@phdthesis{discovery1324543,
            note = {Unpublished},
           month = {August},
            year = {2011},
          school = {UCL (University College London)},
           title = {Electrical responses of oligodendrocytes to pathological stimuli},
             url = {https://discovery.ucl.ac.uk/id/eprint/1324543/},
          author = {Kolodziejczyk, K.},
        abstract = {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.}
}