Currently, a number of rodent models of HD exist, though none fully recapitulate the time-course and full spectrum of disease symptomology. Transgenic HD models have been developed in both mice and rats, with the latter being advantageous due to rats having more complex behaviors than mice, as well as their larger brain mass leading to an increased range of potential neurological assays such as PET imaging which are substantially more difficult in mice. However, due to availability and efforts towards research continuity, mouse models of the disease remain more widely used.[20]

R6/2 mouse model

The transgenic mouse model of HD most often employed is the R6/2 model which expresses a truncated form of the mutated human htt, specifically an exon 1 fragment with approximately 150 allele repeats. The R6/2 mouse develops cognitive signs of the disease as early as 5 weeks of life. The symptoms progress continually throughout their lives, during which the animals exhibit disordered learning and memory as indicated by deficits in the Morris water maze and T-maze among others.[21] In the Morris water maze, changing the location of the platform after learning acquisition may be used as a measure of cognitive flexibility (commonly known as “reversal” training). In this domain as well, R6/2 mice show diminished capacity, in line with the inhibited executive functions seen in HD patients.

The R6/2 HD model also displays significant motor deficits in line with the human condition. Using elevated beams, forced swim tests , and the rotarod test, these motor abnormalities have been observed as early as 5 weeks, though they progress to a more profound level at 8 weeks of age.[22] Finally, using a startle chamber, R6/2 mice have been evaluated for function in the prepulse inhibition assay (also known as the acoustic startle test), in which they develop deficits at approximately 12 weeks of age. As this symptom appears long after the onset of motor abnormalities, it is likely indicative of cognitive decline similar to what is seen in HD patients.

Despite these many similarities in both the motor and cognitive domains of HD between R6/2 mice and human HD patients, there are a number of caveats to the translational validity of the model. Specifically, the early onset of the symptoms is more akin to the relatively rare juvenile-onset form of the disease found in humans than to the more common adult-onset form. Additionally, R6/2 mice are more likely to co-present with epilepsy and cardiac dysfunction, as well as diabetes, none of which are common symptoms of adult-onset HD. Thus, while R6/2 mice may provide a valuable model for certain HD aspects, they do not provide a full and accurate picture of the disease.

HD Rat Model

Unlike the previously discussed HD mouse model, the HD rat model expresses a chimeric form of the rat and human htt gene (rather than only the human htt). In an additional contrast, rather than an early onset of the disease, the rat HD model exhibits a time-course more in line with adult-onset HD. At approximately 10 months of age, HD rats begin to show signs of cognitive decline,[23] indicated by poor performance in the choice reaction time task . At 15 months, the rats exhibit involuntary movements characteristic of HD as observed in the open field setting.

As noted earlier, the larger size of the rat brain leads to the potential for PET imaging. Indeed, researchers have found enlarged ventricles and striatal lesions in this model, concurrent with neurological symptomology in HD patients. However, the development of this model is still in the early stages as compared to the more commonly used mouse models, and thus caution is advised in its use. Nonetheless, the current findings and the vast potential for this rat model of HD indicates potentially immense translational value in researching the disease.