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dc.contributor.advisorLeitch, Beulah
dc.contributor.authorShevtsova, Olga
dc.date.available2014-02-24T00:10:02Z
dc.date.copyright2014
dc.identifier.citationShevtsova, O. (2014). The role of stargazin deficits in brain disorders (Thesis, Doctor of Philosophy). University of Otago. Retrieved from http://hdl.handle.net/10523/4615en
dc.identifier.urihttp://hdl.handle.net/10523/4615
dc.description.abstractGlutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) are the major mediators of fast excitatory transmission in the mammalian central nervous system (CNS). Regulation of AMPAR trafficking into and out of synapses is important for synaptic transmission and synaptic plasticity. AMPARs are trafficked to the synapse by transmembrane AMPAR regulatory proteins (TARPs). TARPs are auxiliary AMPAR subunits, which play a crucial role in AMPAR synaptic trafficking, channel desensitisation and controlling agonist-binding activity. TARP γ2 (stargazin) is ablated in the brain of the stargazer mouse. Emerging evidence implicates abnormal expression of stargazin in numerous neurological disorders, including ataxia and absence epilepsy. This thesis investigates how a mutation in the CACNG2 gene, encoding the protein stargazin, affects normal brain function. In particular, this study explores how the loss of stargazin leads to ataxia and absence epilepsy. This study uses the spontaneous mutant mouse stargazer to investigate how stargazin deficits cause a loss of AMPARs at synapses. It had been previously shown in vitro that stargazin mutation leads to the loss of functional AMPARs in the cerebellum and thalamus of stargazer mouse. However, the mechanisms of AMPAR and TARP interplay at synapses in different brain regions are still unclear. The aim of this study was to investigate in situ at the ultrastructural level how the loss of stargazin affects the expression levels of synaptic proteins involved in signalling at synapses in the cerebellum and thalamus and therefore leads to the brain disorders of ataxia and absence epilepsy respectively in the stargazer mouse. The levels of AMPAR subunits GluA2/3 and GluA4 were evaluated by measuring the relative density of immunogold at the postsynaptic density in ultrathin sections in the cerebellum and thalamus from ataxic and epileptic stargazers compared to matched control littermates. It was found that there was a selective loss in the expression of GluA2/3 and GluA4 at parallel fibre (PF)-Purkinje cell (PC), climbing fibre-PC and PF-interneuron synapses in the cerebellar molecular layer (ML) of ataxic stargazers. In the thalamus of epileptic stargazers, the loss of stargazin leads to region and synapse specific changes in AMPAR expression. The levels of GluA2/3 and GluA4 were selectively decreased at corticothalamic (CT) synapses in the reticular thalamic nucleus (RTN) but not at CT synapses in the ventral posterior thalamic region in epileptic stargazers. Although, there was a loss of AMPAR expression at CT synapses in the RTN of stargazers, no significant changes were observed at thalamocortical synapses in the RTN region. In conclusion, the findings obtained in the present study demonstrated the selective loss of AMPARs at the ML cerebellar synapses, which could affect the cerebellar output to the deep cerebellar nuclei. This could contribute to the ataxic phenotype in stargazers. The selective regional and synapse specific loss of AMPARs in the thalamus of epileptic stargazers leads to disturbances within the cortico-thalamo-cortical circuit and generates spike-wave discharges within this circuit and the absence epilepsy phenotype. Understanding the cellular and molecular mechanisms underlying the impact of stargazin deficits on these brain disorders could contribute to future development of therapeutic strategies.  
dc.language.isoen
dc.publisherUniversity of Otago
dc.rightsAll items in OUR Archive are provided for private study and research purposes and are protected by copyright with all rights reserved unless otherwise indicated.
dc.subjectstargazin
dc.subjectAMPARs
dc.titleThe role of stargazin deficits in brain disorders
dc.typeThesis
dc.date.updated2014-02-23T22:10:17Z
dc.language.rfc3066en
thesis.degree.disciplineAnatomy
thesis.degree.nameDoctor of Philosophy
thesis.degree.grantorUniversity of Otago
thesis.degree.levelDoctoral
otago.interloanno
otago.openaccessAbstract Only
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