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dc.contributor.advisorWyllie, David
dc.contributor.advisorKind, Peter
dc.contributor.advisorJohnstone, Mandy
dc.contributor.authorMizen, Lindsay Anne MacTaggart
dc.date.accessioned2018-03-26T10:21:57Z
dc.date.available2018-03-26T10:21:57Z
dc.date.issued2018-07-10
dc.identifier.urihttp://hdl.handle.net/1842/28968
dc.description.abstractIntellectual disability (ID) and autism spectrum disorders (ASDs) can have a devastating impact on an individual’s functioning and quality of life. Insights from pre-clinical models of monogenic forms of ID and ASD are now revealing the biochemical pathways and aberrations in cellular and synaptic functioning involved. One monogenic cause of ID, ASD and epilepsy is SYNGAP1 ID which results from mutations in the SYNGAP1 gene on human chromosome 6. Although a variety of symptoms have been reported, many affected individuals have moderate to severe intellectual impairment and severe seizure phenotypes. Previous pre-clinical studies have mainly focussed on the effects of altered SynGAP expression in mice. This thesis is therefore the first to explore altered SynGAP expression in a rat model. It also adds to the body of research exploring the roles of SynGAP isoforms in glutamatergic synaptic function. The SynGAP_GAP deletion rat was engineered to have a deletion encompassing the enzymatically active GTPase activating protein (GAP) domain of the protein, via which SynGAP regulates multiple biochemical pathways by enhancing the slow intrinsic hydrolysis of GTP by GTP-binding proteins. SyngapGAP/GAP rats appeared small and failed to thrive. As with Syngap-/- mice, this complete loss of WT SynGAP proved lethal, whereas Syngap+/GAP rats appeared to develop normally. The electrophysiological data obtained from this new model reveals a reduction in the frequency of miniature excitatory post-synaptic currents (mEPSCs) in Syngap+/GAP cultured neurons. However the exaggerated hippocampal long-term depression identified in Syngap+/- mice was not seen in the rats. There was also no evidence of differences in intrinsic cell properties, excitatory and inhibitory currents or ratios of AMPAR / GABAAR and AMPAR / NMDAR between WT and heterozygous rats. In addition to the characterisation of the SynGAP_GAP deletion rat, the impact of the previously unstudied Eα1 isoform on forebrain neuronal synaptic function was examined through mEPSC recordings. A trend towards lower mEPSC frequency was found which supports previous research showing that α1 isoforms reduce synaptic strength. This body of work therefore adds to published evidence of isoform specific functions and provides the first evidence of the impact of SynGAP alterations in rats, the results of which show some intriguing differences from previous work in mice.en
dc.contributor.sponsorMedical Research Council (MRC)en
dc.language.isoenen
dc.publisherThe University of Edinburghen
dc.subjectlearning disabilityen
dc.subjectintellectual disabilityen
dc.subjectautism spectrum disordersen
dc.subjectSYNGAP1en
dc.subjectSynGAPen
dc.subjectanimal modelen
dc.subjectratsen
dc.subjectsignallingen
dc.titleCharacteristics of cellular and synaptic function in rodent forebrain neurons with altered SynGAP expressionen
dc.typeThesis or Dissertationen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD Doctor of Philosophyen


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