The roles and mechanisms of GABA receptor activation in regulating neurogenesis i

GABA受体激活在调节神经发生中的作用和机制

• 批准号: 8123112
• 负责人: Shaoyu Ge
• 金额: $ 29.12万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8123112
• 关键词: Adult; Area; Axon; Brain; Brain Diseases; Butyric Acids; Cells; Confocal Microscopy; Data; Degenerative Disorder; Dendrites; Development; Disease; Electron Microscopy; Electrophysiology (science); Embryo; Embryonic Development; Engineering; Epilepsy; Etiology; Generations; Glutamates; Hippocampus (Brain); Image; Immunohistochemistry; Label; Laboratories; Lead; Life; Light; Mammals; Mental disorders; Molecular; Mus; Nature; Neuraxis; Neuronal Differentiation; Neurons; Neurotransmitters; Newborn Infant; Pathology; Physiological; Play; Process; Receptor Activation; Retroviridae; Role; Series; Staging; Stem cells; Synapses; Techniques; adult neurogenesis; combinatorial; dentate gyrus; embryonic stem cell; gamma-Aminobutyric Acid; granule cell; in vivo; migration; nerve stem cell; nervous system disorder; neural precursor cell; neurodevelopment; neurogenesis; neuron development; newborn neuron; novel; novel therapeutics; progenitor; public health relevance; receptor; synaptogenesis; therapy development; two-photon

DESCRIPTION (provided by applicant): Neurogenesis was traditionally believed to occur only during embryonic development in mammals. Only recently has it become generally accepted that new neurons are indeed continuously produced and integrated in discrete regions of the adult mammalian central nervous system. Adult neurogenesis recapitulates the complete process of the neuronal development, from fate specification of neural progenitors, migration, synaptic integration and maturation of newborn dentate granule cells (DGCs). The molecular mechanisms that regulate these neurogenesis steps are largely unknown. Gamma-amino butyric acid (GABA), one of the major inhibitory neurotransmitters in the adult central nervous system, activates GABA receptors in the tonic/phasic mechanisms. Emerging evidence suggests that GABA receptor activity also plays an essential role in regulating the adult neurogenesis. The specific contribution of tonic and/or phasic GABA activation to the proliferation and differentiation of adult neural progenitors and the synaptic integration of their progeny, however, is unknown, and will be examined in our current proposal. Specific Aim I: To determine the roles of tonic GABA receptor activation in regulating proliferation and fate specification of neural progenitors in the adult brain. Specific Aim II: To examine the specific roles of tonic and/or phasic GABA receptor activation in synapse formation and maturation of newborn DGCs in the adult brain. Specific Aim III: To determine the roles of GABA receptor activation in the formation of functional synapses by the axons of newborn DGCs in the adult brain. The approach will be to use engineered retroviruses to genetically manipulate GABAergic activity of the adult neural progenitors and their progeny. The proliferation and differentiation of these genetically-manipulated adult neural progenitors and the synaptic integration of these newborn neurons will be examined. Understanding these regulatory mechanisms for adult neurogenesis may provide clues into the etiology and pathology of these brain disorders and diseases. More importantly, these studies may shed light on novel therapy development such as functional replacement of damaged neurons in degenerative neurological disease utilizing stem cells, including both embryonic stem cells and adult neural stem cells. PUBLIC HEALTH RELEVANCE: The adult brain is capable of generating new neurons throughout adulthood. These newborn neurons in the adult brain can successfully integrate into the adult brain. However, we have yet to understand how these new neurons are generated and how these neurons can make the right connections with the existing neurons in the brain. The development of these new neurons shares similar mechanisms with embryonic neuronal development, in which the neurotransmitter, gamma-amino butyric acid (GABA) plays an important role. We propose to decipher the mechanisms of GABA receptor activation in regulating adult neurogenesis. Understanding the kind of factors regulating the generation of these new neurons may provide clues into the etiology and pathology of the brain disorders and diseases. Our studies may potentially lead to the development of novel therapy such as functional replacement of damaged neurons in degenerative neurological disease utilizing stem cells, including both embryonic stem cells and adult neural stem cells.

描述（由申请人提供）：传统上认为神经发生仅发生在哺乳动物的胚胎发育期间。直到最近，人们才普遍接受，新的神经元确实是不断产生和整合在成年哺乳动物中枢神经系统的离散区域。成体神经发生是神经元发育的一个完整过程，从神经祖细胞的命运特化、迁移、突触整合到新生齿状核颗粒细胞（dentate granule cells，DGCs）的成熟。调节这些神经发生步骤的分子机制在很大程度上是未知的。γ-氨基丁酸（GABA）是成年人中枢神经系统中主要的抑制性神经递质之一，在紧张/相位机制中激活GABA受体。越来越多的证据表明，GABA受体活性在调节成体神经发生中也起着至关重要的作用。然而，具体的贡献，紧张和/或阶段性GABA激活成人神经祖细胞的增殖和分化及其后代的突触整合，是未知的，将在我们目前的建议进行检查。具体目标一：目的：探讨强直性GABA受体激活在成年脑神经前体细胞增殖和命运特化中的作用。具体目标二：研究GABA受体的强直性和/或时相性激活在成年脑内新生DGC突触形成和成熟中的特定作用。具体目标三：目的：探讨GABA受体激活在成年人新生DGC轴突形成功能性突触中的作用。该方法将使用工程逆转录病毒来遗传操纵成体神经祖细胞及其后代的GABA能活性。将检查这些遗传操作的成年神经祖细胞的增殖和分化以及这些新生神经元的突触整合。了解这些成人神经发生的调节机制可能会为这些脑疾病和疾病的病因和病理提供线索。更重要的是，这些研究可能揭示新的治疗方法的发展，如功能性替代受损的神经元在退行性神经系统疾病利用干细胞，包括胚胎干细胞和成人神经干细胞。 公共卫生相关性：成年人的大脑能够在整个成年期产生新的神经元。这些新生的神经元在成人大脑中可以成功地整合到成人大脑中。然而，我们还没有了解这些新神经元是如何产生的，以及这些神经元如何与大脑中现有的神经元建立正确的连接。这些新神经元的发育与胚胎神经元发育具有相似的机制，其中神经递质γ-氨基丁酸（GABA）起着重要作用。我们建议破译GABA受体激活调节成人神经发生的机制。了解调节这些新神经元产生的因素可能会为大脑疾病和疾病的病因学和病理学提供线索。我们的研究可能会导致开发新的治疗方法，例如利用干细胞（包括胚胎干细胞和成体神经干细胞）功能性替代退行性神经疾病中受损的神经元。