Káradóttir R, Hamilton NB, Bakiri Y, Attwell D.
Spiking and nonspiking classes of oligodendrocyte precursor glia in CNS white matter.
Nat Neurosci. 2008 Apr;11(4):450-6.
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Abnormalities of the white matter are a universal component of aging. These white matter changes appear as hyperintensities on T2-weighted MRI sequences or as alterations of anisotropy, diffusivity, or magnetization transfer on more sensitive MRI techniques. They correlate neuropathologically to rarefaction and mild gliosis of the white matter rather than frank infarction (1). Though the cause of white matter change is still not fully defined, its association with microvascular processes such as arteriosclerosis and cerebral amyloid angiopathy suggests a chronic ischemic mechanism, i.e., a kind of slow-developing stroke. Although once thought to be incidental and clinically unimportant, white matter lesions are now recognized for their association with cognitive impairment, depression, and future risk of dementia (2-4). They are more prevalent in Alzheimer disease than similar aged controls (5) and may act in concert with the Alzheimer process to produce worse clinical impairments than either disorder alone (6).
The current paper by Karadottir and colleagues puts a new spin on the pathogenesis of white matter lesions, focusing not on the vessels but on the white matter itself. The authors report a substantial subset of oligodendrocyte precursor cells with synaptic input and the requisite channels for firing action potentials. This class of cells, which remains present in the adult rat, showed increased cell death to ischemic insult. Ischemia-induced cell death was driven not by the action potential machinery (it was insensitive to tetrodotoxin) but rather by glutamate release and possible secondary release of vesicular calcium. Although no evidence was presented to link these findings to age-related abnormalities of white matter, the cells’ sensitivity to low levels of ischemia not injurious to other cell types makes them logical candidates to be involved. The message at this point for investigators of age-related white matter disease is to stay tuned.
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This study demonstrated two groups of oligodendrocyte progenitor cells (OPCs) in developing and adult white matter. Although these are glial cells, one of the groups of OPCs is found to be highly electrically excitable, firing repetitive action potentials when depolarized. This same group responds to glutamate and is found to be highly vulnerable to ischemia. These findings are extremely interesting for several reasons. It has always been thought that only neurons are electrically excitable, but this work now shows that many OPCs are also highly excitable. As these same cells have been shown to receive synaptic inputs, they now appear to resemble neurons in many key respects, and thus it is possible that these cells are participating in some sort of novel white matter circuit activity that may be key to the normal functioning of white matter. Thus, it will be interesting to further understand their functional roles and how these functions are perturbed when these cells are lost in ischemia.
The other interesting question raised by these new findings is whether they are relevant to neurodegenerative diseases such as Alzheimer's, where white matter degeneration also occurs. Blood flow anomalies have been repeatedly associated with Alzheimer disease. Thus, it will be interesting to see whether these excitable OPCs are lost in the white matter of these patients and, if so, whether this contributes to the neurodegenerative process.
Although the authors suggest that these OPCs are separate cell types, I think it is more likely that they represent two consecutive stages of the oligodendrocyte lineage. The authors' argument that this is unlikely because the electrically quiescent set of OPCs does not label with O4 or GC antibodies does not quite convince me because these are antibodies to surface epitopes and thus do not label the vast majority of positive cells in vivo in standard cryosection staining procedures. But this caveat does not in any way detract from the great interest of this work.