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Title: Analysis of a new mouse model of mental illness : Derived (1)
Author: Bonneau, Marion Géraldine France
ISNI:       0000 0004 7969 1149
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2019
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In a Scottish family, a t(1;11) (q42;q14) translocation between chromosome 1 and 11, is linked with mental illness. People carrying this translocation are diagnosed with mental illnesses such as schizophrenia, schizoaffective disorder, bipolar disorder and recurrent major depressive disorder. The DISC1 gene localised on the chromosome 1 is known to be disturbed by this translocation. The DISC1 protein is involved in neurite outgrowth, cortical development, cell proliferation, differentiation, migration, mitochondrial activity, and cytoskeletal organisation and function. Multiple animal models have been created to study the effect of disrupting DISC1 on brain development and mental illness. Rodent models have shown critical changes in behaviour, brain function and structure, as well as alterations in various molecular pathways. These modifications are consistent with an involvement for DISC1 in psychiatric disorders. However, none of these Disc1 mouse models accurately model any known causal events. This thesis aims to characterise a new mouse model of the derived chromosome 1 carrying a modified endogenous Disc1 gene, in order to reproduce the human transcript obtained from the chromosome 1 after the translocation happens. While MRI analysis of its brain structure showed no gross changes, histological analysis of brain structure revealed an enlargement of the lateral ventricles and a trend towards smaller cortical layer and corpus callosum thickness in heterozygous mice. There was also increased apoptosis in the prefrontal cortex of these mice. Investigation of cell density, GABAergic neuron density and hippocampal neural precursor proliferation and migration showed no significant change. Cultured homozygous mutant cortical neurons showed impaired neuronal outgrowth and somal hypertrophy. Lastly, RNAseq analysis and gene ontology analysis revealed disturbed RNA expression of numerous genes including genes involved with transport mechanisms, vesicular trafficking, cell signalling and communication in the cortex as well as genes involved with transport mechanisms and the electrical activity of the neurons in the hippocampus. Moreover, in both these regions, these alterations are more prominent in the synapse. Overall, the t(1;11) (q42;q14) translocation seems to lead to subtle structural changes in the brain, neuronal outgrowth impairment and major changes in RNA expression. The latest suggests critical alteration in molecular pathways such as signalling pathway and synaptic pathway indicating that Disc1 is necessary for neuronal signalling and synaptic activity. As those characteristics are known to be strongly affected in psychiatric disorders, this indicates that the Der1 mice model could be a great model to study the underlying genetic and molecular pathway leading to developing those disorders. These results support the hypothesis that DISC1 is a susceptibility gene for the development of mental disorders.
Supervisor: Millar, Kirsty ; Price, David Sponsor: Medical Research Council (MRC)
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: translocation chromosomes 1 and 11 ; DISC1 ; mouse model