Transgenic Rat Models of Huntington’s Disease João Casaca Carreira, Ali Jahanshahi, Dagmar Zeef, Ersoy Kocabicak, Rinske Vlamings, Stephan von Hörsten and Yasin Temel
Abstract Several animal models for Huntington’s disease (HD) have been created in order to investigate mechanisms of disease, and to evaluate the potency of novel therapies. Here, we describe the characteristics of the two transgenic rat models: transgenic rat model of HD (fragment model) and the Bacterial Artificial Chromosome HD model (full-length model). We discuss their genetic, behavioural, neuropathological and neurophysiological features.
Keywords Transgenic rat model Huntington’s disease Striatum ganglia Behaviour BACHD Neuropathology Neurophysiology
Basal
Contents 1 2
Transgenic Rat Models of HD................................................................................................ 1.1 Transgenic Rat Models of HD ....................................................................................... Construction of the tgHD and BACHD Rats......................................................................... 2.1 Behavioural Phenotype ................................................................................................... 2.2 Motor Symptoms ............................................................................................................ 2.3 Non-motor Symptoms.....................................................................................................
J. C. Carreira A. Jahanshahi D. Zeef E. Kocabicak R. Vlamings Y. Temel Departments of Neuroscience and Neurosurgery, Maastricht University Medical Center, Maastricht, The Netherlands E. Kocabicak Department of Neurosurgery, Ondokuz Mayis University, Samsun, Turkey S. von Hörsten (&) Department of Experimental Therapy, Universitätsklinikum Erlangen, Franz-Penzoldt-Center, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany e-mail:
[email protected] J. C. Carreira A. Jahanshahi D. Zeef R. Vlamings Y. Temel European Graduate School of Neuroscience (EURON), Maastricht, The Netherlands
Curr Topics Behav Neurosci DOI: 10.1007/7854_2013_245 Ó Springer-Verlag Berlin Heidelberg 2013
J. C. Carreira et al. 2.4 Neuropathological Phenotype......................................................................................... 2.5 Neurophysiological Phenotype ....................................................................................... 3 Conclusion ............................................................................................................................... References......................................................................................................................................
1 Transgenic Rat Models of HD Huntington’s disease (HD) is an autosomal dominantly inherited progressive neurodegenerative disorder characterised by motor and non-motor symptoms. The mutation involves the expansion of the CAG trinucleotide repeat within exon 1 of the HTT gene on the short arm of chromosome 4. The result is the formation of the mutant form of the huntingtin (htt) protein. The symptoms of HD usually appear in midlife, leading to death within a period of 10–20 years. The cause of death is mainly due to complications, such as dysphagia, aspiration and overall exhaustion. Suicide is also an important cause of mortality in patients with HD. At the level of the neuropathology, late-stage HD is characterised by a profound loss of neurons, especially in the striatum and the cortex. In particular, the enkephalin positive medium spiny neurons in the striatum are substantially affected cells, already in the early stages of the disease. This leads to dysfunctional cortico-basal gangliathalamocortical circuits and as a result neurological and psychiatric symptoms (Frank and Jankovic 2010). For a detailed description of the symptomatology, please see other chapters in this book. Several animal models for HD have been created in order to investigate mechanisms of disease, and to evaluate the potency of novel therapies. Here, we describe the characteristics of two transgenic rat models: transgenic model of HD (tgHD) and the Bacterial Artificial Chromosome HD (BACHD) model. Although it is more common to use mice for transgenic modifications, the advantages of having a transgenic rat model are evident. Rats have a bigger brain and skull size, allowing cranial surgical approaches more conveniently. In addition, rats can be more easily evaluated using a variety of simple and complex motor, cognitive and emotional behavioural tests. Last but not least, Rattus norvegicus has been the species of choice for decades in scientific environments, the pharmaceutical industry and toxicology with extensive knowledge on its behaviour and physiology generated, until only during the last few decades, when the feasibility of genetic manipulation made Mus musculus the mammalian species of choice in biomedical research. Despite these developments, it should not be forgotten that many pharmacological and metabolic features are closer to human responsiveness implicating a higher predictability of this species for the development of therapies in humans (Aitman et al. 2008).
Transgenic Rat Models of Huntington’s Disease
1.1 Transgenic Rat Models of HD In 1998, the first transgenic rat model of HD (tgHD) was developed by Riess and colleagues and characterised by von Hörsten and co-workers in the following years (von Horsten et al. 2003). The tgHD rats carry 51 CAG repeats under the control of the native rat htt promoter in the genetic background of the Sprague-Dawley outbred rat strain. The original animals were derived from a Sprague-Dawley (SD) founder oocyte (Max Delbrück Center, Berlin-Buch, Germany; MDC), by classical pronucleus microinjection using a transgene with the coding sequence of a truncated (t), mutant (m), huntingtin (htt) protein carrying 51 CAG repeats (human PCR product) under control of the endogenous rat htt promotor (von Horsten et al. 2003). This model is a so-called ‘‘fragment model’’ and more recently the tgHD rats’ transgene has been transferred by selective breading onto the genetic background of Fischer 344 inbred rats (von Hörsten et al. unpublished). While SD rats (the strain of oocyte donors) represent an outbred rat strain, this transgenic line was subsequently inbred by strict brother x sister matings for C26 generations. According to the international nomenclature of laboratory rodents, these animals are coded ‘‘SD/MdcSvh-Tg(tmHTT51CAG)’’. Presently, for abbreviation purpose, this transgenic rat model of HD should be referred to as tgHD or ‘‘tgHDCAG51n’’ rats, contrasting the novel BACHD rat model, recently generated. Very recently, a second transgenic rat model has been described (Yu-Taeger et al. 2012). This BACHD transgenic rat expresses the full-length human mutant HTT under the control of the human HTT promoter and all its regulatory elements (Yu-Taeger et al. 2012). As far as we are aware of, these models are the only published transgenic rat models of HD. A detailed description of the characteristics of these two HD models will be provided below.
2 Construction of the tgHD and BACHD Rats The tgHD rat was developed by inserting a transgene, which was obtained from the DNA of a HD patient (19/51 CAGs) (von Horsten et al. 2003). The first 154 nucleotides of a partial huntingtin cDNA spanning 1962 base pairs (bp) of the Nterminal rat sequence (RHD10) (Schmitt et al. 1995) were replaced by a PCR (Polymerase Chain Reaction) product from the affected allele of the HD patient. The cDNA was driven by an 885 bp fragment of the rat HD promoter (position 900 to -15 bp) (Holzmann et al. 1998) and a 200 bp fragment containing the SV40 polyadenylation signal was added downstream of the cDNA resulting in RHD/Prom51A (Holzmann et al. 1998). Finally, the insert was microinjected into oocytes of Sprague-Dawley female rats (von Horsten et al. 2003). In order to verify the transgene, DNA was extracted from the tails of the offspring animals and a Southern blot was performed. Western blot analysis showed the expression
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of mutant htt in the frontal and temporal cortices, hippocampus, basal ganglia and mesencephalon (Schmidt et al. 1998; von Horsten et al. 2003). The BACHD rat was generated by microinjection of a BAC construct containing human genomic DNA expressing the full-length HTT gene with 97 CAG/ CAA repeats, as well as all regulatory elements (Gray et al. 2008) into the oocytes of Sprague-Dawley female rats. Determination of BAC transgene integrity and genotype was done by PCR analysis of genomic DNA extracted from ear biopsy tissue (Yu-Taeger et al. 2012). The BACHD construct was designed by using a BAC containing the full 170 kb of the HTT genomic locus with approximately 20 kb upstream and 50 kb downstream flanking sequences (Yu-Taeger et al. 2012). Wild-type (WT) HTT exon 1 was replaced by mutant HTT exon 1 containing 97 mixed CAA/CAG repeats flanked by two LoxP sites. Therefore, the BAC construct permitted a conditional and inducible elimination of the mutant HTT exon 1 by Causes recombination (Cre) recombinase activity. The number of CAG repeats was analysed and the conclusion was that the polyQ encoding sequence was stable in different brain regions, at different ages and gender over the generations (Yu-Taeger et al. 2012).
2.1 Behavioural Phenotype In this section we will describe the motor and non-motor features of both rat models of HD. The tgHD rats have been characterised reasonably well. However, the BACHD model has recently become available for studies, and therefore to this end there are only limited data available.
2.2 Motor Symptoms The motor symptoms of the tgHD rats have been reasonably well studied. Gait and balance abnormalities, hyper and hypokinetic features and chorea-like movements are the main motor symptoms observed in this model (Zeef et al. 2012b; von Horsten et al. 2003; Cao et al. 2006; Hohn et al. 2011; Nguyen et al. 2006; Vandeputte et al. 2010; Ortiz et al. 2012). The accelerod is a test that is used to assess motor coordination and balance of the fore and hind limbs (von Horsten et al. 2003). While at younger ages being significantly better than corresponding WT littermate controls, at 6 months of age, tgHD rats show a significant decreased performance when compared to WT animals (Nguyen et al. 2006). The performance on the accelerod worsens at 10 months of age, indicating a progression of the symptoms (von Horsten et al. 2003). Using a different test for gait and balance, the force-plate actometer, abnormalities were found in 12–15-month-old animals (Ortiz et al. 2012).
Transgenic Rat Models of Huntington’s Disease
Another characteristic motor abnormality is the hypermobility in these animals, already at the early stage of the disease. In the open field test, a test to assess spontaneous locomotion and generalised anxiety-like (‘‘emotional’’) behaviour, the animals show increased mobility times (Zeef et al. 2012b). This hypermobility decreases after the age of 12 months, and is probably indicative of bradykinesia at the later stage. An interesting movement disorder, again observed in the fragment tgHD model, is the chorea-like movement. These are abrupt, rapid, brief and unsustained irregular movements of the neck, also classified as opisthotonus-like movements (Cao et al. 2006; von Horsten et al. 2003). These movements, which are only seen at the level of the neck, have similarities with the human HD chorea (Cao et al. 2006). It is also claimed that the tgHD rat model is the first animal model to show this type of choreiform movement disorder (Cao et al. 2006). The frequency of the choreiform movements increases with disease progression and are present till death in these animals. The BACHD animals have been evaluated using the rotarod test and the footprint analysis method (Yu-Taeger et al. 2012). The rotarod performance was significantly worse in the transgenic animals already at 1 month of age, which further deteriorated with disease progression. Older animals, 14 months of age, showed also gait abnormalities in the footprint analysis. They made shorter steps (Yu-Taeger et al. 2012).
2.3 Non-motor Symptoms The non-motor symptoms are an important aspect of the disease, since patients with HD often are suffering more from the non-motor symptoms when the disease progresses. The tgHD rats show several non-motor deficits including cognitive and emotional disturbances at the early and late stages of the disease. The onset of these symptoms is usually prior to the development of the classical motor symptoms. Several studies have investigated the non-motor features of the tgHD rats (Kirch et al. 2013; Lawrence et al. 1996; Vlamings et al. 2012b; Nguyen et al. 2006; Zeef et al. 2012a, b; Cao et al. 2006). Cognitive decline starts between 6 and 9 months of age and this decline increases with ageing (Nguyen et al. 2006). Animals have difficulty with acquisition in the water maze and the double-H maze tasks (Kirch et al. 2013). In the object location task and object recognition task, tgHD rats show impaired visuospatial and visual object memory (Zeef et al. 2012a). Reduced spatial learning and working memory has been reported as well (Ortiz et al. 2012). Impulsivity-related symptoms have been observed in the tgHD rats. Increased numbers of premature responses were found in the choice reaction time test, which increased with disease progression (Cao et al. 2006). Another non-motor feature of the tgHD rats is the impaired anxiety levels. Reduced anxiety-like behaviour was
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noticed in the social interaction test when compared to the WT littermates (Nguyen et al. 2006). Similar findings were found in the open field test and the elevated zero maze, already at a very early stage of the disease (Zeef et al. 2012b). The BACHD rats have been evaluated using an automated homecage tracking system. The animals showed decreased exploratory behaviour and similarly to the tgHD rats, decreased levels of anxiety-related behaviour (Yu-Taeger et al. 2012).
2.4 Neuropathological Phenotype From a neuropathological perspective, in the tgHD rats intranuclear polyglutamine (polyQ) aggregates and neuropil aggregates can be found (Nguyen et al. 2006). PolyQ aggregates have been detected in the caudate-putamen, thalamus, substantia nigra pars compacta and the deep layers of the cortex (Nguyen et al. 2006). There is a profound progressive striatal cell loss in tgHD rats, contributing to reduced striatal volumes and enlarged ventricles (Kantor et al. 2006). In addition, we observed at the later stages of the disease, a profound cortical thinning (Fig. 1). Another neuropathological finding in this animal model was the significantly higher number of dopaminergic cells in the substantia nigra pars compacta, ventral tegmental area and the dorsal raphe nucleus, leading to an enhanced dopamine release into the dorsal and ventral striatum (Jahanshahi et al. 2010; Jahanshahi et al. 2013). This hyperdopaminergic status has been linked to the choreiform movements observed in this model (Fig. 2). Neuropathologically, BACHD rats develop polyQ aggregates in axons, synaptic terminals, as well as dark neurons (Yu-Taeger et al. 2012). There are also early changes in the pattern of the striosome and matrix compartments, accompanied by a decrease in the total and mean striosome area (Yu-Taeger et al. 2012).
2.5 Neurophysiological Phenotype The metabolic and neuronal activities of basal ganglia nuclei in the tgHD rats have been investigated at different levels. First, the overall neuronal activity at a supracellular level, by cytochrome oxidase histochemistry was determined. Second, the subcellular metabolic activity was assessed, by immunohistochemistry for peroxisome proliferator-activated receptor-c transcription co-activator (PGC-1a), a key player in the mitochondrial machinery. Finally, extracellular single unit recordings were performed to determine the cellular activity. Results showed a significantly increased cytochrome oxidase levels in the globus pallidus and subthalamic nucleus in the tgHD animals. PGC-1a expression was only enhanced in the subthalamic nucleus and electrophysiological recordings revealed decreased firing frequency of the majority of the neurons in the globus pallidus and increased
Transgenic Rat Models of Huntington’s Disease
Fig. 1 Representative low-power photomicrographs, showing Nissl stained coronal brain sections of a 16-month-old WT and a 16-month-old transgenic Huntington’s disease rat (tgHD). Note the striatal volume and cortical volume loss in the tgHD rat. There is an evident enlargement of the lateral ventricles, which is considered as a ex vacuo dilatation effect due to tissue loss. cc corpus callosum, LV lateral ventricle, aca anterior commissure ant, scale bar = 1 mm
Fig. 2 Representative low-power photomicrographs of frontal brain sections stained for TH tyrosine hydroxylase showing the SNc substantia nigra pars compacta, OT optic tract and a small part of the VTA ventral tegmental area of a WT littermate rat and a transgenic HD homozygous (+/+) rat. Note the increased TH containing cell density in the SNc of the transgenic HD rat upon close inspection adopted from Jahanshahi et al. 2010. Scale bar is approximately 500 lm
firing frequency of the majority of the neurons in the subthalamic nucleus. These data suggest that the globus pallidus and subthalamic nucleus play a role in the neurobiology of HD (Vlamings et al. 2012a). Another line of data suggested already an impaired corticostriatal information processing using a combined electrophysiological-behavioural approach (Hohn et al. 2011). The BACHD rats are being characterised in terms of neurophysiological activity of brain structures.
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3 Conclusion To our knowledge there are two published transgenic rat models of HD. The first is the tgHD rat model and the second is the BACHD model. The tgHD model is a socalled ‘‘fragment model’’ and the BACHD is a full-length model. The tgHD rats are relatively well characterised (Table 1). The tgHD rats have a slow progressive behavioural and neuropathological phenotype. In general, the symptoms can be divided into two stages: early and late. The early stage is characterised by hypermobility and reduced anxiety behaviour. Although some scientists have found early subtle cognitive changes, in our hands these do not have a large impact on the animals. This early stage is not accompanied with striatal cell degeneration or cortical cell damage, which occur later in the disease (Kantor et al. 2006; Nguyen et al. 2006). Nevertheless, there might already be striatal cell dysfunction (Miller et al. 2010). Already some choreiform movements can be seen in this early stage. We think that this stage ends around 11–12 months of age. The later stage is mainly characterised by the presence of more choreiform movements. Upon testing, the animals show impaired cognitive functioning and features of increased impulsivity (Cao et al. 2006; Zeef et al. 2012a). There is a profound loss of striatal cells and signs of cortical cell damage (Kantor et al. 2006). The life expectancy of these animals is shorter than controls, probably a few months (unpublished observations). There are a few issues that need to be considered in this animal model. The first is the effect of sex. There are differences in the behavioural phenotype between the sexes (Bode et al. 2008). This needs to be taken into account when comparing sets of data. In our studies, we often used males. The second is the gene-dose effect. We have been working with both homozygous and hemizygous animals. Homozygous animals show more robust behavioural and neuropathological features (Cao et al. 2006; Kantor et al. 2006), mimicking human HD. We decided to work only with homozygous rats. The third issue is a potential gene-drift effect. In a recent publication, researchers could not establish robust cognitive changes in this animal model (Fielding et al. 2012; Brooks et al. 2009). One explanation could be a potential gene-drift, but the existence of such mechanism still needs to be demonstrated. Furthermore, standardization of breeding might be an issue of differences observed between labs. TgHD rats should be bred by strict brother x sister matings of hemizygous (HET) males and females. From the offspring of 25 % WT, 50 % HET, and 25 % HOM animals, in most studies male WT littermates were compared with male HOM transgenics. In our colonies of animals, we have observed slight differences between generations of further inbred homozygous rats, but consistently found the clear behavioural and neuropathological phenotypes as described above. The congenic tgHD rat line on F344 rat genetic background confirms the impact of the truncated mHtt transgene in producing an HD-like phenotype in rats, even in front of a different genetic
Domain Test/Procedure
Accelerod test
Beam walking test Open field test Choreiform movements
Gait analysis
Nguyen et al. (2006) Zeef et al. (2012a, b) Cao et al. (2006)
Ortiz et al. (2012)
Motor
7, 8 and 10 months 6 and 7 months
1 month 3 months
14 months
6 and 12 months
15–20 months
9 and 12 months 10 and 16 months
Age
(continued)
2 months; progressive worsening from 6 months onwards tgHD showed impaired fine motor coordination and balance 9 months Hyperkinetic feature in tgHD 6, 7, 8 and 10 months Significant increased number of choreiform movements in homozygous tgHD 20 months animals Gait disturbances 12–15 months
Bimodal; initial improvements are followed in tgHD rats’ reduced balance and motor coordination
Reduced anxiety-like behaviour in tgHD Reduced anxiety in tgHD animals compared with WT
Elevated zero maze Open field test
Nguyen et al. (2006)
HD animals showed reduced anxiety-like behaviour tgHD animals presented decreased anxiety-like behaviour
Impaired working memory Deficits in visuospatial and visual object memory at early and late stages in tgHD rats 120 Decreased number of correct responses and increased response bias in tgHD rats Deficit in acquisition, poorer retention, more procedural errors and the learning process is slower in tgHD rats compared with WT and heterozygous animals tgHD rats showed increased premature responses, reduced number of correct responses and higher response bias
Main findings
Social interaction test Elevated plus maze test
Choice reaction time task
Kántor et al. (2006)
Emotion
Water-maze task and Double-H maze
Kirch et al. (2013)
Nguyen et al. (2006) Von Hörsten et al. (2003), Nguyen et al. (2006) Zeef et al. (2012a) Zeef et al. (2012a)
Choice reaction time task
Cao et al. (2006)
Cognition Nguyen et al. (2006) Radial maze Zeef et al. (2012b) Object recognition test and object location test
Study authors
Table 1 This table summarises the main findings with respect to the different features of the tgHD rats
Transgenic Rat Models of Huntington’s Disease
Stereological analysis
Stereological analysis of ventral tegmental area and substantia nigra pars compacta Striatal atrophy Brain stem analysis
Kantór et al. (2006)
Jahanshahi et al. (2010)
Details regarding the first author, year of publication and the age of the animals are provided as well
Temel et al. (2004)
Treatment Deep brain stimulation
Prefontostriatal function
Hohn et al. (2011)
Nguyen et al. (2006) Jahanshahi et al. (2013)
Dopamine release measurements
Metabolic changes in tgHD rats
12 months 11 months
11 months
12 months
4 months
20–26 months
2 months
10–12 months
11 months
12 months
9 months
Age
Globus pallidus stimulation improved cognitive dysfunction and reduction of 20 months chorea movements
Increased number of dopamine cells and decreased number of serotonincontaining cells in Dorsal Raphe Nucleus in tgHD Increased cytochrome oxidase levels in globus pallidus and subthalamic nucleus of tgHD PGC-1alfa increased in the subthalamic nucleus Decreased firing frequency in globus pallidus and increased firing frequency in the subthalamic nucleus N-acetylaspartate decreased in serum. Increased glutamine, succicinic acid, glucose and lactate in serum. Lactate and glucose increased in CSF Decreased dopamine release in tgHD rats after application of single and multiple electrical stimulus at different frequencies In tgHD rats, poorer temporal sensitivity was found in a bisection task and assessment of field- potentials showed enhanced plasticity at prefrontostriatal afferents Reduction of striatal volume (more pronounced in the medial paraventricular striatum) in tgHD animals Significantly increased tyrosine-hydroxylase immunoreactive cells in the VTA and SNc when compared with controls. Higher TH expression in dorsal and ventral striatum as compared with controls Decreased striatal volume in tgHD rats Increased number of dopamine cells and decreased number of serotonincontaining cells in the dorsal raphe nucleus
Brain stem analysis
Electrophysiological changes in basal ganglia
Decreased striatal volume in tgHD rats
Aggregation foci in thalamus, substantia nigra pars compacta, cortex and caudate-putamen
Main findings
Striatal atrophy
Pathology Aggregates
Domain Test/Procedure
Verwaest et al. (2011) Ortiz et al. (2012)
Von Hörsten et al. (2003), Nguyen et al. (2006) Von Hörsten et al. (2003), Nguyen et al. (2006) Jahanshahi et al. (2013) Vlamings et al. (2012a, b)
Study authors
Table 1 (continued)
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Transgenic Rat Models of Huntington’s Disease Table 2 This table summarises the main findings with respect to the different features of the BACHD rats Study Domain Test/Procedure Main findings Age authors Yu-Taeger Emotion et al. Elevated plus (2012) maze Motor Accelerated rotarod
Reduced anxiety-like behaviour
1, 4 and 12 months
Balance problems with subsequent falls
Progressive worsening from 1 month onwards till 15 months 14 months
Footprint analysis Shorter steps and reduced overlap limbs Automated home Reduced rearing and locomotor cage-like activity in BACHD animals environment Pathology Htt aggregates In the cortex, nucleus accumbens, bed nucleus of stria terminalis and hippocampus. Electron Htt deposits are found in axons and microscopy synaptic terminals Dynamic PET Reduction of dopamine receptor scan in the binding striatum Metabolic Food intake Reduced food consumption
Only at 3- and 6-months old 3 months
13 months 18 months 6 months
3–18 months
These findings were reported by Yu-Taeger et al. 2012
background. After evaluating the different phenotypes of the tgHD rats, we consider the tgHD rat model suitable to evaluate therapeutic approaches. The phenotype of the BACHD model in terms of behaviour and neuropathology seems to be clinically relevant and therefore it is a promising model (Table 2). However, thus far there are no hyperkinetic movements observed in these animals. The model needs more characterisation to draw final conclusions. There are differences between the two models in terms of construct validity as well, such as the number of trinucleotide repeats (51 CAG in tgHD vs. 97 CAGCAA in BACHD), being a fragment model (tgHD) versus a full-length model (BACHD), using homozygous animals (tgHD) versus heterozygous (BACHD), keeping an inbred background (tgHD) versus outbred background (BACHD), which should be taken into account when a model is chosen for a specific purpose.
J. C. Carreira et al.
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