Characterisation of genetic risk factors for mental illness in rodent models : impact of Map2k7+/- and Fxyd6-/- mice on neural systems and working memory

Awarding institution
  • University of Strathclyde
Date of award
  • 2015
Thesis identifier
  • T14148
Person Identifier (Local)
  • 201274576
Qualification Level
Qualification Name
Department, School or Faculty
  • Even in wealthy and seemingly prosperous countries like the United Kingdom, the spectre of mental illness and psychiatric disorders remains highly prevalent. These disorders present a huge economic burden to societies, where in the UK alone, mental disorders cost the economy an estimated €134 billion a year; along with the unmeasurable societal and human costs. This has led to an intense debate over the past few decades just as to what factors contribute to these illnesses. It is now understood that a number of biological and non-biological factors contribute. These include socio-economic pressures, early-life trauma, gestational and peri-natal infections; genetic and familial factors, and molecular and cellular factors. However, while the definitions and diagnostic criteria of mental disorders remain based in the subjective realms of the DSM and ICD, treatment and understanding of psychiatric illness has had little chance to progress over the last fifty years. As a result, neuroscientists are starting to direct psychiatric disorder research from the bottom-up; where genetic, cognitive and neuroconnectivity factors are being investigated to serve as a future basis for diagnosis and treatment. One of the most complex and debilitating psychiatric disorders, schizophrenia, exhibits a complex array of genetic, cognitive and neuroconnectivity abnormalities. Current challenges in schizophrenia research is to understand how identified genetic abnormalities contribute to neuroconnectivity and cognitive impairments which are prominent in schizophrenia. Recently, genetic association studies have implicated two genes as risk factors for schizophrenia - FXYD6 and MAP2K7. Currently it is unclear exactly how these genes contribute to schizophrenia pathology, particularly cognitive symptoms and neural circuitry.;This thesis investigates these two genes by utilising two mouse models, first a heterozygous mouse line of Map2k7+/- and second, a gene knock-out line of Fxyd6-/-. MAP2K7 is a gene that expresses a kinase that is involved in the c-Jun N-terminal kinase (JNK) pathway, which is implicated in neuronal activity, receptor function, and cortical and hippocampal plasticity. Recent studies have found a decreased expression of MA2PK7 in the PFC, ACC and hippocampal regions in schizophrenia patients; regions associated with memory and decision making. A component of the cognitive profile of MAP2K7 was therefore investigated using Map2k7+/- mouse lines in a working memory paradigm in the radial arm maze. This test is known as the n-back test or the retention interval test. For the first time this investigation reveals that Map2k7+/- mice exhibit a subtle yet significant spatial working memory deficit compared to WT mice; as judged by their average performance over the whole experiment. WT mice exhibited an overall average performance of 70% and MAP2K7+/- mice 66% (p<0.001). This indicates that MAP2K7 may play a subtle role in working memory function in rodents, and may represent a component of the aberrations in the genetic architecture that gives rise to working memory impairments in psychiatric disorders, particularly schizophrenia. This experiment also backs up previous evidence for this radial arm maze paradigm as a robust behavioural test for testing rodent working memory.;FXYD6 belongs to a group of proteins that are known to be involved in modulating NaKATPase activity. Previously, NaKATPase has been associated with bipolar disorder and depression, but has now also been implicated in schizophrenia. Previous studies have found that FXYD6 is also abnormally expressed in the PFC of schizophrenia patients, and therefore may contribute to the cognate symptoms of the disorder. This experiment, therefore, investigated how Fxyd6 contributes to local brain activation, particularly in neural systems relevant to cognition, using gene knockout Fxyd6-/- mouse models and semi quantitative 2DG autoradiographic imaging. Three regions showed a significant deviation in activity in Fxyd6-/- mice compared to WT mice. The subiculum, medial septum and lateral septum all exhibited significant reductions in activity in Fxyd6-/- mice compared to WT mice. Notably the subiculum is heavily implicated with memory functions, particularly working memory and disambiguation of previously learned memory. Indicating a possible role for FXYD6 and NaKATPase in working memory processing and memory disambiguation in the subiculum. Finally, the role of glutamate in relation to FXYD6 function and brain activity was assessed by administering the NMDA receptor antagonist ketamine and analysing regional brain activity using semi quantitative 2DG autoradiographic imaging. Generally, regions which were affected by ketamine in WT mice including PFC, thalamic and septal regions, were not affected in Fxyd6-/- mice. It is hypothesized that this may be down to a compensatory effect that knocking-out Fxyd6 may have on glutamate reuptake. Because NaKATPase is involved in glutamate reuptake into glia and neurons, the blockage of NMDA receptors may have less effect due to a reduction in glutamate reuptake, and therefore higher than normal postsynaptic glutamate concentrations. In conclusion, this investigation highlights two genes which may have roles in working memory functioning and neural circuitry that contribute to cognitive processes. While the evidence from this investigation does not explicitly associate these genes with symptoms of schizophrenia and other psychiatric disorders; the evidence does provide indication that they are involved in cognitive processes in rodents, and possibly humans. This investigation provides an interesting path of investigation for the potential roles of these genes regardless of their relationship to psychiatric disorders and will inform future research into the genetic architecture of neural circuits and cognition.
Resource Type
Date Created
  • 2015
Former identifier
  • 1238291