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dc.contributor.advisorGrant, Seth
dc.contributor.advisorKomiyama, Noboru
dc.contributor.authorLemprière, Sarah Alice
dc.date.accessioned2018-11-01T13:14:21Z
dc.date.available2018-11-01T13:14:21Z
dc.date.issued2018-11-30
dc.identifier.urihttp://hdl.handle.net/1842/33190
dc.description.abstractMajor depressive disorder (MDD) is a growing health problem. Current treatment options are not always effective and take several weeks of regular administration before an improvement can be seen in symptoms. Sub-anaesthetic doses of ketamine have been found to have antidepressant effects in previously treatment-resistant MDD after just one dose. However, ketamine also produces short term psychosis-like side effects which are undesirable for MDD patients. Ketamine is known to be an NMDA receptor antagonist, binding within the channel pore to block ion flow, however the molecular mechanism(s) underlying its antidepressant and psychosis-like effects are still unclear. In this thesis several genetically modified mouse lines were used to probe the molecular events involved in ketamine’s actions. Firstly, a mouse line in which the c-terminal domain (CTD) of the NMDAR subtype GluN2B had been replaced with that of GluN2A, and a second line in which the opposite replacement had taken place, were used to investigate the role of the CTD in the NMDAR response to ketamine. It was found that the GluN2B CTD is required for the short-term psychosis-like response to a sub-anaesthetic dose of ketamine. This is interesting as the channel pore region, containing the binding site for ketamine, is unaltered in these mutants. Therefore, this finding implicates GluN2B CTD specific intracellular signalling molecules in this action of ketamine and raises the question of whether the CTD itself is able to respond to ketamine binding within the pore to induce signalling changes, perhaps via a conformational change. Secondly, a mouse line, in which the activity-regulated synaptic protein Arc has been tagged with a fluorescent marker, was used to investigate the response of synapses to both anaesthetic and sub-anaesthetic doses of ketamine. In this experiment tagged Arc protein was visible as punctate accumulations at synapses. A novel method termed ‘synaptome mapping’ was used to image these accumulations across entire coronal sections and to quantify their number, size and intensity. Using this method alterations to the Arc synaptome map were detected 1h, 6h and 24h following ketamine administration. The two doses used produced different changes to this map, with the sub-anaesthetic antidepressant dose inducing increases in Arc puncta number across many brain regions, whereas the anaesthetic dose induced short term (1h) increases followed by longer term decreases in Arc puncta number. This finding links long-term increases in Arc at the synapse with an antidepressant response to ketamine.en
dc.language.isoenen
dc.publisherThe University of Edinburghen
dc.relation.hasversionFernandez E, Collins MO, Frank RAW, Zhu F, Kopanitsa MV, Nithianantharajah J, Lempriere SA, Fricker D, Elsegood KA, McLaughlin CL, Croning MDR, McLean C, Armstrong JD, Hill WD, Deary IJ, Cencelli G, Bagni C, Fromer M, Purcell SM, Pocklington AJ, Choudhary JS, Komiyama NH & Grant SGN. (2017). Arc Requires PSD95 for Assembly into Postsynaptic Complexes Involved with Neural Dysfunction and Intelligence. Cell Reports 21, 679-691.en
dc.subjectketamineen
dc.subjectArcen
dc.subjectNMDA receptorsen
dc.subjectantidepressant responsesen
dc.subjectpsychosis-like effectsen
dc.titleStudying the synaptome: insights into ketamine actionen
dc.typeThesis or Dissertationen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD Doctor of Philosophyen


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