Genetic Rodent Models of Huntington Disease

  • J. Stricker-Shaver
  • A. Novati
  • L. Yu-Taeger
  • H. P. Nguyen
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1049)

Abstract

The monogenic nature of Huntington disease (HD) has led to the development of a spectrum of useful genetically modified models. In particular, rodents have pioneered as the first HD model being generated and have since been the most widely used animal model for HD in both basic research and preclinical therapeutic studies. Based on the generation strategies, these rodent models can be classified into 3 major groups, the transgenic fragment models, the transgenic full-length models and the knock-in models. These models display a range of HD-like characteristics which resemble the clinical symptoms of HD patients. Their applications in research are thus regarded as an invaluable approach to speeding up the unraveling of the underlying pathological mechanisms of HD and for finding a disease-modifying treatment for this devastating disease. In this chapter, the similarities and differences of the most commonly used rodent HD models and their relevance to human HD will be compared and discussed. This also serves to guide the selection of an appropriate rodent HD model according to the nature of investigation.

Keywords

Huntington disease Transgenic Knock-in Mouse Rat 

2.1 Introduction

The discovery of the sole genetic cause of Huntington disease (HD)—the expansion of the CAG repeats in the huntingtin gene (HTT) [1]—allowed the generation of animal models to different extents that mimic the genetic aspects of the disease [2]. These HD animal models have made core contributions to understanding HD pathogenesis [3], identifying potential therapeutic approaches [4, 5, 6] and developing new diagnostic methods for assessing the disease stage in patients. Among all HD animal models, rodents are the most frequently used species. At present, these genetically modified HD rodent models can be classified into 3 groups based on their generation strategies. The first group of animal models, the transgenic fragment models, carries only the N-terminal portion of the human HTT gene where the CAG expansion is located. The second group is the transgenic full-length models that carry the entire mutant huntingtin (Htt) protein. While these 2 groups involve the insertion of the human HTT gene into the rodent genomes, the third group of animal models are generated by modifying the length of the CAG repeats of the endogenous rodent HTT gene and they are known as the knock-in models. The constructs used for generating these models commonly differ in the number of CAG repeats, type of transcription promoter, strain and genetic background (i.e. homozygosity and heterozygosity). In some cases, genetic tools and strategies (such as the Cre/LoxP system) are used to generate constructs with conditional and reversible expression of mutant huntingtin (mHtt). As a result, in addition to the acute lesion models, where HD-like features are generated by direct injection of neurotoxic chemicals (e.g. quinolinic acid and 3-NP) to the striatum, we have currently a variety of rodent models available that displays a diversity of HD-like properties. Hence, in this chapter, we aim to provide a comprehensive description of the commonly used models, their constructs, phenotypes and predictability of various HD-related pathologies and their relevance to basic research and preclinical therapeutic studies in HD.

2.2 Mouse Models

The mouse represents an excellent model organism for studying genetic disorders and identifying therapeutic targets due to their well-established and extensive use within various fields of genetics research [7]; reviewed in [8]. As a result, mouse was chosen as the first transgenic mammalian model for HD [9]. A range of HD mouse models have since then been established. In this chapter, we will highlight the important characteristics relevant to human HD and details will be summarized in Table 2.1.
Table 2.1

Mouse models of Huntington disease

Transgenic fragment mouse models

Transgenic full-length mouse models

Mouse models

R6/1

R6/2

N171-82Q

N586-82Q

YAC128

BACHD

Promoter

Human HTT

Human HTT

Murine prion

Murine prion

Human HTT locus

Human HTT locus

PolyQ size

115 CAG

145 CAG

82 CAG

82 CAG

128 CAG

97 CAG/CAA

Strain

CBA C57BL/6 mixed background

CBA C57BL/6 mixed background

C3H/HEJ C57BL/6JF1 mixed background

C57BL/6 C3H

FVB/N

FVB/NJ

Gene/protein context

Human Htt Amino acids 1–82

Human Htt Amino acids 1–82

Human Htt Amino acids 1–171

Human Htt Amino acids 1–586

Human full-length mHtt

Human full-length mHtt

Protein expression level (relative to endogenous Htt) (%)

31

75

20

Approx. 100

75

150–200

Repeat stability

Unstable

Unstable

Unstable

  

Stable

Body weight

Weight loss

Weight loss (10 wks)

Weight loss (8 wks)

Weight loss

Weight gain

Weight gain

Brain atrophy

Yes

Yes

Yes

Yes

Yes

Yes

Life span

Reduced life span (32–40 wks)

Reduced life span (10–13 wks)

Reduced life span (Line 77–2.5 months,

lines 81 and 100–5–6 months, Line 6–8–11 months)

Reduced life span (8–9 months for N586-82Q-63C)

Reduced life span in male

Normal

Motor performance

Progressive decline—rotarod (8 wks), tail suspension (16–20 wks)

Reduced activity—open field (23 wks)

Mild tremor and intermittent movement disorders as in R6/2 (24–28 wks)

Progressive decline from 5 wks—rotarod (5–6 wks), swimming test, beam walking, footprint test and home cage behaviour (8–9 wks), grip strength and limbs weakness (9–11 wks), severe impairments (12 wks onwards)

Progressive decline—gait abnormalities (2 months), rotarod (3 months), hypoactivity (5 months), tail suspension (end-stage)

Progressive decline—rotarod (3 months), open-field (4 months)

Dyskinesia with ataxia-like movements (4 months onwards)

Progressive decline—

rotarod (4 months)

Gait abnormalities—beam—walking and footprint tests (8 months)

Hyperactivity (3 months) followed by hypoactivity (12 months)

Progressive decline—rotarod (2 months)

Gait deficits—Catwalk analysis (9–10 months)

Decreased activity in the open field (from 6 months)

Psychiatric phenotypes

Anxiety-like behaviour—open field

Anxio-depressive-like phenotype—novelty suppressed feeding test

Depressive-like phenotype—sucrose preference test (female, 8 wks), forced swim test (female, 8 wks), tail suspension (female, 12 wks)

Anxiety-like behaviour—open field (8 wks), light/dark box (12–14 wks)

Depressive-like behaviour—forced swim test (14 wks)

 

Depressive-like phenotype (3 months)—sucrose consumption, forced swim and tail suspension tests

Anxiety-like phenotype—light/dark box (12 months), elevated plus maze (2 months), zero maze and open field tests (6 months)

Depressive-like phenotype (2 months)—sucrose consumption and forced swim tests

Anxiety-like phenotype (2 months)—light/dark box, elevated plus maze, zero maze and open field tests

Emotional alteration—fear conditioning test (9–10 months)

Cognitive phenotypes

Impairments in acoustic startle and prepulse inhibition (PPI) (8 wks)

Social behaviour and social interaction (12 wks)

Spatial learning deficits—Morris water maze, food reinforcement in open maze, Barnes maze (12 wks)

Progressive learning and memory deficits

Spatial learning—Morris water maze (3.5 wks), T-maze (5 wks)

Reversal learning—Two-choice swim tank (6.5 wks)

Exploratory and fear conditioning (5–6 wks)

Avoidance—visual cliff avoidance (7 wks)

Working and reference memory deficits—radial arm water maze (14 wks)

Motor learning deficit—rotarod (14 wks)

Contextual and cue dependent memory impairments—fear conditioning (8 months)

Progressive motor learning deficit—rotarod (2 months)

Novel recognition memory deficit—novel object location and preference tests (6–7 months)

Procedural learning impairment—simple swimming test (8 months)

Spatial learning deficit—3 stage water maze test (4 months)

Reversal learning impairments—swimming T maze (2 months), 3 stage water maze and novel water T-maze set-shifting setup (post 2 months)

Extra-dimensional shift deficits—17 months

Sensorimotor gating disturbances—startle response and prepulse inhibition (12 months)

Progressive motor learning deficit—rotarod (2 months)

Novel object recognition memory deficit (6 months)

Reversal learning and strategy shift deficits—water T maze and cross maze (9–10 months)

Sensorimotor gating disturbances—startle response (9 months) and prepulse inhibition (7 months)

Other/ peripheral phenotypes

Mild alterations in circadian activity patterns (12 wks)

Sleep disturbance (16 wks)

Cardiac dysfunction (8–12 wks)

Sleep abnormalities (9 wks)

Muscle atrophy (9 wks)

Testicular atrophy (5 wks)

  

Abnormal morphology of the testis and decreased number of developing sperm (9 months)

Lower testis weight (12 months)

 

NeuropathologyNeuropathology

Neuronal intranuclear Inclusions

Neurotransmitter receptors level alternation

Neuronal intranuclear inclusions (first observed at 4 wks in cerebral cortex)

Reduced brain volume but no white matter degeneration (12–13 wks)

Decreased mRNA expression of mGluR1, mGluR2, mGluR3, D1 and D2 receptors

Neuronal intranuclear inclusionsInclusions

No neuronal loss

Reduced brain volume

Neuron apoptosis

Neuritic aggregates

Diffuse nuclear localization of mutant huntingtin

Dopamine and serotonin levels unchanged

Astrogliosis in cerebellum, striatum and cortex

Large inclusions in all brain regions

Progressive degeneration of granule cells in cerebellum

No diffuse accumulation of huntingtin

Reduced total brain volume Cerebellar and hippocampal atrophy

Intranuclear inclusions in striatum, nucleus accumbens, cortex and cerebellum (15 months)

Neuronal loss in cortex and striatum (12 months)

Forebrain weight reduction (9 months)

Progressive decrease of total brain, striatal, cortical and white matter volume (3 months)

mHtt inclusions in cortex and striatum (12 months)

No neuronal loss

Cortical and striatal volume reduction (12 months)

Knock-in nouse models

Mouse models

HdhQ111

CAG140

zQ175

HdhQ150

(HdH(CAG)150 or CHL2)

HdhQ200

HdhQ250

Promoter

Murine HTT

Murine HTT

Murine HTT

Murine HTT

Murine HTT

Murine HTT

PolyQ size

111 CAG

140 CAG

175 CAG

150 CAG

200 CAG

250 CAG

Strain

129/CD1 mixed background

129/Sv C57BL/6 mixed background

129/Sv C57BL/6 mixed background

129/Ola C57BL/6J mixed background (when generated in 2001)

CBA C57BL/6 mixed background (when generated in 2007)

129/Ola C57BL/6J mixed background

129/Ola C57BL/6J mixed background

Gene/ Protein context

Endogenous murine HTT gene, chimeric human/mouse exon 1

Endogenous murine HTT gene, chimeric human/mouse exon 1

Endogenous murine HTT gene, chimeric human/mouse exon 1

Endogenous murine HTT gene

Endogenous murine HTT gene

Endogenous murine HTT gene

Protein expression level (relative to endogenous Htt) (%)

50 or 100

50 or 100

Approx. 75

Approx. 100

Approx. 100

 

Repeat stability

Unstable

     

Body weight

No observable changes until 12.5 months

Decreased body weight from 12 months in males and 25 months in females

Weight loss

Weight loss starts at 14 months of age in both genders

Weight loss from 3 months (homozygous) or 10 months of age (heterozygous)

Weight loss from 5 months of age

Brain atrophy

No

Yes

Yes

Yes

Yes

Yes

Life span

Normal life span

Normal life span

Reduced life span(19 months)

Normal life span

  

Motor performance

Gait abnormalities—tunnel walk (24 months), Catwalk and vertical pole

No detectable changes in spontaneous locomotor activity in an automated cage

Hyperactivity (1 month) and hypoactivity (4 months)

Sensorimotor performance impairment—vertical pole, non-accelerating rotarod, running wheels (4 months)

Gait abnormalities (12 months)

Progressive decline—open field (2 months), grip strength (homozygous, 1 month), Phenotube (homozygous, 4 months), climbing activity (homozygous, 8 months), cylinder test (heterozygous, 1 month), nesting (heterozygous, 16 months)

Impairments (earliest 4 months)—clasping, grip strength, rotarod, beam walking, activity cages

(homozygous,25 months)

Impaired performance—balance beam (homozygous, 4 months, heterozygous, 12.5 months)

Decreased muscle strength—grip strength test (20 months)

Gait abnormalities (15 months)

No impairment observed on rotarod

Impaired performance—open field, beam walking (12 months)

Psychiatric phenotypes

Depressive-like phenotype (female)—splash test and forced swim test

Anxiety-like phenotype (male)—open field test

Anxio-depressive-like phenotype—novelty suppressed feeding test

Olfactory discrimination deficit

Impaired social discrimination (males)

Anxiety-like phenotype—light/dark box (1.5 months)

No detectable depressive-like behaviour—forced swim and tail suspension tests

   

Depressive-like phenotype—forced swim test (3 months)

Cognitive phenotypes

Altered motor learning—rotarod

Long-term object recognition memory impairment (4 months)

Spatial memory impairment (8 months)

Reversal learning and working memory deficits—delayed matching and non-matching to position tasks (8 months)

Long term recognition memory impairment (4 months)

Procedural learning deficit—two choice swim test (homozygous, 10 months)

Working memory deficit—Y maze (heterozygous, 16 months)

Executive functioning impairment—go/no go test (7 months)

Cognitive flexibility—two choice visual discrimination test (7 months)

Impaired spatial and reversal learning—3 stage water maze (4 and 8 months respectively)

Extra-dimensional shift performance impairments (6 months)

Decreased reactivity to startle stimuli (homozygous, 6 months)

  

Other/ Peripheral phenotypes

 

Altered leptin and adiponectin levels (7 months)

40–60% decrease in female gonadal and subcutaneous fat mass (22 months)

Declined circadian rhythm

   

Neuropathology

mHtt inclusions (12 months)

Neuronal loss (24 months)

No striatal atrophy

Nuclear and neurophil aggregates in striatum, nucleus accumbens and olfactory tubercle (2–4 months)

Gliosis in cortex (12 months) and striatum (23 months)

Neuronal loss (23 months)

Reduced corpus callosum volume (20–26 months)

Nuclear inclusions (heterozygous)

Striatal atrophy

Cortical thinning

Dopamine and BDNF levels reduction

Intranuclear inclusions (13 months)

Gliosis (heterozygous, 14 months)

Neuronal loss (12.5 months)

Striatal atrophy (12.5 months)

Decreased D1 and D2 (only homozygous) receptor binding

Intranuclear inclusions in striatum and cortex (13 months)

Striatal and cortical astrogliosis (20 months)

50% reduction in striatal dopamine receptor binding (20 months)

Cerebellar abnormalities—reduced mRNA and protein levels of Purkinje cell markers, Purkinje cell number and firing rate (11.5 months)

mHtt aggregates in striatum (6 months)

Striatal and cortical atrophy (6 months)

Disturbed myelination (postnatal day 14)

Neuronal loss

Reduced BDNF levels in striatum and cortex

The time points in brackets indicate the earliest assessed/detectable ages for the respective changes or the time points when the tests were performed

wks, weeks

2.2.1 Transgenic Fragment Models

This group represents the first type of rodent model generated for HD. In 1996, 2 transgenic lines, R6/1 and R6/2, were established with a 1.9 kb human genomic fragment containing the human huntingtin (human HTT) promoter, exon 1 of the human HTT gene carrying expanded CAG repeats and the first 262 bp of intron 1 [9]. The R6/1 model carries 115 CAG repeats while the R6/2 model has 145 CAG repeats [10, 9] although variability of repeat expansions have been reported due to germ line instability [10, 11]. The resulting phenotypes observed in the R6 models highly resemble the clinical symptoms in HD patients with the R6/2 model displaying a more aggressive phenotype than the R6/1 model. In 1999, Schilling et al. generated another HD fragment mouse model, N171-82Q [12]. These transgenic mice express steady-state level of N-terminally truncated huntingtin cDNA that encodes the first 171 amino acids of human huntingtin with 82 CAG repeats driven by the mouse prion promoter. Based on the findings that a fragment terminating at residue 586 of human Htt protein can be generated by caspase-6 is critical in mediating the HD phenotypes in YAC128 mice [13], Tebbenkamp et al. generated the N586-82Q model that expresses the N-terminal 586 amino acids of human mHtt with 82 CAG repeats, which corresponds to the fragments generated by caspase-6 [14]. 2 lines (C62 and C63) have been established with the N586-82Q-C63 model showing a more robust phenotypic profile and relatively stable phenotypes over generations. In addition to these models, many fragment models have been generated over time due to their robust phenotypes and similarities to human HD. However, we will focus on these fragment models in this chapter for their popularity and relevance to preclinical trials.

2.2.1.1 Life Span, General Health Status and Body Weight

Consistent with the clinical observation in HD patients, R6, N171-82Q, and N586-82Q mice show progressive weight loss and shortened life span (Table 2.1) [10, 12, 14, 15, 16]. For R6/2 and N171-82Q models, weight loss occurs despite normal food intake when the disease progresses. Autopsy of the R6/2 mice shows the weight loss of muscle tissues with no signs of myopathy as indicated by muscle fibre regeneration [9, 17], whereas N171-82Q mice show no gross abnormalities in visceral organs and blood glucose levels [12].

2.2.1.2 Behavioural Abnormalities

Progressive motor dysfunction such as tremors, stereotypical grooming, hypokinesis, abnormal gait and dyskinesia of the hind limbs have been observed in R6 and N171-82Q mice [9, 12, 15, 18, 19], whereas profound dyskinesia with ataxia-like movements in addition to motor impairments has been observed in the N586-82Q mice [14, 20]. While the abnormal gait sets in at 4 months of age (Line C63), the dyskinesia continues to increase in severity until the mice are 8 months old. At this time point, these mice are heavily affected by the movement disorder and they are not capable of feeding and drinking [14]. In some colonies of R6/2, it has been reported that they develop handling-induced seizures [21].

In HD patients, cognitive decline has been documented and most often appears prior to the motor deficits [22, 23]. As in humans, the R6/2 mice have been reported to have learning and memory deficits [24]. R6/2 mice begin to show spatial learning deficits in the Morris water maze (3.5 weeks), T-maze (5 weeks) and exploratory and fear conditioning abnormalities [25] before the onset of motor symptoms [15]. In 2006, Morton et al. introduced an automated touchscreen-based cognitive-testing system to evaluate the cognitive decline of motor impaired R6/2 mice and reported learning deficits in the R6/2 model from 9 to 16 weeks of age [26]. The N171-82Q mice show deficits in the radial arm water maze test of working and reference memory [27] and motor learning at 14 weeks [28]. In HD patients, cognitive decline has been suggested to be the result of impaired fronto-striatal circuitry. However, as in previously described studies, this cognitive deficit in these mouse models may be due to the numerous Htt inclusions in the hippocampus rather than the fronto-striatal circuitry [27]. In addition, the N586-82Q model also shows contextual and cue dependent memory deficits in the fear conditioning test [20].

Neuropsychiatric disturbances in HD patients can appear already in the prodromal phase of the disease and do not worsen with time. Major psychiatric symptoms are depression, anxiety, impulsivity and irritability [29]. In HD mouse models, neuropsychiatric-like phenotypes have mostly been studied in terms of depressive- and anxious-like behaviours. Depressive-like phenotype has been demonstrated in N171-82Q [28] and R6 models [30] by, for instance, their decreased consumption of sucrose in the sucrose preference test, their increased immobility duration in the forced swim and tail suspension tests. Anxiety-related behaviour of R6/2 has been demonstrated by the open field test [28], and R6/1 mice are shown to exhibit progressive anxiety-like behaviour at a later stage (peak at 24 weeks of age) [30]. Using the light/dark box test, R6/2 mice are shown to have anxiety-like behaviour with gender differences (males start earlier than females). Anxio-depressive-like behaviour assessed by novelty suppressed feeding test was also reported in R6/1 mice [30].

2.2.1.3 Neuropathology and Neurochemical Alterations

All the fragment models described here show neuropathological features that recapitulate the human HD condition. Both R6/2 and end-stage N171-82Q mice develop neuronal intranuclear inclusions, containing the proteins huntingtin and ubiquitin, which are highly similar to nuclear abnormalities observed in biopsy material from HD patients [10]. In both N586-82Q lines (C62 and C63), large mHtt inclusions are also found in all brain structures but are predominantly cytoplasmic [14]. These inclusions are composed of a mixture of full-length N586-82Q protein and Cp-A/1-sized fragments, the latter of which have been described as principal components of intranuclear inclusions [14, 31, 32]. Unlike the R6/2 and N171-82Q models [10, 12], no diffuse nuclear localization of mHtt has been observed in N586-82Q mice [14].

As in human HD [33], brain volume reduction has been observed in N586-82Q, R6 and N171-82Q models. Brains from the R6/2 mice are 20% smaller than those of their wild-type littermates by 12–13 weeks of age [9, 10] although there is no difference in brain weight during weaning [16]. Note that the reduction in brain weight is not a consequence of the reduction in total body weight, as the loss in brain weight precedes the loss in body weight as shown by a longitudinal study [10]. In the basal ganglia of R6/2 mice, while the white matter of the corpus callosum and the fascicles of fibres forming the internal capsule show no difference from those of the wild-type littermates [9], the reduction in size was constant throughout all central nervous system (CNS) structures with normal neuronal density [10]. In N586-82Q-C63, the brain weight is approximately 50% of their wild-type littermates attributed to hippocampal and cerebellar atrophy [14]. The obvious loss of cerebellar granule cells is the main reason for the ataxia-like abnormalities [14]. Unlike the R6 and N586-82Q models, N171-82Q mice have slightly smaller brains than their control littermates with no signs of abnormal development [12]. No severe neuronal loss has been observed [12].

It has been reported that the neurotransmitter systems of the fragment models have been disrupted. Using receptor-binding autoradiography, R6/2 mice are found to have marked decreases in mRNA expression for mGluR1, mGluR2 and mGluR3 metabotropic receptors, and D1 and D2 dopamine receptors. The decreases in mGluR1, D1 and D2 receptor mRNA levels in the striatum are significant by 4 weeks of age, and the decrease in mGluR2 mRNA expression in the cortex is significant by 8 weeks of age. In N171-82Q, their dopamine and serotonin levels are unchanged at 4 weeks and 6 months of age although alterations of motor performance are associated with abnormalities of the dopaminergic neurotransmitter systems [34]. Hence it has been speculated that their respective receptors have been disrupted resulting in the motor impairments [34].

2.2.2 Transgenic Full-Length Models

The most studied transgenic HD mouse models in this category are yeast artificial chromosome (YAC) and bacterial artificial chromosome (BAC) models carrying the human HTT transgene in yeast and bacterial chromosome respectively [35, 36]. The first Huntington YAC mouse models to be generated are YAC18 expressing normal Htt with 18 glutamines and YAC46 and YAC72 mice which express mHtt with 46 and 72 CAG repeats respectively [37]. YAC46 and YAC72 were to a certain extent representative of the human disease and showed early electrophysiological alterations followed by selective degeneration of medium spiny neurons along with some alterations in motor behaviour and activity [37]. Even though these models have been useful for understanding pathological aspects in HD, they were not optimal for quantitative measurements in preclinical studies partly due to the high sample size required. In order to improve the expression of the phenotype, a model with 128 glutamines, named YAC128 was created [35]. By having a higher number of glutamines, YAC128 mice develop an HD-associated phenotype earlier and stronger when compared to the first YAC models. More recently, 2 BAC models of HD have been generated. The first one is the BACHD model that expresses full-length human Htt with 97 CAG/CAA repeats [36] and the second one is BAC-225Q. The latter is a recently generated model which carries the full-length mouse Htt with 225 CAG repeats driven by the mouse Htt promoter [38].

In this chapter only YAC128 and BACHD models will be described as their pattern and selectivity of neuropathological alterations resemble the neuropathology in human HD brains. The progressive development of motor abnormalities, cognitive and neuropsychiatric disturbances in these models mimics HD symptoms in humans and hence are regarded as popular models for HD research.

2.2.2.1 Life Span, General Health Status and Body Weight

BACHD mice have a normal life span while survival is decreased in male YAC128 mice and this effect is aggravated if wild-type huntingtin is lost [39]. Unlike HD patients that experience body weight loss [40], in HD full-length models body weight is increased (Table 2.1) [36, 41]. BACHD female mice have been reported to have more body fat when compared to non-transgenic female [42]. In HD models, altered body weight is a meaningful parameter pertinent to the physiological alterations of the disease and could be a confounding factor for behavioural measures. In YAC128, a 20–30% body weight gain can be detected at 2–6 months and is maintained till 12 months [43]. This body weight increase is attributed to increased total fat mass, but is independent of food and water consumption [43]. Interestingly, most organs in this model show weight gain except the brain and testis that are atrophic and display the highest mHtt toxicity [43, 44, 45]. Unlike YAC128 mice, altered body weight in BACHD mice has been suggested to be related to increased food intake [46]. With an early obese phenotype (2 months of age), BACHD mice show endocrine abnormalities including increased basal glucose and insulin levels, impaired glucose tolerance and insulin resistance and altered levels of central and peripheral factors regulating food intake, appetite and adipose tissue metabolism [42, 46]. Some of these neuroendocrine aberrations like insulin resistance are also known in HD patients [47]. In these full-length models, one important factor related to body weight increase is the dosage of full-length Htt [48, 43]. Accordingly, BACHD mice have both higher mHtt levels and body weight when compared to YAC128 mice [41]. The opposite direction of change in body weight in these full-length models and HD patients should be taken into account when considering their use in therapeutic studies.

Abnormalities in HD are not limited to the brain [45, 49] and one of the affected systems is the hypothalamic-pituitary-gonadal axis. Male HD patients have decreased luteinizing hormone and testosterone levels [50] as well as decreased number of germ cells and anomalous morphology of the seminiferous tubules [45]. Similarly, YAC128 mice show abnormal morphology of the testis at 9 months and decreased number of developing sperm as well as lower testis weight by 12 months [44, 45]. Such peripheral physiological changes have been suggested to be a direct effect of the highly expressed Htt in the testis as the number of hypothalamic gonadotropin-releasing hormone neurons and the testosterone level are normal [45].

2.2.2.2 Behavioural Abnormalities

Both BACHD and YAC128 models show progressive motor deterioration [36, 39, 51]. They have shorter fall latency on the rotarod and at later ages they develop balance and gait abnormalities [35, 39, 52, 51]. YAC128 mice display hyperactivity at 3 months but hypoactivity at 12 months of age [35] and motor impairments begin before the hypoactive phase. The early hyperactive phenotype observed in YAC128 mice has not been shown in young BACHD mice that display decreased activity in the open field from 6 months onwards [53]. In YAC128, motor deficits on the rotarod appear before neuronal loss [35]. As motor performance at 6 months correlates with neuronal loss at later time points, it has been suggested that some neuronal dysfunction may be already present at the onset of the motor impairment.

In HD, cognitive decline precedes motor symptoms and is associated to cortical and hippocampal neuronal dysfunctionality [54, 55]. Both BACHD and YAC128 mice display learning deficits of different types that resemble clinical symptoms, including deficits in motor learning [36], novel object recognition memory [56, 57], sensorimotor gating [41, 51, 58], reversal learning and strategy shift [58, 59, 60, 61, 62]. Interestingly, cognitive impairment in YAC128 mice has been shown with tests mostly sensitive to corticostriatal and hippocampal dysfunction and deficits can manifest before the appearance of the first neuropathological signs [58].

For neuropsychiatric phenotypes, similarities have been observed in the YAC128 and BACHD mice, and these phenotypes have been shown to appear early and not to be progressive [63, 64]. Both models display increased immobility in the forced swim test which is indicative of behavioural despair [41, 42, 60, 63, 64] and show decreased preference/consumption for a sweet solution in the sucrose preference test [63, 64]. These observations have been suggested to be independent of motor inabilities [63, 64]. The anxious-like phenotype is evident in both models by open field [28, 60], zero maze [28, 60] and light dark choice [51], and in BACHD mice also by elevated plus maze [63]. An additional emotional alteration in BACHD mice is an increased freezing response in the fear conditioning test which has been shown in 9–10 month-old animals [59].

2.2.2.3 Neuropathology and Neurochemical Alterations

Neuropathology in YAC128 mice is characterized by typical HD features including development of aggregates, striatal and cortical atrophy and striatal neuronal loss [65, 35], whereas BACHD mice display a late onset neuropathology with cortical and striatal atrophy by 12 months of age with detectable mHtt inclusions but not neuronal loss [36]. In contrast, the number of striatal neurons in YAC128 mice is significantly reduced by 12 months and such neuronal loss is paralleled by decreased neuronal size [35]. Revealed by magnetic resonance imaging (MRI), YAC128 shows a progressive decrease in total brain, striatal, cortical and white matter volumes [35, 66, 67]. White matter changes have also been observed in other animal models of HD like YFP(J16)-R6/2, HdhQ250 and BACHD rats [68, 69, 67] and in human HD brains [70]. At the neurochemical level, the expression of a series of striatal mRNA transcripts (e.g. DARPP-32, enkephalin, cannabinoid receptor 1 and dopamine receptors D1 and D2) is altered in YAC128, but not in BACHD mice [41].

2.2.3 Knock-in Models

Knock-in (KI) mouse models can carry 1 or 2 copies of the mHTT gene and are regarded as genetically precise because they are genetically representative of the human condition. They have overcome the random gene insertion problem as in transgenic models, which lead to gene copy number and expression variations over generations. As they exhibit HD-like features and late onset phenotype, they are suitable for investigating early neurophysiological changes that are casual to the observed behavioural alterations. In most of these models, behavioural and neuropathological alterations are milder and progress more slowly when compared to transgenic models [71].

Until now, 2 strategies have been used to generate the KI models. The first knock-in lines, HdhQ20, HdhQ50, HdhQ92 and HdhQ111, were generated by inserting a chimeric murine Huntington disease gene homolog (Hdh)/human mHtt exon 1 into the endogenous murine Hdh locus under the control of the endogenous mouse Htt promoter [72]. The same strategy was later used to generate the CAG140 [73] and the zQ175 models, the latter of which was a result from a spontaneous expansion of the CAG repeat number in the CAG140 model [74]. The second subtype of KI models was generated by replacing the short CAG repeat of the mouse HTT exon 1 with a repeat containing 50-365 CAG repeats. Amongst these models, HdhQ150 [75] and the HdhQ200 [7] and HdhQ250 [69] models derived from its selective breedings are more well-characterized and hence will be described here.

2.2.3.1 Life Span, General Health Status and Body Weight

Unlike the transgenic full-length models, the KI models show a reduction in body weight that resembles the clinical observation of HD patients [7, 69, 74, 75, 76, 77], though the onset of weight loss differs in each model. The lifespan of zQ175 [74] have been reported to be decreased while HdhQ150 [75], HdhQ111 [78] and CAG140 [79] have normal life span. Interestingly, as in the BACHD rat model (will be described later in this chapter) that exhibits metabolic alterations, the leptin and adiponectin levels and the fat mass in the CAG140 model have also been reported to be altered [77].

2.2.3.2 Behavioural Abnormalities

All the KI mouse models described here (Table 2.1) exhibit varying degrees of motor impairments. Their performance deteriorates with age as shown by decreased activity, rotarod impairments and gait abnormalities [7, 69, 73, 74, 75, 76, 79, 80].

As in the transgenic mouse models, cognitive disturbances have been investigated and described in the KI models (HdhQ111, CAG140, zQ175 and HdhQ150). In line with findings in HD subjects [80], they exhibit learning and memory impairments [55, 79, 81, 82, 83] in both homozygous and heterozygous animals. In particular, learning deficits of Hdh150 have been shown in homozygous mice prior to major motor impairment [84]. The early appearance of cognitive deficits relative to motor alterations is an important characteristic of Hdh150 since in human HD cognitive disturbances are among the earliest symptoms and often appear before motor deficits [54].

Neuropsychiatric phenotypes have only been reported in some of the KI models (HdhQ111, CAG140 and HdhQ250). The neuropsychiatric phenotype in HdhQ111 mice is characterized by alterations of different nature in male and female animals at around 3–4 months [85]. An anxious-like phenotype is evident in male HdhQ111 mice in the open field test with a shorter time and a decreased number of entries in the central area of the field. Females instead show a depressive-like phenotype suggested by increased grooming time in the splash test and increased immobility in the forced swim test. Both genders of HdhQ111 take a longer time to feed in the novelty suppressed feeding test which suggests an anxio-depressive-like phenotype [85]. For CAG140, they are impaired in long term recognition memory at 4 months and take longer time to enter the light compartment in the light/dark box at 1.5 but not at 8 months. The latter could be interpreted as an early non-persisting anxious-like phenotype [79]. Note that CAG140 mice do not display depressive-like behaviour in the forced swim and tail suspension tests [79]. On the contrary, HdhQ250 displays an increased floating score at 3 months and a decreased score at 12 months when tested in the forced swim test [86]. This indicates an early but non-progressive depressive-like phenotype as in HD patients [29, 86].

2.2.3.3 Neuropathology and Neurochemical Alterations

The KI models have been reported to display a spectrum of HD-distinctive neuropathological characteristics with each model exhibiting unique features resembling human HD. HdhQ111 lacks striatal atrophy but shows nuclear localization of mHtt especially in medium spiny neurons and formation of N-terminal inclusions and insoluble aggregates [87]. Nuclear EM48 reactivity in HdhQ111 is first shown at the age of 1.5 months and EM48 puncta are visible by 5 months while nuclear inclusions are evident only starting from 12 months [87, 78]. Neurodegeneration shown by the presence of toluidine blue stained neurons take place only at later phases, 24 months, and seems not to involve apoptosis [78]. Neuropathological alterations in the CAG140 model follow behavioural changes and have been reported to appear between 2 and 4 months of age [79, 73]. Both nuclear and neuropil aggregates have been observed starting from dorsal striatum, nucleus accumbens and olfactory tubercle [73]. By 12 months of age, CAG140 mice show reduced levels of DARPP32 in striatum and gliosis in cortex. By 23 months, gliosis can also be detected in the striatum [79]. At this stage, striatal atrophy and loss of mature and immature neuronal spines as well as decreased dendritic complexity become evident [88]. Electrophysiological studies have also shown impaired corticostriatal circuitry function and altered synaptic transmission of medium spiny neurons [89]. Late stage neuropathological features include reduced corpus callosum volume and loss of tyrosine hydroxylase immunostaining in 20–26 months old mice [88]. zQ175 brains are characterized by striatal atrophy, development of mHtt inclusions, decreased striatal dopamine and brain-derived neurotrophic factor (BDNF) levels as well as cortical thinning [83]. Analyses in heterozygous mice show degeneration of medium spiny neurons while studies in both homozygous and heterozygous mice demonstrated medium spiny neuron electrophysiological alterations [82, 83]. Both homozygous and heterozygous mice show changes in the expression of different mRNA transcripts including DARPP-32, cannabinoid receptor 1 and phosphodiesterase which start at 3 months and progress faster in homozygous than in heterozygous mice [74]. Nuclear inclusions in heterozygous mice have first been observed in the dorsal striatum and cortex and later in other brain regions including nucleus accumbens, hippocampus, amygdala, hypothalamus and thalamus [83].

Neuropathology in HdhQ150 mice include reactive gliosis, development of mHtt nuclear inclusions, degeneration of cytoplasmic organelles in both neuronal axons and cell bodies, neuronal and volume loss in striatum as well as decrease in striatal dopamine D1 and D2 receptor binding potential [80, 75, 90]. Besides nuclear inclusions, EM48 positive neuropil aggregates have also been detected [90]. Recent research using a time-resolved fluorescence resonance energy transfer (TR-FRET)-based immunoassays demonstrated that the levels of soluble mHtt are inversely correlated with the load of aggregated mHtt in the aging HdhQ150 mouse brain [91]. Size exclusion chromatography coupled to TR-FRET showed that mHtt fragments and not full-length mHtt form a soluble pool of oligomers that is visible already in the first month of life and declines with age [92]. Importantly, a comparable oligomer pool has also been shown in a human brain [92]. While the pool-size of soluble mHtt oligomers is comparable in heterozygous and homozygous HdhQ150 mice, the formation of insoluble aggregate is faster in the homozygous and pathological alterations have been shown to be dependent on the mHtt dosage in HdhQ150 mice [92, 18]. Similar to HD patients, 2 copies of the mHTT gene correlate with a more severe clinical disease course [93]. Stereological measurements of HdhQ150 brains show decreased striatal volume and neuronal number in homozygous and heterozygous mice by about 25 months and the volume loss is stronger in the homozygous population [80]. The related model, HdhQ200, displays early brain pathology characterized by accumulation of Htt aggregates in cytoplasmic foci by 9 weeks of age and neuronal intranuclear inclusions that are first observable at 20 weeks and reach a massive distribution at 40 weeks [7]. HdhQ200 intranuclear inclusions are limited to striatum and cortex with higher density in the striatal area [7]. Their shape and size (3–5 µm) is comparable to that in HD human brains [65]. Interestingly, intranuclear inclusions at 40 weeks have a perinuclear distribution and are associated to ubiquitin and autophagosome marker LC3 [94]. By 80 weeks heterozygous HdhQ200 brains show striatal and cortical astrogliosis [7] that is also reported in the HdhQ150 model [75], which is a neuropathological hallmark of human HD [33]. Astrogliosis in HdhQ200 mice is paralleled by a 50% reduction of striatal dopamine receptor binding that was not observed in HdhQ150 mice [7]. Besides striatal dysfunction, cerebellar abnormalities have also been described in this model at the age of 50 weeks. These consist of reduced mRNA and protein levels of Purkinje cell markers as well as decreased Purkinje cell number and firing rate [95].

Myelination deficiency has been reported in early postnatal development in HdhQ250 mice [69]. Comparing to wild-type mice, HdhQ250 mouse striatum has lower levels of all isoforms of myelin basic protein and myelin oligodendrocyte glycoprotein and displays fewer myelinated axons in the corpus callosum. Importantly, these white matter abnormalities persist in adulthood as shown by the high number of small hypomyelinated axons in the corpus callosum of 12-month-old mice, and are paralleled by altered proliferation of oligodendrocyte precursor cells in both corpus callosum and striatum [69]. At 6 months of age, mHtt aggregates are observable in striatum and atrophy occurs selectively in cortex and striatum. Cortical and striatal levels of BDNF and DARPP32 in medium spiny neurons are also reduced [69]. Most of these alterations are consistent with changes in HD human brains where white matter morphology and integrity are disrupted [70], medium spiny neurons undergo selective degeneration [96] and BDNF levels and transport are altered [97].

2.3 Rat Models

Although the mouse represents an excellent model organism for HD due to its established use in genetics research, it has certain shortcomings. Because mice have a small body size, it limits the resolution and quality of in vivo imaging methods such as MRI and positron emission tomography (PET), which are currently being developed as diagnostics for HD [98]. Another reason is that mice generally require more training in psychiatric and/or cognitive tests (e.g. operant conditioning tasks) that are of interest when evaluating these aspects of HD. To overcome these problems, a small number of genetically modified rat models have been developed for HD.

2.3.1 Transgenic Fragment Models

At present, only 1 transgenic rat fragment model of HD has been generated. These rats, known as the TgHD rats, carry a transgenic construct that expresses a human/rat mixed fragment of the HTT gene. The fragment contains 51 CAG repeats and is governed by the rat endogenous promoter, which is included in the construct [99]. So far, the TgHD rats have only been kept on a Sprague-Dawley background. Published studies have focused on either male or female hemi- or homozygote TgHD rats, although the following text will focus on the general consensus.

In contrast to the frequently used mouse fragment models (e.g. R6/2), the TgHD rats show a late and slowly progressing disease phenotype [99]. This is primarily thought to be due to the more limited number of CAG repeats and the longer fragment used in the TgHD rats’ construct. Thus, the TgHD rat is generally considered to be a good model for the adult onset HD that is commonly seen in patients.

The TgHD rat’s transgenic fragment is expressed at a lower level than the endogenous rat Htt. The translated protein is detectable in most of the CNS, although the expression is low in the cerebellum and spinal cord [99]. Like other transgenic animal models of HD, the expression of the mutated protein results in gradual development of Htt-containing protein aggregates [100, 101, 102, 99]. This is first apparent at around 6 months of age, with the nucleus accumbens being particularly affected [101, 99]. As the animals age, additional brain regions are also affected. In the caudate-putamen, aggregate formation is primarily in its dorsomedial parts, which becomes apparent at around 9 months of age [101, 99].

Volumetric analyses, using either MRI or stereology, have yielded conflicting results concerning HD-related neuropathology in the TgHD rat [103, 101, 102, 99, 104]. Some studies have found enlarged ventricles and reduced striatal volume [103, 101, 102] already at 8 months of age [99], while others have failed to detect these phenotypes [105, 100] even in 18 months old rats [104]. A smaller number of studies that specifically investigated neuronal loss have detected the presence of darkly stained degenerated neurons in both striatum and cortex and a reduced number of striatal neurons at 12 months of age [103, 102]. In addition, a range of other neuropathological features has been reported, including shrinkage of striatal neurons [106], a drop in striatal D2R density [100], reduced proliferation of neuronal stem cells [107] and changes in brain metabolism [106, 99].

There has also been extensive characterization of behavioural phenotypes in the TgHD rats. Accordingly, the TgHD rat has been found to display a head movement phenotype reminiscent of the chorea found in HD patients [108, 105, 99], with an onset at around 15 months of age [108, 105]. In addition, impaired performance in specific tests of motor function has been found [100, 101, 109, 99], although the exact onset of these phenotypes is uncertain. TgHD rats have been found to be less anxious than wild-type rats in several behavioural tests [101, 109, 99], a phenotype which appears to be present already before 5 months of age [101, 99]. TgHD rats have also been assessed in quite a wide range of tests for cognitive function. Initial studies found indications that TgHD rats had impaired spatial working memory starting at 6 months of age [101, 99], while spatial reference memory was impaired at 12 months of age [101]. TgHD rats have also shown impaired recall memory [110] and indications of learning deficits in tests of spatial navigation [100]. These phenotypes appear to emerge when animals are around 6–10 months old. Investigation in more complicated operant conditioning protocols have indicated an attentional impairment among TgHD rats, which is present at 9–15 months of age, depending on the respective protocol [108, 103]. Although a range of other studies have also investigated the rats’ performance using other cognitive tests, most of which have not been repeated or have shown conflicting results [105, 109]. Regarding the life span of this model, they have been reported to show increased mortality at 24 months of age [99], although the phenotype has not been further investigated (Table 2.2).
Table 2.2

Rat models of Huntington disease

Model name

TgHD rat

BACHD rat

Host animal

Rat

Rat

Generic manipulation

Transgenic

Transgenic

Promoter

Rat HTT

Human HTT

PolyQ size

51 CAG

97 CAG/CAA

Protein context

Amino acids 1-727 of mixed human/rat sequence

Full-length human protein

Protein expression level (relative to endogenous Hdh)

Not stated, but lower than endogenous

TG5 line: 450%

TG9 line: 250%

Repeat stability

Stable

Stable

Body weight

Generally unchanged, although stunted growth has been reported

Unchanged, although rats are obese

Brain atrophy

Conflicting results, although several indications of neuropathology

Frequently found to have smaller brains, although interplay between progressive atrophy and developmental deficits is unclear

Aggregate formation

Throughout most of CNS

Throughout most of CNS

Neuropathology

Structural alterations of brain regions, neuron shrinkage and loss

Structural alterations, and presence of deteriorating neurons

Premature death

Yes, around 24 months of age

Nothing reported until age of 16 months

Motor phenotypes

Chorea-like movements, impaired performance on rotarod and beam walk tests

Impaired rotarod performance and gait abnormalities

Psychiatric phenotypes

Reduced exploration anxiety

Reduced exploration anxiety

Cognitive phenotypes

Indications of impaired performance in several tasks. Impaired spatial working and reference memory as attentional deficits appear to be robust

Indications of impaired performance in several tasks, although most results are preliminary and not extensively reproduced

Onset and progression of phenotypes

Visible aggregate formation starts at around 6 months of age. Onset of behavioural phenotypes varies, with anxiolytic behaviour appearing as early as 2 months of age, while motor and cognitive phenotypes become apparent at around 6–9 months

Visible aggregate formation starts at around 3 months of age. Onset of behavioural phenotypes varies with impairments on rotarod being detectable after 1 month of age and anxiolytic behaviour appearing at 4 months

2.3.2 Transgenic Full-Length Models

Similar to the rat fragment model, there is currently only 1 transgenic full-length rat model available for HD, the BACHD rat. This model was established more recently than the TgHD rats [111]. The rats carry the same genetic construct used to create the BACHD mice [36, 111], and so far all published work has focused on hemizygote rats with Sprague-Dawley background [112, 113, 114, 115, 116, 117, 118, 111]. 2 different lines (TG5 and TG9) were initially established, which overexpress the transgene to different extents. However, with the exception of the initial publication, characterization and treatment studies have hitherto been using male rats of the TG5 line [112, 113, 111]. In these rats, the transgene shows a 4.5 fold overexpression when compared to the endogenous rat Htt. Characterization data obtained from these rats are summarized below. Additionally, dysregulation of gene expression in the striatum of BACHD rats was found as early as 3 months in both transgenic lines TG5 and TG9, reduced TFIID formation might contribute to this in a certain extent [119].

The transgenic construct is expressed throughout most of the CNS [111]. Development of mHtt aggregates largely follow the expression pattern of the protein, initially becoming apparent at around 3 months of age, then increasing in both number and size as the animals grow older [111]. At 13 months of age, most brain regions show aggregate formation, although the cerebral cortex, hippocampus, amygdala and nucleus accumbens are among the most heavily affected areas, while the striatum shows a relatively lower amount of aggregates [113, 111]. Other noted indications of neuropathology are the presence of darkly stained degenerated neurons in several brain regions, a change in the surface area of the striosome compartment of the striatum, a decrease in D2R availability (detectable at 18 months of age) [111] and an impaired auditory gating response at 4 months of age [120].

BACHD rats of the TG5 lines have frequently been found to have an early and progressive impairment on the rotarod with the phenotype becoming apparent already at 2 months of age [121, 113, 111]. In addition, a phenotype of disturbed walking gait appears to be present at 14 months [111] but not earlier [121, 111]. Similar to the TgHD rats, TG5 rats have been found to be less anxious than WT rats when tested on the elevated plus maze. This phenotype appears at around the age of 4 months, and becomes more pronounced with age [111]. When considering more cognition-oriented characterization, the BACHD rats have been found to show discreet impairments in reversal learning [122, 113] and reduced fear conditioning response [121] at 4–6 months of age. Moreover, impaired performance on operant conditioning tests that are sensitive to fronto-striatal lesions was observed already at 4 months of age [114]. Furthermore, BACHD rats have been found to show some impulsivity disorder at 3 months of age [112, 117]. A recent study reported an altered reactivity of central amygdala to GABAAR antagonist picrotoxin in BACHD rats at 4.5 months of age [116]. Considering the metabolic aspects of the BACHD rats, male rats have been found to be obese without showing an increased body weight [123]. This interesting phenotype is observed in parallel to the reduced body size and reduced lean mass [123]. The obesity phenotype is maintained despite the fact that BACHD rats consume less food than wild-type rats [123, 111], although it is hard to be conclusive given the reduced lean mass in the transgenic rats. Impairments in cellular metabolism have also been found, indicating glycolysis dysfunction at early ages [124] and mitochondrial dysfunction at older ages [113]. The latter of these phenotypes has been suggested to play a major part in the pathology in BACHD rats and to be linked to increased proteolytic cleavage of mHtt [113]. Reduced life span has not yet been observed in BACHD rats, although mortality beyond the age of 17–18 months of age has not yet been evaluated [112, 111].

2.3.3 Knock-in Models

Several knock-in rat models of HD are currently being developed. There is, however, at this time no published data available.

2.4 Concluding Remarks

The generation of genetic rodent models for HD has given us a valuable tool for deciphering the disease mechanism and discovering therapeutic treatments. The wide range of models available since the discovery of the causative mutation in the HTT gene has provided us a variety of choices but at the same time poses difficulty on deciding which is the appropriate model for a particular study. Depending on the aim(s) of investigation, the duration of study, the feasible sample size and the extent of correlation to human HD at the biochemical and behavioural aspects should be considered. Consistency and stability of genetic variation due to breeding and background strain is another concern. These considerations are not limited to current utilization but also provide future directions to the generation of new animal models for HD as well as other neurodegenerative diseases.

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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • J. Stricker-Shaver
    • 1
  • A. Novati
    • 1
  • L. Yu-Taeger
    • 1
  • H. P. Nguyen
    • 1
  1. 1.Institute of Medical Genetics and Applied GenomicsUniversity of TuebingenTuebingenGermany

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