Schizophrenia is a serious psychiatric disorder characterised by a breakdown in thought, emotion and perception, which leads to alterations of normal behaviour and feelings, a withdrawal from reality and an impression of mental defragmentation. Of the positive, negative and cognitive symptoms, the positive symptoms are perhaps the most striking. However, it is the severity of cognitive deficits that are most closely associated with a patients’ functional outcome in the long-term. Despite this, the successful treatment of the cognitive deficits has been met with difficulty, partly due to a lack of suitable animal models. There is an urgent need for animal models with appropriate face, construct and predictive validity for schizophrenia so that improved drug targets can be identified, and new drugs tested. In 2012, Winchester et al. discovered that sequence variations in the Map2k7 gene were associated with increased risk for schizophrenia, and Map2k7 mRNA was decreased in the prefrontal cortex of the post mortem brains of patients. The primary aim of this thesis is to behaviourally and molecularly characterise mice which are heterozygous for Map2k7 (Map2k7+/- mice) as a potential animal model of relevance to schizophrenia. Sequence variants in the Map2k7 gene are moderately common in the population and they almost double the disease risk (OR~1.9); hence, alterations of the Map2k7 gene in mice represent an ideal basis for an animal model with good construct validity. The Map2k7 gene produces the MKK7 protein, a kinase within the stress-activated JNK pathway, and is involved in a diverse range of cellular processes, such as apoptosis, synaptic plasticity and regulation of the immune response. First and foremost, the components of the MKK7/JNK pathway were quantified in Map2k7+/- mice and MKK7γ was found to be significantly decreased in the prefrontal cortex compared to their wildtype (WT) littermates, a highly disrupted brain region in patients with schizophrenia. Map2k7+/- mice also exhibited behavioural phenotypes relevant to schizophrenia: hyperactivity in the open field and attentional dysfunction. Minocycline showed promise in alleviating the attentional deficits and hyperactivity in the open field, but did not influence protein levels of signalling pathway components. Map2k7+/- mice did not show a decrease in sensorimotor gating as many patients do; however, they exhibited signs of altered response to amphetamine administration just prior to testing of sensorimotor gating, compared to WT mice. Decision-making abilities were also investigated: Map2k7+/- mice showed normal learning and performance of the rodent gambling task. Additionally, all mice were able to alter their choice pattern to be more optimal when the task contingencies were subtly switched, which was the first time this has been shown in mice in the touchscreen apparatus. However, when the task demands were altered such that ‘punishment’ no longer featured as prominently, Map2k7+/- mice showed huge difficulty compared to their WT littermates in shifting their choice pattern to be more optimal, suggesting they have a deficit in aspects of cognitive flexibility. Finally, Map2k7+/- mice were investigated as a gene x environment interaction model, by injecting pregnant dams with Poly I:C and examining the resultant immune response in maternal serum and embryonic brain. Map2k7+/- dams exhibited an altered immune response to Poly I:C compared to WT dams; however, future experiments will be required to confirm whether this altered cytokine response is also present in embryonic brain. Overall, Map2k7+/- mice show utility for dissecting the cognitive deficits and some aspects of the positive symptoms of schizophrenia that could be targeted by novel compounds. This would be aimed at restoring the function of the MKK7/JNK pathway. Further molecular and behavioural characterisation will be required, particularly into the potential gene x environment interaction model. Although no mouse model can recapitulate the full symptom spectrum of a human neuropsychiatric disorder, Map2k7+/- mice exhibit an interesting accumulation of phenotypic abnormalities relevant to schizophrenia.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:739224 |
| Date | January 2017 |
| Creators | Openshaw, Rebecca Louise |
| Publisher | University of Glasgow |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://theses.gla.ac.uk/8890/ |
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