A Longitudinal Motor Characterisation of the HdhQ111 Mouse Model of Huntington’s Disease

Abstract

Background: Huntington’s disease (HD) is a rare, incurable neurodegenerative disorder caused by a CAG trinucleotide expansion with the first exon of the huntingtin gene. Numerous knock-in mouse models are currently available for modelling HD. However, before their use in scientific research, these models must be characterised to determine their face and predictive validity as models of the disease and their reliability in recapitulating HD symptoms.Objective: Manifest HD is currently diagnosed upon the onset of motor symptoms, thus we sought to longitudinally characterise the progression and severity of motor signs in the HdhQ111 knock-in mouse model of HD, in heterozygous mice.Methods: An extensive battery of motor tests including: rotarod, inverted lid test, balance beam, spontaneous locomotor activity and gait analysis were applied longitudinally to a cohort of HdhQ111 heterozygous mice in order to progressively assess motor function.Results: A progressive failure to gain body weight was demonstrated from 11 months of age and motor problems in all measures of balance beam performance were shown in HdhQ111 heterozygous animals in comparison to wild type control animals from 9 months of age. A decreased latency to fall from the rotarod was demonstrated in HdhQ111 heterozygous animals in comparison to wild type animals, although this was not progressive with time. No genotype specific differences were demonstrated in any of the other motor tests included in the test battery.Conclusions: The HdhQ111 heterozygous mouse demonstrates a subtle and progressive motor phenotype that begins at 9 months of age. This mouse model represents an early disease stage and would be ideal for testing therapeutic strategies that require elongated lead-in times, such as viral gene therapies or striatal transplantation.

A Longitudinal Operant Assessment of Cognitive and Behavioural Changes in the HdhQ111 Mouse Model of Huntington’s Disease

“…In the SILT Hdh Q111/+ animals were significantly slower in responding to both the S1 and S2 stimuli, than wild type animals, thus further reflecting motor deficits previously observed in Hdh Q111/+ animals [ 53 ]. The S1 accuracy deficits demonstrated in Hdh Q111/+ animals at 18 months of age were surprising, given that these deficits did not exist in the 5-CSRTT.…”

“…This observation is also reflected in the results of the 5-CSRTT, with Hdh Q111/+ animals initiating significantly less trials than wild type animals. Motor deficits have been previously demonstrated in Hdh Q111/+ mice [ 53 ] from 9 months of age and thus the reduction in responding may be due to significant motor impairments which are also reflected in the response time measures. Therefore, Hdh Q111/+ animals may not be physically able to initiate a response as rapidly as wild type animals.…”

“…It may also be the case that the response time deficits observed in Hdh Q111/+ animals are reflective of an inability to initiate movement. Difficulties in the initiation of movement have been described in Hdh Q111/+ animals progressively from 9 months of age on the balance beam [ 53 ]. Although the initiation of movement has not yet been thoroughly explored in HD mouse models, people with HD have showed a decrease in the initiation of movement from early in the disease progression [ 54 , 55 ].…”

“…The precise reason for this may be due to multiple underlying behavioural or psychological factors, such as depression or apathy. But, given the considerable motor dysfunction that has been demonstrated in Hdh Q111/+ animals at 18 months of age [ 53 ], it is perhaps the case that animals are simply unable to physically get to the stimulus to make a response within the required time.…”

Is there a place for human fetal-derived stem cells for cell replacement therapy in Huntington's disease?

“…Optimal grafts result when transplants are derived from fetal WGE collected during the peak period of MSN neurogenesis (i.e., approximately embryonic day 14 in rat and 8–10 weeks gestation in human) ( Dunnett and Rosser, 2011 ). Transplantation of developing MSNs into the degenerating striatum has been shown to ameliorate motor and cognitive deficits in animal studies, primarily in rats and primates ( Schackel et al., 2013 , McLeod et al., 2013 , Paganini et al., 2014 , Yhnell et al., 2016 ). Such studies have allowed the mechanisms underlying the functional improvement to be explored, and have shown that implanted cells can integrate into the circuitry and make functional synaptic connections, providing that they are of the appropriate phenotype (i.e., destined to become MSNs) and were procured within the appropriate developmental window ( Dunnett and Rosser, 2014 ).…”