The capacity to generate action potentials, prime purview of neurons, is actually not exclusive to those cells, according to new research showing some glia are also capable of spiking electrical activity. In the March 2 issue of Nature Neuroscience online, Ragnhildur Karadottir, David Attwell, and colleagues at University College London present evidence that a subset of oligodendrocyte precursor glia can display action potentials and receive synaptic input. Apparently these same cells are preferentially vulnerable to ischemia-induced glutamate toxicity.

Besides being important to understanding the basic functions of glia, the finding puts a spotlight on white matter, the stuff of the brain made up of myelinated axons plus their associated glia. Degeneration of these white matter tracts is a common finding in Alzheimer disease, although the causes are not clear. The new results raise the possibility that excitotoxicity, or some other processes related to the activity of glia, could play a role in white matter loss.

In the study, Karadottir and colleagues distinguished two subtypes of oligodendrocyte precursor glia cells (OPCs) in postnatal rat CNS white matter. The two kinds of cells look morphologically identical, but whole cell recording experiments revealed that one type showed voltage-gated sodium and potassium currents. The current-generating cells expressed voltage-gated sodium channels, while the electrically silent cells did not. Ultimately, the researchers found that cells expressing the sodium channels generated action potentials upon depolarization.

In adult rats, the two cells types were readily apparent, where 70 percent of OPCs expressed sodium channels. To the authors, the channel expression did not appear to be a function of the developmental stage of the cells or their place in the cell cycle, based on the cells’ morphology and expression of maturation markers.

Axons in white matter can release neurotransmitters onto OPCs (see ARF related news story), and the new study indicates that spiking OPCs have the capacity to respond to that stimulus. Both glutamate- and GABA-induced currents were detected in the sodium channel-expressing cells, while cells without the sodium current rarely showed detectable synaptic input. “Thus, the two classes of OPCs sense their environment in different ways,” the authors write.

Because the spiking glia respond more avidly to glutamate, the authors hypothesized that they might be sensitive to the toxic elevation of that neurotransmitter that occurs in stroke or trauma. When the investigators induced ischemia in brain slices, OPCs with sodium channels experienced larger glutamate-induced currents. One hour later, a third of the cells of the spiking subtype were dead, compared with only 2 percent of the cells lacking the sodium channel. Cell death was blocked by glutamate receptor antagonists, consistent with a mechanism of death by excitotoxicity. The results suggest that spiking glia are preferentially damaged in stroke or injury.

“Our demonstration that white matter glial cells can generate trains of action potentials challenges current concepts of the distinction between neurons and glia,” the authors write. They do not yet understand the role of the glial activity, but as the cells have no known synaptic output mechanism, the scientists speculate that the action potentials could regulate cell activity such as myelination of nearby axons.—Pat McCaffrey

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  1. 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.

    References:

    . Neuropathology of white matter changes in Alzheimer's disease and vascular dementia. Dement Geriatr Cogn Disord. 1998 Jul;9 Suppl 1:6-12. PubMed.

    . Clinical correlates of white matter findings on cranial magnetic resonance imaging of 3301 elderly people. The Cardiovascular Health Study. Stroke. 1996 Aug;27(8):1274-82. PubMed.

    . Cerebral white matter lesions and depressive symptoms in elderly adults. Arch Gen Psychiatry. 2000 Nov;57(11):1071-6. PubMed.

    . Silent brain infarcts and the risk of dementia and cognitive decline. N Engl J Med. 2003 Mar 27;348(13):1215-22. PubMed.

    . Plasma homocysteine levels, cerebrovascular risk factors, and cerebral white matter changes (leukoaraiosis) in patients with Alzheimer disease. Arch Neurol. 2002 May;59(5):787-93. PubMed.

    . Brain infarction and the clinical expression of Alzheimer disease. The Nun Study. JAMA. 1997 Mar 12;277(10):813-7. PubMed.

    View all comments by Steven Greenberg
  2. 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.

References

News Citations

  1. Extrasynaptic Receptors Make Their Mark

Further Reading

Primary Papers

  1. . Spiking and nonspiking classes of oligodendrocyte precursor glia in CNS white matter. Nat Neurosci. 2008 Apr;11(4):450-6. PubMed.