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

传统上认为神经发生仅发生在胚胎发育过程中， 哺乳动物直到最近，人们才普遍认为，新的神经元确实是 在成年哺乳动物中枢神经系统的不连续区域连续产生和整合 系统成体神经发生再现了神经元发育的完整过程， 从神经祖细胞的命运特化，迁移，突触整合和成熟， 新生齿状颗粒细胞（DGC）。调节这些的分子机制 神经发生步骤在很大程度上是未知的。γ-氨基丁酸（GABA），一种主要的 抑制性神经递质在成人中枢神经系统，激活GABA受体在 紧张/相位机制。新出现的证据表明，GABA受体活性也起着重要作用。 在调节成年神经发生中起重要作用。补药的具体贡献和/或 阶段性GABA激活成年神经祖细胞的增殖和分化， 然而，它们后代的突触整合是未知的，将在我们的 目前的提案。具体目的I：确定紧张性GABA受体激活在 调节成人脑中神经祖细胞的增殖和命运特化。具体 目的II：研究强直性和/或时相性GABA受体激活的具体作用， 成年脑中新生DGC的突触形成和成熟。具体目标三： 确定GABA受体激活在功能性突触形成中的作用， 成年人大脑中新生DGC的轴突。这种方法将使用工程逆转录病毒 对成体神经祖细胞及其后代的GABA能活性进行遗传操纵。 这些基因操作的成体神经祖细胞的增殖和分化 并检查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为病因学和病理学提供线索 这些大脑紊乱和疾病。更重要的是，这些研究可能会揭示小说 治疗方法的发展，例如退行性疾病中受损神经元的功能替代 利用干细胞的神经系统疾病，包括胚胎干细胞和成人神经系统疾病， 干细胞

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-aminbutyric acid (GABA), one of the major inhibitory neurotransmitter 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.