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GABA action on subventricular zone progenitors

GABA 对室下区祖细胞的作用

基本信息

批准号：
6603175
负责人：
Angelique Bordey
金额：
$ 15.17万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-07-01 至 2004-05-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): The postnatal subventricular zone (SVZ) is a germinal zone containing distinct immature cell types, including stem cells and migrating neuronal progenitors. Understanding the in situ physiological properties of SVZ cells and the diffusible factors influencing SVZ cell physiology is critical to allow endogenous activation of stem cells/progenitors and induction of self-repair. In situ SVZ cell physiology and SVZ signaling factors are, however, largely unknown. Because the identity of neural stem cells is still debated, we propose to identify the signaling factors that regulate SVZ cell properties and could in particular influence neuronal progenitor migration. GABA is a likely candidate as a signaling factor because it regulates migration of embryonic cells and its synthetic enzyme is present in the SVZ. We thus hypothesize that GABA is a signaling factor locally released by migrating progenitors at rest resulting in activation of GABA autoreceptors and ion channels known to be involved in cell migration. The two following aims will be addressed with whole-cell and perforated patch-clamp recordings, and with fluorimetric Ca2+ measurements in SVZ slices. The first aim will determine whether GABA activates GABA receptors (GABAR5) on neuronal progenitors and whether GABAR activation leads to Ca2+ increase and Ca2+-dependent K+ (KCa) channel activation, which triggers membrane potential changes. KCa channel activation is known to be a prerequisite for migration of other cell types. The second aim will investigate whether GABARs are activated by transport-mediated GABA efflux from progenitors following membrane potential depolarization. Neuronal progenitors will be recorded from transgenic mice expressing yellow fluorescent protein in such progenitors under the control of the tubulin promoter. Data from these studies will provide the first fundamental insight into the physiology of SVZ cells in situ and exposes a novel concept of cell migration governed by an interplay between GABARs and GABA transporters.

描述（由申请人提供）：出生后心室下区（SVZ）是一个包含不同未成熟细胞类型的生发区，包括干细胞和迁移的神经祖细胞。了解SVZ细胞的原位生理特性和影响SVZ细胞生理的扩散因子对于干细胞/祖细胞的内源性激活和诱导自我修复至关重要。然而，SVZ细胞的原位生理和SVZ信号因子在很大程度上是未知的。由于神经干细胞的身份仍然存在争议，我们建议确定调节SVZ细胞特性的信号因子，特别是可能影响神经元祖细胞迁移的信号因子。GABA是一个可能的候选信号因子，因为它调节胚胎细胞的迁移，其合成酶存在于SVZ中。因此，我们假设GABA是一种由迁移祖细胞在静止状态下局部释放的信号因子，导致GABA自身受体和已知参与细胞迁移的离子通道激活。以下两个目标将通过全细胞和穿孔膜片钳记录，以及SVZ切片中的荧光Ca2+测量来解决。第一个目的是确定GABA是否激活神经元祖细胞上的GABA受体（GABAR5），以及GABAR激活是否导致Ca2+增加和Ca2+依赖性K+ (KCa)通道激活，从而触发膜电位变化。已知KCa通道激活是其他细胞类型迁移的先决条件。第二个目的是研究在膜电位去极化后，转运介导的来自祖细胞的GABA外排是否会激活gabar。在微管蛋白启动子的控制下，从表达黄色荧光蛋白的转基因小鼠中记录神经元祖细胞。这些研究的数据将提供SVZ细胞原位生理学的第一个基本见解，并揭示gabar和GABA转运体之间相互作用控制的细胞迁移的新概念。