Neuronal Regulation of NG2 Cells

描述(申请人提供)：哺乳动物CMS中的神经胶质细胞负责创造和维持神经元活动持续的环境，并能够调节这种活动。神经元和非神经元细胞之间的这种密切的相互关系表明，可能存在快速调整神经胶质细胞行为的机制，以响应周围神经元需求的变化。我们以前的研究表明，NG2细胞(也称为少突胶质前体细胞，OPC)是一类广泛存在于灰质和白质中的前体细胞，原位表达谷氨酸和GABA的功能性离子受体，提示传统的神经递质可能在细胞信号转导中发挥广泛的作用。在NG2细胞中，这些低亲和力受体通过神经元递质的量子释放而被激活，从而导致NG2细胞膜的瞬时去极化。海马区神经元和NG2细胞之间突触信号的存在提出了许多新的问题，即这种快速通信在调节这些神秘细胞的性质和发育中所起的作用。我们假设神经元-NG2细胞突触信号是大脑中调节NG2细胞增殖和发育的普遍机制。在所有NG2细胞中表达荧光蛋白DsRed的转基因小鼠的出现为我们提供了一个前所未有的机会来研究哺乳动物完整脑片中神经元和NG2细胞之间的相互作用。我们建议使用单细胞电生理方法、高分辨电子显微镜和NG2细胞中谷氨酸受体的转基因操作，来确定NG2细胞在不同脑区表达的受体的特性，这些受体的激活机制，以及这种信号在调控NG2细胞行为中的作用。这些研究将评估通过这些AMPA受体的钙离子内流在调节NG2细胞的增殖和分化中发挥核心作用的具体假设。由于这些细胞作为少突胶质前体细胞并具有多潜能，更好地了解原位调节NG2细胞行为的因素可能会导致新的策略，以防止早产儿的髓鞘损伤，并取代因缺血或疾病而丢失的神经元和神经胶质细胞。

DESCRIPTION (provided by applicant): Glial cells in the mammalian CMS are responsible for creating and maintaining an environment where neuronal activity can be sustained, and are capable of modulating this activity. This close interrelationship between neurons and non-neuronal cells suggests that mechanisms may exist to rapidly adjust glial cell behavior in response to changes in the needs of surrounding neurons. Our previous studies indicate that NG2 cells (also known as oligodendrocyte precursor cells, or OPCs), a class of progenitor cells found ubiquitously in both gray and white matter, express functional ionotropic receptors for glutamate and GABA in situ, suggesting that conventional neurotransmitters may have widespread roles in cell signaling. These low affinity receptors are activated in NG2 cells by the quantal release of transmitter from neurons, which result in transient depolarizations of the NG2 cell membrane. The existence of synaptic signaling between neurons and NG2 cells in the hippocampus raises many new questions about the role of this rapid communication in regulating the properties and development of these enigmatic cells. We hypothesize that neuron-NG2 cell synaptic signaling is a ubiquitous mechanism for regulating the proliferation and development of NG2 cells in the brain. The availability of transgenic mice in which the fluorescent protein DsRed is expressed in all NG2 cells provides us with an unprecedented opportunity to study the interaction between neurons and NG2 cells within intact slices of mammalian brain. We propose to use single cell electrophysiological methods, high resolution electron microscopy, and transgenic manipulation of glutamate receptors in NG2 cells, to define the properties of receptors expressed by NG2 cells in different brain regions, the mechanisms responsible for activation of these receptors, and the role of this signaling in regulating NG2 cell behavior. These studies will evaluate the specific hypothesis that Ca2+ influx through these AMPA receptors plays a central role in regulating the proliferation and differentiation NG2 cells. Because these cells serve as oligodendrocyte progenitors and have multipotent capability, a better understanding of the factors that regulate the NG2 cells behavior in situ may lead to new strategies for preventing myelin damage in pre-term infants, and replacing neurons and glia that have been injured as a result of ischemia or lost through disease.