Year: 2013
Type: dissertation
Abstract: Genetic variation in the gene ZNF804A has been shown to be related to risk for psychopathology, especially schizophrenia and bipolar disorder. The main aim of this thesis was to characterise the behavioural effects of Zfp804a, the mouse orthologue of ZNF804A, in order to understand more about how this gene influences brain and psychological functioning, and hence provide clues as to its possible role in mediating risk for mental disorders. Prior to this work, two ENU-mutant mouse lines had been generated from a DNA library of ENU mutagenised mice with two non-synonymous mutations selected as viable candidates for further investigation. The C59X mutation encodes a premature stop codon in exon 2, thought to lead to a functional null of the gene, and the C417Y mutation is missense, substituting cysteine for tyrosine in exon 4. A first series of experiments examined the early development of the ENU-mutant lines and showed no gross developmental abnormalities, although the C59X mutants weighed significantly less than their WT littermate controls at weaning and during adulthood. A comprehensive series of behavioural tests then assayed aspects of emotion, motivation, hedonia, sensorimotor gating and response control. In general, the C59X mutants showed the greatest effects, displaying reduced anxiety, anhedonia, and sensorimotor gating deficits, together with evidence of enhanced response inhibition. The C417Y mutants only showed selective effects in terms of enhanced motivation. The data dissociate between the effects of the two ENU-induced mutations of Zfp804a. Furthermore, the findings with the C59X mutants would suggest, a priori, that genetic variance leading to alterations in ZNF804A expression may be an important mechanism contributing to risk for psychopathology.
Author: Jessica B Eddy
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W1484236567