Glial Cell Function on SVZ Neurogenesis

描述（由申请人提供）：出生后脑室下区（SVZ）是一个生殖中心，由胶质细胞酸性蛋白免疫阳性（GFAP+）细胞包裹的迁移和增殖神经母细胞链网络组成，显示干细胞的特征。祖细胞迁移整个SVZ和沿着吻侧迁移流（RMS）向嗅球，在那里他们不断取代interneurons整个生命。识别影响SVZ祖细胞行为的信号将导致对影响嗅球中间神经元替代的机制的更好的基本理解，并且对于设计促进神经发生和自我修复的策略是必要的。祖细胞的产生被认为是由提供神经母细胞和GFAP+细胞之间的通信信号的分子调节的，然而我们对这种信号传导的知识仍然是基本的。这项研究的中心假设是，从GFAP+细胞到成神经细胞的神经递质信号通过促进出生后SVZ祖细胞的增殖来平衡GABA的抑制功能。将讨论三个目标。首先，我们将确定是否存在从GFAP+细胞到成神经细胞的快速神经递质信号传导。由于成神经细胞通过GABA能信号传导至GFAP+细胞，因此GABA能信号传导将提供这两种细胞类型之间双向通信所必需的反馈回路。其次，我们将确定是否从SVZ细胞释放的PGE2调节从GFAP+细胞释放谷氨酸，从而mGluR激活。最后，我们将确定谷氨酸和PGE2对谷氨酸释放的调节是否对细胞增殖提供了正控制，以抵消GABA的抑制作用。我们将使用膜片钳和Ca2+成像技术，并在脑切片和体内进行增殖测定。我们将使用CD 1小鼠和几种转基因小鼠来实现我们的目标。希望这些实验能够共同确定GFAP+细胞和神经母细胞之间双向通讯的存在和功能，并进一步了解细胞间信号传导如何调节出生后的神经发生。

DESCRIPTION (provided by applicant): The postnatal subventricular zone (SVZ) is a germinal center composed of a network of chains of migrating and proliferative neuroblasts ensheathed by glial fibrillary acidic protein immunopositive (GFAP+) cells, which display the characteristics of stem cells. The progenitors migrate throughout the SVZ and along the rostral migratory stream (RMS) toward the olfactory bulb where they continuously replace interneurons throughout life. Identifying the signals influencing the behavior of SVZ progenitors would lead to a better basic understanding of the mechanisms influencing replacement of olfactory bulb interneurons, and is necessary to design strategies to promote neurogenesis and self-repair. The production of progenitors is thought to be regulated by molecules providing communication signals between neuroblasts and GFAP+ cells, yet our knowledge of such signaling remains rudimentary. The central hypothesis of this grant is that glutamatergic signaling from GFAP+ cells to neuroblasts balances GABA's inhibitory function by promoting the proliferation of postnatal SVZ progenitors. Three aims will be addressed. First we will determine whether a fast glutamatergic signaling from GFAP+ cells to neuroblast exists. As neuroblasts signal to GFAP+ cells via GABAergic signaling, glutamatergic signaling would provide a feedback loop necessary for a bidirectional communication between these two cell types. Second, we will determine whether PGE2 released from SVZ cells modulates glutamate release from GFAP+ cells and thus mGluR activation. Finally, we will determine whether glutamate and PGE2's modulation of glutamate release provide a positive control on cell proliferation to counterbalance GABA's inhibitory influence. We will use patch-clamp and Ca2+ imaging techniques, and perform proliferation assays in brain slices and in vivo. We will use CD1 mice and several lines of transgenic mice to address our aims. It is hoped that together the proposed experiments will identify the existence and function of a bidirectional communication between GFAP+ cells and neuroblasts, and further our understanding of how intercellular signaling regulates postnatal neurogenesis.