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Investigations of the potential schizophrenia susceptibility gene Kinase Interacting with Stathmin (KIS)

Single nucleotide polymorphisms (SNPs) within the gene encoding the serine threonine kinase KIS (Kinase Interacting with Stathmin, also known as UHMK1) have recently been associated with schizophrenia. However, little is known about the neurobiology of KIS or the mechanisms through which disease-associated SNPs may increase susceptibility to schizophrenia. The studies presented in this thesis focus on the distribution of KIS and its mRNA, address the mechanisms through which KIS may confer susceptibility to schizophrenia, and investigate the physiological role(s) of KIS in the brain using two lines of knockout mice. The regional and cellular distribution of KIS was characterised in the brains of adult humans and mice, and through mouse neurodevelopment. The results of these experiments demonstrated that KIS is widely expressed in neurons in the brain regions examined in both species, its encoded protein is localised to the nucleus and cytoplasm, and KIS expression in mouse brain peaked around seven days after birth. KIS protein and mRNA was quantified in two large human post-mortem brain series to determine if KIS expression is altered in schizophrenia or bipolar disorder, or in relation to the leading schizophrenia-associated SNP (rs7513662). Using tissue from the superior temporal gyrus, dorsolateral prefrontal cortex, anterior cingulate cortex, and cerebellum, no difference in KIS expression (either mRNA or protein) was found between diagnostic or genotype groups in any brain region examined. Furthermore, KIS expression in lymphoblast cell lines also did not differ between diagnostic or genotype groups. Lastly, KIS expression (mRNA and protein) was characterised in two separate lines of KIS knockout mice. The results were complex, and left uncertainty as to whether either line was a true knockout or, conversely, whether any of the available KIS antibodies were specific. Nevertheless, the absence of KIS mRNA was robustly confirmed in one knockout mouse line, and brains from this line were subsequently used in three experiments. First, investigation of the quantity and phosphorylation state of the KIS targets stathmin and p27<sup>kip1</sup>; no differences were found compared to wildtype mice. Second, quantification of mRNA expression of several other genes of interest with regard to schizophrenia; altered expression of GAP43, VGlut1, MAP2, spinophilin, and stathmin was found. Finally, stereological measurements were performed, and while no differences in whole or regional brain volumes in KIS knockout mice were found, there was a relative reduction in hippocampal volume. The results of these studies do not support the hypothesis that altered expression is the mechanism by which genetic variation of KIS may increase susceptibility to schizophrenia, nor that KIS expression is altered in the disease. However, the knockout mice data suggest that KIS may play a role in synaptic plasticity and function, providing novel information on the potential neurobiological roles of KIS.

Identiferoai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:540130
Date January 2010
CreatorsBristow, Greg
ContributorsHarrison, Paul J. ; Eastwood, Sharon L.
PublisherUniversity of Oxford
Source SetsEthos UK
Detected LanguageEnglish
TypeElectronic Thesis or Dissertation
Sourcehttp://ora.ox.ac.uk/objects/uuid:432fc195-815c-4bc6-945f-c2b59aa3538c

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