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Investigating the transcriptional correlates of cognition in the heterozygous HdhQ150 mouse model of Huntington’s disease

Scoberg-Evans, Jordan 2016. Investigating the transcriptional correlates of cognition in the heterozygous HdhQ150 mouse model of Huntington’s disease. PhD Thesis, Cardiff University.
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Huntington’s disease (HD) is a progressive autosomal dominant neurodegenerative disorder caused by expansion of a trinucleotide CAG repeat in the Huntingtin gene (HTT) on chromosome 4. HD symptomatology is characterised by a triad of motor, cognitive, and psychiatric disturbances, as well as transcriptional dysregulation. The identification of HTT as the single causative gene in HD has led to the development of a number of animal models that are designed to recreate the molecular and behavioural phenotypes of the human disease; one such model is the HdhQ150 mouse model of HD. Investigation into the cognitive capacities of animals heterozygous for the HdhQ150 mutant allele (HdhQ150/+) revealed a series of novel cognitive impairments that recapitulate aspects of the cognitive phenotype observed in human HD patients; deficits in conditioning task acquisition and performance were identified in HdhQ150/+ mice, as were impairments in visuospatial attention, and delayed acquisition and cognitive processing of spatial discrimination (SD) learning. However, implicit learning capabilities of HdhQ150/+ animals were analogous to those of wild-type mice. Microarray and reverse transcription quantitative polymerase chain reaction (RT-qPCR) investigations into the transcriptional correlates of cognition did not identify significant learning-dependent gene expression level changes in the striata of HdhQ150/+ or wild-type mice. Similarly, these techniques did not report significant striatal gene expression level alterations across distinct stages of SD and reversal learning operant task performance in wild-type animals. In contrast, RT-qPCR revealed significant differences in the striatal expression levels of Adora2A, Arc, Drd2, and Homer1 genes between HdhQ150/+ and wild-type mice at 44-60 weeks of age, supporting previous evidence of abnormal expression or signalling of these genes in the HD phenotype. Overall, this body of work contributes novel evidence that HdhQ150/+ animals present with molecular and cognitive phenotypes comparable to those seen in the human form of the disease.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Medicine
Subjects: R Medicine > R Medicine (General)
Date of First Compliant Deposit: 18 August 2016
Last Modified: 27 Sep 2018 01:30

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