Calcium Cell Cycle Cell Proliferation Cells Cerebellum Cerebrospinal Fluid Characteristics Chicago Clonal Expansion Cognitive Communication Confocal Microscopy Contractor Data Development Disease Dominant-Negative Mutation Doxycycline DsRed Electrophysiology (science)Electroporation Emotional Excitatory Amino Acid Transporter 1 Fiber GLAST Protein GRM5 gene Genes Genetic Glial Fibrillary Acidic Protein Glutamate Receptor Glutamates Green Fluorescent Proteins Human IGL@ gene cluster Image Individual Inositol Investigation Kainic Acid Receptors Knock-out Knockout Mice Letters Link Medical center Metabotropic Glutamate Receptors Mitotic Motor Mus N-ethylmaleimide-sensitive protein Names Neuraxis Neurodevelopmental Disorder Neuroglia North Carolina Oregon Pharmaceutical Preparations Pharmacology Plasmids Process Production Proteins Purkinje Cells RNA Interference Receptor Activation Role S-nitro-N-acetylpenicillamine SNAP receptor Schizophrenia Signal Pathway Signal Transduction Slice Social Interaction Source Staging Students Symptoms Synapses Synaptosomes System Testing Tetracyclines Time Trans-Activators Transgenic Mice Ventricular analog autism spectrum disorder axon growth base behavioral impairment coral design executive function genetic manipulation granule cell in vivo inorganic phosphate interest intraperitoneal knock-down loss of function metabotropic glutamate receptor 5 migration motor deficit neurogenesis overexpression paraform postnatal precursor cell public health relevance receptor receptor expression red fluorescent protein research study vesicular glutamate transporter 2 voltage

项目摘要

DESCRIPTION (provided by applicant): This proposal will test the hypothesis that glutamatergic signaling orchestrates early stages of granule cell development necessary for proper cerebellar circuit formation. Glutamate, which has a conserved signaling function across phyla, controls multiple intracellular signaling pathways through diverse receptors. Glutamate receptor expression in the brain is tightly developmentally regulated, suggesting specific functions of each receptor subtype at different stages of cell development. Indeed, emerging evidence implicates glutamate receptors in brain development. However, our understanding of such functions lags behind the known diversity of glutamate receptor subtypes. Previous and preliminary data suggest that granule cell precursors (GCPs) transiently express functional GluK2-containing kainate receptors (KAR) and group I metabotropic glutamate receptor 5 (mGlu5R) in the external germinal layer (EGL) when they exit the cell cycle and extend axons. However, it is not known whether, and if so how, gain or loss of function in GluK2 receptor and mGlu5R alters GCP development. In this proposal, Aim 1 and Aim 2 will examine the function of GluK2 and mGlu5R on GCP proliferation and axon extension, respectively. Aim 3 will explore whether Bergmann glial cells, a specialized astrocytes extending processes through the EGL, release glutamate controlling GCP cell-cycle exit through mGlu5R. We will use a combination of time- lapse confocal microscopy (for calcium imaging, migration, and axon extension) in acute slices and in vivo approaches (drugs, RNA interference via electroporation, and genetic manipulation) in wild-type and transgenic mice, including mGlu5Rfl/fl (fl, floxed) and GluK2- knockout (KO). PUBLIC HEALTH RELEVANCE: This proposal focuses on understanding the function of GluK2 and metabotropic glutamate receptor 5 (mGlu5R) on the early stages of granule cell development necessary for proper cerebellar circuit formation. One of the most important reasons for pursuing this line of investigation is that the GluK2 gene (GRIK2) and mGlu5R gene (GRM5) have been linked with neurodevelopmental disorders, in particular autism spectrum disorder and schizophrenia, and individuals with such disorders have abnormalities in cerebellar size and circuitry that are thought to contribute to some of the behavioral impairments.

描述（由申请人提供）：该提案将检验以下假设：谷氨酸能信号策划了适当的小脑电路形成所需的颗粒细胞发育的早期阶段。谷氨酸在门上具有保守的信号传导功能，通过多种受体控制多个细胞内信号通路。大脑中的谷氨酸受体表达受到严格的发育调节，表明在细胞发育的不同阶段，每个受体亚型的特定功能。实际上，新兴的证据暗示谷氨酸受体在大脑发育中。但是，我们对此类功能的理解落在已知的谷氨酸受体亚型多样性之后。以前的和预防性数据表明，颗粒细胞前体（GCP）在外部生发层（EGL）中暂时表达富含GLUK2的Kainate受体（KAR）和I组代谢性谷氨酸受体5（MGLU5R），当它们渗入细胞周期并扩展细胞周期时。但是，尚不清楚GLUK2受体和MGLU5R中的功能的增长或丧失是否会改变GCP的发展。在此提案中，AIM 1和AIM 2将分别研究GLUK2和MGLU5R对GCP增殖和轴突扩展的功能。 AIM 3将探索Bergmann神经胶质细胞（专门的星形胶质细胞通过EGL扩展过程，释放通过MGLU5R出口的GCP细胞周期退出的谷氨酸，释放谷氨酸。我们将在急性切片和包括野生型和转基因小鼠（包括mglu5rfl/fl，flox nocking（flox ocknity）中（包括mglu5rfl/flox nocking（flox nocked），我们将使用急性切片和体内方法（药物，通过电穿孔和遗传操纵的RNA干扰和遗传操作）和体内方法（用于药物，通过电穿孔和遗传操纵的RNA干扰和遗传操作）的时间流逝的共聚焦显微镜（用于钙成像，迁移和延伸）的组合。公共卫生相关性：该提案的重点是理解Gluk2和代谢型谷氨酸受体5（MGLU5R）在颗粒细胞发育的早期开发的早期阶段的功能。追求这一调查的最重要原因之一是GLUK2基因（GRIK2）和MGLU5R基因（GRM5）与神经发育障碍有关，尤其是自闭症谱系障碍和精神分裂症，并且患有这种疾病的人在脑大小和coutival术中具有某些促成某些行为的异常。