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.
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