Abstract
RationaleHuntington disease (HD) is frequently first diagnosed by the appearance of motor symptoms; the diagnosis is subsequently confirmed by the presence of expanded CAG repeats (> 35) in the HUNTINGTIN (HTT) gene. A BACHD rat model for HD carrying the human full length mutated HTT with 97 CAG-CAA repeats has been established recently. Behavioral phenotyping of BACHD rats will help to determine the validity of this model and its potential use in preclinical drug discovery studies.ObjectivesThe present study seeks to characterize the progressive emergence of motor, sensorimotor and cognitive deficits in BACHD rats.Materials and MethodsWild type and transgenic rats were tested from 1 till 12 months of age. Motor tests were selected to measure spontaneous locomotor activity (open field) and gait coordination. Sensorimotor gating was assessed in acoustic startle response paradigms and recognition memory was evaluated in an object recognition test.ResultsTransgenic rats showed hyperactivity at 1 month and hypoactivity starting at 4 months of age. Motor coordination imbalance in a Rotarod test was present at 2 months and gait abnormalities were seen in a Catwalk test at 12 months. Subtle sensorimotor changes were observed, whereas object recognition was unimpaired in BACHD rats up to 12 months of age.ConclusionThe current BACHD rat model recapitulates certain symptoms from HD patients, especially the marked motor deficits. A subtle neuropsychological phenotype was found and further studies are needed to fully address the sensorimotor phenotype and the potential use of BACHD rats for drug discovery purposes.
Highlights
Huntington disease (HD) is a progressive neurodegenerative disorder that is associated with widespread degeneration of cortical neurons and striatal medium spiny neurons (MSN) [1,2,3]
Gross inspection of each BACHD rat prior to the experiments did not reveal any visible differences in phenotype between wild type (WT) and transgenic (TG) animals: all animals appeared healthy
Acoustic Startle Response (ASR) (Figure 4) We evaluated sensorimotor gating in different BACHD rat cohorts
Summary
Huntington disease (HD) is a progressive neurodegenerative disorder that is associated with widespread degeneration of cortical neurons and striatal medium spiny neurons (MSN) [1,2,3]. Huntingtin (htt) has many functions in cells and is essential for development [5,6,7,8]. It is not wellknown why MSN neurons are selectively vulnerable in HD [9]. A wide variety of motor, cognitive and neuropsychiatric symptoms have been observed in HD patients [10,11]. Patients become completely dependent and eventually require full-time care. Clinically proven treatments that can cure or halt the disease’s progression have not yet been discovered
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