Electrical responses of oligodendrocytes to pathological stimuli.
Doctoral thesis, UCL (University College London).
The white matter is crucial for rapid transmission of information between different parts of the brain and spinal cord, and is damaged in diseases including the genetic leukodystrophies, stroke, spinal cord injury and multiple sclerosis. While damage in the grey matter of the CNS is well known to often involve over-activation of glutamate receptors, our understanding of white matter pathology is less advanced. The experiments in this thesis used patch-clamping and [Ca2+]i imaging to examine the cerebellar white matter oligodendrocyte response to pathological insults mimicking those occurring in the leukodystrophies and in the ischaemia that occurs in stroke or after spinal cord injury. Oligodendrocytes responded to simulated ischaemia with an inward current, which was triggered by glutamate release mediated by reversal of glutamate transporters, and not by exocytosis, NKCC1 or cystine/glutamate exchange. Surprisingly, this inward current was not mediated by glutamate receptors, nor by ASICs, gap junctional hemichannels, P2X receptors or GABAA receptors, but reflected the closing of potassium channels. In current clamp mode this initial closing of K+ channels produced a depolarisation of the cells, followed by a repolarisation as other K+ channels activated. These data indicate, for the first time, a significant role for K+ channels in the response of oligodendrocytes to ischaemia. In Canavan and Pelizaeus-Merzbacher-like leukodystrophies, elevated levels of Nacetylaspartylglutamate (NAAG) and N-acetylaspartate (NAA) occur. These compounds can activate or block neuronal NMDA receptors. Since oligodendrocytes are reported to express NMDA receptors, I tested their response to NAAG and NAA. NAAG, but not NAA, evoked a small inward NMDA receptor-mediated current in oligodendrocytes, but no [Ca2+]i rise. Much of the inward current was a secondary effect of NAAG acting on neurons. Thus, actions of NAAG and NAA on oligodendrocyte NMDARs are unlikely to be a major contributor to white matter damage in the leukodystrophies.
|Title:||Electrical responses of oligodendrocytes to pathological stimuli|
|Open access status:||An open access version is available from UCL Discovery|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Life Sciences > Biosciences (Division of) > Neuroscience, Physiology and Pharmacology|
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