Investigation of the behavioural phenotype of a mouse model of Williams-Beuren Syndrome (Gtf2ird1)

Abstract

Williams-beuren syndrome (WBS) is caused by a deletion of ~25 genes and is characterised by cardiovascular dysfunction, an uneven cognitive profile and a hypersocial personality. Studies with partial deletion patients suggest that hemizygosity of less than half of the genes within the critical region are sufficient to cause WBS. One of these genes, GTF2IRD1, is thought to be an important contributor to the cognitive and behavioural deficits, as well as the craniofacial morphology associated with WBS. However, it is still unclear what contribution GTF2IRD1 alone makes to the WBS phenotype, as these patients are rare and, therefore, studies lack adequate effect size to generate convincing genotype-phenotype links. A method used to investigate the role of a gene in development is through the creation of a mouse model with a mutation in this gene. Tassabehji et al. (2005) partially phenotyped a Gtf2ird1 knockout mouse model (Gtf2ird1Tg(Alb1-Myc)166.8Sst), identifying craniofacial and growth defects, and an abnormal hind limb grasping reflex indicative of neurological abnormalities. The aim of this thesis was to screen this model for behavioural deficits using a comprehensive test battery and thus provide a direct link between changes in the level of Gtf2ird1 expression and behaviour. The test battery investigated four core behavioural domains relevant to WBS: motor function, anxiety, social behaviour and learning and memory. Loss of either one or two copies of Gtf2ird1 resulted in motor dysfunction. Both heterozygous and homozygous mutant groups were hypoactive on the open field and pressure sensitive activity plates, and displayed a reduced ability to coordinate their movements on the static rods. In homozygous mice, however, the motor phenotype was more severe. It extended to a deficit in fine motor control in the shredded nest experiment, coordination problems on the accelerating rotarod and reduced muscular strength on the horizontal bar. Anxiety was elevated in Gtf2ird1 mutant mice, but was more pronounced in homozygotes. Both groups were more hesitant to eat the novel foodstuff on the hyponeophagia test, and displayed diminished exploration on the Light/Dark box. Homozygotes displayed prolonged risk assessment behaviour on the elevated plus maze, increased displacement behaviour (grooming) and a stronger thermogenic response to a stressor. An unexpected finding was lower core body temperature in homozygote mice, suggesting altered thermoregulation. Gtf2ird1 mutant groups displayed altered social behaviour. Only homozygous male mice were less aggressive in response to territorial threat on the resident- intruder test. In females, both homozygote and heterozygote mice were less aggressive, and displayed increased interest in the intruder. Homozygous mice also displayed elevated sociability on the social recognition test. These two findings are similar to the increased anxiety and elevated social drive observed in WBS.Learning and memory were assessed using a range of tests. Homozygous mice displayed a mild deficit in social recognition ability. Spatial working memory in the spontaneous alternation test was intact; as was short-term object memory (measured by the object recognition test) spatial reference memory, and procedural memory (assessed using the visual platform test). Overall, examination of the behavioural phenotype has demonstrated that loss of Gtf2ird1 results in widespread abnormalities in motor, anxiety and social behaviour. This shows that this gene is likely to play an important role in the development of some of the behavioural features characteristic of WBS. Although further work is needed to identify the neuroanatomical basis of these phenotypes, it is proposed that abnormal brain development may have affected cerebellar-basal ganglia, hypothalamic and frontal-amygdala cortical connections in this mouse model.

Date of Award	31 Dec 2013
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Mayada Tassabehji (Supervisor)