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Title: Group I metabotropic glutamate and GABAB receptor signalling in oligodendrocyte precursor cells
Author: Spittle, Alexandra Clare
ISNI:       0000 0004 5923 803X
Awarding Body: University of Bristol
Current Institution: University of Bristol
Date of Award: 2014
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Oligodendrocytes (OLs) are the myelinating cells of the central nervous system. In the brain, oligodendrocyte precursor cells (OPCs) arise from the subventricular region and proliferate and migrate to axons requiring myelination. Loss of OLs is involved in multiple sclerosis and periventricular leukomalacia. OLs and OPCs express a variety of neurotransmitter receptors, including ionotropic and metabotropic glutamate and GABA receptors. Activation of GABAB receptors (GABABR) has been shown to increase proliferation and migration of OPCs. lonotropic AMPA/kainate receptors mediate excitotoxicity in OPCs caused by oxygen/glucose deprivation, where as group I metabotropic glutamate receptor {mGluR} activation has been shown to be attenuate excitotoxic injury and staurosporin-induced apoptosis in OPCs. mGluR can regulate the expression of AMPAR in the cell membrane of neurons and OPCs and GABABR can affect this interaction in neurons. The aim of this study was to characterise group I mGluR and GABABR-mediated responses in OPCs and to investigate interactions between these and KAR/AMPARmediated responses. Activation of mGlu5 in cultured primary OPCs produces a rise in intracellular [Ca 2+]i that involves both intracellular Ca 2+ stores and extracellular Ca 2+. Repeated agonist application induced desensitisation of this response. GABABR activation failed to produce an increase in [Ca 2+]i, but decreased the mGlu5-mediated [Ci+2]i rise. Kainate application elicited an inward current in white matter OPCs and an increase in [Ca 2+]i in cultured OPCs. This response was dependent on extracellular Ca 2+ and was partially mediated by AMPAR. Group I mGluR activation did not affect kainatemediated responses in white matter OPCs. In cultured OPCs however, group I mGluR activation increased kainate-induced [Ca 2+]i rises. This mGluR-mediated effect was blocked by activation of GABABR. These results suggest that mGluR and GABABR signalling pathways in OPCs can interact and that this interaction can have effects on the modulation of AMPAR/KAR responses by group I mGluR. With both GABABR and AMPAR/KAR being involved in the control of OPC proliferation and maturation, and AMPAR/KAR-mediated OPC cell death being implicated in white matter damage, the interactions between mGluR, GABABR and KAR/AMPAR in OPCs are likely to be important for the regulation of OPC behaviour in normal and pathological conditions.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available