Genetic and functional investigation of FXYD6 and MAP2K7 as risk factors in schizophrenia

Thompson, Rhiannon (2013) Genetic and functional investigation of FXYD6 and MAP2K7 as risk factors in schizophrenia. PhD thesis, University of Glasgow.

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Schizophrenia is a debilitating psychiatric disorder with a prevalence of around 1% worldwide. It is an extraordinarily complex syndrome, which encompasses multiple psychological domains leading to the impairment of a range of symptoms. These symptoms are categorised as positive symptoms, negative symptoms and cognitive deficits. The profile of cognitive deficits is broad and severe, and is likely to be present in most, if not all patients. Despite cognitive enhancement being recognised as an important treatment target in schizophrenia, the discovery of an effective treatment has been met with difficulty.

The degree of psychosis is subject to numerous genetic and environmental factors. Family, twin and adoption studies show schizophrenia is unequivocally a genetic disorder, however the genetics behind schizophrenia are indisputably complex as it is not characterised by a single causative gene. A number of candidate genes have been implicated in schizophrenia. Recent genetic association studies have found an association for two genes, FXYD6 and MAP2K7, as risk factors in the susceptibility to schizophrenia. However the roles of these genes in the underlying mechanisms of the symptoms of schizophrenia are unknown. To address this I utilise two mouse models, one containing homozygous disruption of Fxyd6 (Fxyd6-/-) and one heterozygous for Map2k7 (Map2k7+/-). I employ a range of molecular and behavioural tests to investigate the roles FXYD6 and MAP2K7 in schizophrenia- like phenotypes in these mice.

FXYD proteins are a family of seven single-span transmembrane proteins, all thought to be regulators of the Na+ K+ ATPase pump in a tissue-specific fashion. Up until now, FXYD6 function and its role in the risk to schizophrenia remain unclear. To address this I firstly investigated the association between FXYD6 and schizophrenia in a Northern European population using a genetic association study. However from this study I was unable to confirm an allelic or haplotypic association between FXYD6 and schizophrenia. Furthermore there was also no evidence for a role of epistatic interactions between FXYD6 and MAP2K7 in the risk of schizophrenia.

A putative functional link for FXYD6 in schizophrenia was explored further using Fxyd6-/- mice. The in situ hybridisation technique was utilised to reveal the expression of Fxyd6 in the mouse brain. Fxyd6 is interestingly expressed in the prefrontal cortex and hippocampus, two brain regions associated with schizophrenia and learning and memory. In addition, I have shown for the first time that disruption of Fxyd6 results in a significant deficit in Na+ K+ ATPase activity in the forebrain, confirming that FXYD6 is a modulator of mouse brain Na+ K+ ATPase activity. Anxiety- like behaviours and hyperlocomotion were explored Fxyd6-/- mice. However activity in plus maze and open field tests, and response to amphetamine or ketamine was not altered in comparison to wildtype mice. Nonetheless subtle deficits observed in prepulse inhibition suggest potential deficits in neurotransmission in Fxyd6-/- mice may be present. Interestingly, Fxyd6-/- mice displayed deficits in working memory at delays of 5 seconds, indicating cognitive deficits. The molecular characterisation and insight into the phenotype of Fxyd6-/- mice are encouraging to investigate the role of FXYD6 in underlying mechanisms of schizophrenia-like symptoms further.

MAP2K7 belongs to the family of Map Kinases which have key roles in the regulation of a diverse range of cellular processes such as gene expression, apoptosis and synaptic plasticity. The brain expression of Map2k7 was previously unknown, however this study utilised the in situ hybridisation technique to show expression in regions associated with schizophrenia, including the PFC and the hippocampus.
For the reason that the homozygous disruption of Map2k7 is embryonically lethal, mice heterozygous for the disruption Map2k7 were used to explore the role of MAP2K7 in the susceptibility to schizophrenia. RTqPCR confirmed a modest but significant reduction of Map2k7 in these mice. The heterozygous deletion of Map2k7 results in alteration of glutamate receptor Grin1 expression, a receptor reported to have altered expression in schizophrenia. Furthermore, Map2k7+/- mice display cognitive deficits, as observed by increased perseverative responding in the working memory task. Despite not exhibiting deficits in PPI, social behaviours or neurochemical deficits in GABAergic markers, Map2k7+/- mice revealed altered sensitivity to amphetamine, suggesting alterations in dopaminergic circuitry.
In conclusion, this study provides an insight in to the functional roles of FXYD6 and MAP2K7. Although the roles of FXYD6 and MAP2K7 as risk factors in schizophrenia still requires further elucidation, these results provide evidence of a putative role for both genes in some areas of the underlying neuronal activity associated with schizophrenia-associated symptoms. Furthermore, results from this study suggest both strains of mice are potential rodent models of cognitive impairments.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: fxyd6, map2k7, schizophrenia, cognition, mouse model, working memory,
Subjects: Q Science > Q Science (General)
Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Psychology & Neuroscience
Supervisor's Name: Morris, Prof. Brian , Pratt, Prof. Judith and Winchester, Dr. Catherine
Date of Award: 2013
Depositing User: Miss Rhiannon J Thompson
Unique ID: glathesis:2013-4157
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 12 Apr 2013 12:56
Last Modified: 12 Apr 2013 12:59

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