Control of neural stem cell proliferation and lineage progression in the postnatal subventricular zone by GABAergic signaling

脑室下区（SVZ）是哺乳动物出生后大脑的主要神经发生区域，干细胞在整个成年期继续产生新的神经元。最近的证据表明，γ-氨基丁酸（GABA）通过激活GABAA受体（GABAARs）直接控制出生后SVZ前体细胞的增殖、分化和迁移。然而，哪些细胞类型的影响是不清楚的，这些影响的机制仍然是unknowed.We在这里建议使用慢病毒介导的细胞tagging进一步调查的功能作用的GABA能信号对干细胞和他们的后代在其完整的生态位，并阐明所涉及的机制。我们还将调查存在的旁分泌/自分泌反馈机制的神经原性龛通过分析的贡献的各种前体类型的GABA浓度的调节在细胞外空间。此外，通过在体内特异性调节GABAAR信号，我们将研究内源性GABA对出生后SVZ神经发生的作用。该分析将阐明GABAAR信号在成体干细胞增殖调控中的作用。这也将对涉及GABAAR调节剂给药的神经系统疾病的治疗具有潜在的意义。

The subventricular zone (SVZ) is the major neurogenic region of the postnatal mammalian brain, where stem cells continue to generate new neurons throughout adulthood. Recent evidence suggests that γ-aminobutyric acid (GABA) directly controls proliferation, differentiation and migration of precursors in the postnatal SVZ by activating GABAA receptors (GABAARs). However, which cell types are affected is not clear and the mechanisms underlying these effects are still unknown.We here propose to use lentiviral mediated cell tagging to further investigate the functional role of GABAergic signalling on stem cells and their progeny in their intact niche and elucidate the mechanisms involved. We will also investigate the existence of paracrine/autocrine feedback mechanisms in the neurogenic niche by analysing the contribution of the various precursor types to the regulation of GABA concentration in the extracellular space. In addition, by specifically modulating GABAAR signalling in vivo we will investigate the role of endogenous GABA on neurogenesis in the postnatal SVZ.This analysis will clarify the role of GABAAR signalling in the regulation of adult stem cell proliferation. It will also have potential implication for the therapy of neurological disorders involving administration of GABAARs modulators.