Cognitive and synaptic dysfunction in a mouse model of Huntington's disease
Huntington’s disease (HD) is a neurodegenerative disorder characterised by an unstable polyglutamine repeat expansion within the Huntingtin gene. Although clinical diagnosis of HD relies on the manifestation of a motor phenotype, cognitive symptoms often appear prior to diagnosis. This study has characterised the motor, cognitive and electrophysiological phenotypes of the homozygous and heterozygous HdhQ111 mouse models of HD. Although the heterozygous HdhQ111 mouse is more clinically relevant to the human disorder, it has received little attention in previous studies. Assessments of the motor phenotype of the HdhQ111 mouse were inconclusive. However, HdhQ111 mice exhibited a mild motor phenotype on the rotarod, showing hyperactivity at 2 and 3 months. Subtle changes within the hippocampus are thought to underlie the cognitive abnormalities that characterise the early stages of HD. A series of recognition tasks were used to assess the episodic memory of the HdhQ111 mouse. Although these tasks had been used to assess the ability of rats to discriminate the ‘what’, ‘where’ and ‘when’ of episodic memory, this was the first time that they had been successfully utilised in mice. HdhQ111 mice showed impairments in episodic memory as early as 2 months. In mouse models, cognitive deficits are often accompanied by impairments in hippocampal synaptic plasticity, the molecular correlate of learning and memory. In agreement, HdhQ111 mice showed impairments in long-term potentiation (LTP) at 2 months. A novel, shortened version of the protocol was developed to accurately assess the changes in cognition in the small development window available. A hippocampus-dependent 24-hour novel object recognition task was also used to assess the integrity of the hippocampus. Hippocampal function in 1 month old HdhQ111 mice was not significantly different from that in wild type mice. The early cognitive deficits present in the HdhQ111 mice were progressive, with cognitive deficits spreading to include the individual components of episodic memory by 13 months. Drugs inhibiting the function of a5-GABAA receptors are known to enhance cognition and hippocampal LTP. In agreement, the LTP and cognitive deficits of the HdhQ111 mouse were rescued following treatment with the a5-GABAA receptors selective inverse agonist a5IA. Importantly, the clinically relevant heterozygous HdhQ111 mice exhibited an identical phenotype to homozygous HdhQ111 mice indicating that, reminiscent of the human disorder, only one copy of the mutant gene is necessary to produce abnormalities associated with the disorder, further supporting the validity of the HdhQ111 mouse as a clinically relevant model of HD. Collectively, this thesis provides evidence that a5-GABAA receptors antagonists have the potential to improve cognitive function in HD.
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