What is a glial cell?

Abstract

The last few years has seen a revolution in our understanding of glial cells. We now know that astrocytes, in addition to mopping up transmitters and maintaining extracellular ion levels, actively control synaptogenesis, synapse number, synapse function, and synaptic plasticity. Even oligodendrocytes and Schwann cells, are active participants in nervous system function. In addition to providing insulation and trophic support to neurons, they sculpt the structure and electrical properties of axons by controlling their diameter, the spacing and clustering of ion channels at the node and paranode. Schwann cells also control the regeneration of axons and the function of synapses at the neuromuscular junction. Neurons and glia divide metabolic labor in a way that, though still poorly understood, no doubt underlies an interaction vital to proper nervous system function and perhaps much of the brain’s response to ischemia. In short, virtually every aspect of brain development and function involves a neuron-glial partnership. It is no longer tenable to consider glia as passive support cells. There are an endless number of important questions about neuron-glial interactions. Exactly how is metabolic labor divided between neurons and glia and what is the point of this? What is the identity of the signals flowing between neurons and glia and what is their purpose? Might astrocytes be the primary synthesizers of neurotransmitters or their immediate biochemical precursors, rather than neurons? Do astrocytes play a role in inducing and maintaining the blood-brain barrier, or is another cell type responsible? Do astrocytes actually help to signal neuronal survival in vivo? And what is the point of reactive astrocytes; are they good, bad, or both? I know of little convincing data that addresses most of these questions, but newly developed methods for genomics, proteomics, RNA interference, neural cell purification and culture, all offer a way forward. These new methods provide powerful new ways to better characterize glia and their interactions with neurons, and to perform question-oriented, hypothesis-driven research about glial function. An important, closely related set of questions is raised by recent studies on neural stem cells and gliogenesis reviewed in this special issue. These papers review the amazing findings of the last few years that some “glia” can actually behave as multipotent neural stem cells that can generate neurons, both in vitro and in vivo. Radial glia and subventricular zone astrocytes have all been shown to do this in developing and adult brains, respectively. A subset of ependymal cells also appears to have the capacity to generate new neurons, although they now appear to lack the self-renewing ability of a true stem cell. In addition, in the adult chick, Muller glial cells in the retina and supporting glial cells in the inner ear can be induced after injury or growth factor stimulation to generate new neurons. Even oligodendrocyte precursor cells in culture can be induced with certain growth factors to become multipotent neural stem cells. It is quite important to note, however, that most glial cells in the CNS are not neural stem cells, but rather a distinct subset. The new findings that glia can be neural stem cells raise a difficult question. When should a cell be called a glial cell? Several papers in this issue will review the astounding recent discovery that in developing rodent brains, radial glia give rise to the majority of pyramidal neurons. So, are these radial glia actually glial cells after all? This question is especially thorny given that radial glia also subserve a traditional “glial” function of guiding the migration of developing neurons. Nonetheless I would argue that they should no longer be called glial cells because we now know that their most important function is to be neural stem cells. That radial glia also guide migration does not sway me, because I believe that all cell classes in the brain, including neurons and glia, simultaneously perform both passive support roles and more active roles. For instance, considerable evidence now indicates that neurons provide trophic support for glia. In fact, the evidence that neurons support glia in the brain in vivo is far stronger than the evidence that glia support neurons. Thus, I see no reason why we shouldn’t return to the nomenclature of the early neurohistologists and refer to radial glial cells as neuroepithelial cells, just as we do in the developing retina.