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Title: AMPAR trafficking and GTPase activation in response to oxygen/glucose deprivation in cortical and hippocampal neurons
Author: Blanco Suarez, Elena M.
ISNI:       0000 0004 5347 0962
Awarding Body: University of Bristol
Current Institution: University of Bristol
Date of Award: 2014
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Distinct neuronal populations show different sensltivity to global ischaemia, with hippocampal CAl neurons showing a greater vulnerability compared to cortical neurons. The oxygen/glucose deprivation (OGD) protocol was used in order to mimic the ischaemic insult in vitro. It has been previously demonstrated that OGD induces a rapid change in AMPA receptors (AMPARs) subunit composition at synapses in hippocampal neurons, promoting the expression of Ca2+-permeable AMPARs, responsible for the Ca2+ influx that triggers the damaging mechanisms that lead to neuronal death. In the CWTent study it is showed that the OGD-induced AMP AR trafficking mechanisms in cortical neurons differ from those in hippocampal neurons. This may contribute to the higher resistance in response to OGD displayed by cortical neurons. In order to explore the downstream consequences of these trafficking events, the small GTPases pathways were investigated. The OGD-induced activation of NMDARs and Ca2+_ penneable AMPARs stimulated the RacGEF Tiaml, via CaMKII activation in hippocampal neurons. However, OGD did not promote changes in Tiaml activation in cortical neurons. Differences in Tiaml activation affected the levels of GTP-bound active Racl , a small Rho GTPase involved in a wide variety of cellular processes, such as synapse and spine morphogenesis in neurons via actin remodelling. Rac l, under OGO conditions, significantly increased its activation in hippocampal neurons but in contrast, the activation decreased in cortical neurons. The differences discovered between hippocampal and cortical neurons potentially indicate an OGD-induced mechanism downstream of Ca +-permeable AMPARs that has repercussions on Racl activation that may affect spine density and morphology. This compromises neuron survival in response to OGD and could explain the differential vulnerability found in cortical and hippocampal neurons, as well as providing a new insight into neuroprotective mechanisms.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available