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

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过程中。直到最近，人们才普遍认为新神经元确实在成年哺乳动物中枢神经系统的离散区域中不断产生和整合。成人神经发生概括了神经元发育的完整过程，从神经祖细胞的命运规范、迁移、突触整合到新生齿状颗粒细胞（DGC）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) 是成人中枢神经系统中主要的抑制性神经递质之一，可激活强直/时相机制中的 GABA 受体。新的证据表明，GABA 受体活性在调节成人神经发生中也发挥着重要作用。然而，强直性和/或阶段性 GABA 激活对成年神经祖细胞的增殖和分化及其后代的突触整合的具体贡献尚不清楚，并将在我们当前的提案中进行研究。具体目标 I：确定强直性 GABA 受体激活在调节成人大脑神经祖细胞增殖和命运规范中的作用。具体目标 II：检查强直性和/或阶段性 GABA 受体激活在成人大脑中新生 DGC 突触形成和成熟中的具体作用。具体目标 III：确定 GABA 受体激活在成人大脑中新生 DGC 轴突形成功能性突触中的作用。该方法将使用工程化逆转录病毒来基因操纵成年神经祖细胞及其后代的 GABA 活性。将检查这些基因操纵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。了解成人神经发生的这些调节机制可能为这些脑部紊乱和疾病的病因学和病理学提供线索。更重要的是，这些研究可能有助于新疗法的开发，例如利用干细胞（包括胚胎干细胞和成体神经干细胞）对退行性神经系统疾病中受损神经元进行功能替代。 公共卫生相关性：成人大脑能够在整个成年期产生新的神经元。成人大脑中的这些新生神经元可以成功融入成人大脑。然而，我们尚未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）发挥着重要作用。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生成的因素可能为大脑紊乱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新疗法的开发，例如利用干细胞（包括胚胎干细胞和成体神经干细胞）对退行性神经系统疾病中受损的神经元进行功能替代。

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.