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The Journal of Neuroscience, April 15, 1999, 19(8):3248-3257
Characterization of Progressive Motor Deficits in Mice Transgenic
for the Human Huntington's Disease Mutation
Rebecca J.
Carter1,
Lisa A.
Lione2, 3,
Trevor
Humby2,
Laura
Mangiarini5,
Amarbirpal
Mahal5,
Gillian P.
Bates5,
Stephen B.
Dunnett2, 4, and
A. Jennifer
Morton1
1 Department of Pharmacology, 2 Centre for
Brain Repair, 3 Parke-Davis Neuroscience Research, and
4 Department of Experimental Psychology, University of
Cambridge, Cambridge, CB2 1QJ, United Kingdom, and
5 Division of Medical and Molecular Genetics, Guy's
Hospital, London SE1 9RT, United Kingdom
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ABSTRACT |
Transgenic mice expressing exon 1 of the human Huntington's
disease (HD) gene carrying a 141-157 CAG repeat (line R6/2) develop a
progressive neurological phenotype with motor symptoms resembling those
seen in HD. We have characterized the motor deficits in R6/2 mice using
a battery of behavioral tests selected to measure motor aspects of
swimming, fore- and hindlimb coordination, balance, and sensorimotor
gating [swimming tank, rotarod, raised beam, fore- and hindpaw
footprinting, and acoustic startle/prepulse inhibition (PPI)].
Behavioral testing was performed on female hemizygotic R6/2 transgenic
mice (n = 9) and female wild-type littermates
(n = 22) between 5 and 14 weeks of age. Transgenic mice did not show an overt behavioral phenotype until around 8 weeks of
age. However, as early as 5-6 weeks of age they had significant difficulty swimming, traversing the narrowest square (5 mm) raised beam, and maintaining balance on the rotarod at rotation speeds of
33-44 rpm. Furthermore, they showed significant impairment in prepulse
inhibition (an impairment also seen in patients with HD). Between 8 and
15 weeks, R6/2 transgenic mice showed a progressive deterioration in
performance on all of the motor tests. Thus R6/2 mice show measurable
deficits in motor behavior that begin subtly and increase progressively
until death. Our data support the use of R6/2 mice as a model of HD and
indicate that they may be useful for evaluating therapeutic strategies
for HD, particularly those aimed at reducing the severity of motor
symptoms or slowing the course of the disease.
Key words:
transgenic mice; Huntington's disease; CAG repeat; motor
behavior; prepulse inhibition; sensorimotor gating; polyglutamine
repeat diseases
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INTRODUCTION |
Huntington's disease (HD) is a
progressive, genetic neurodegenerative disorder characterized by
movement abnormalities, cognitive impairments, and an emotional
disturbance (Harper, 1996 ). The predominant movement abnormality is
chorea, although other motor abnormalities including dyskinesia,
dystonia, rigidity, and tremor are also seen, the latter particularly
in juvenile-onset HD.
An expanded unstable CAG trinucleotide repeat within the coding region
of the HD gene has been identified as the genetic mutation responsible for the disease (The Huntington's Disease Collaborative Group, 1993). It now appears that HD belongs to a family of
neurodegenerative disorders associated with an expansion of CAG repeats
in the causative gene. To date, seven additional CAG "triplet
repeat" diseases have been identified, including spinal and bulbar
muscular atrophy, spinocerebellar ataxia types 1, 2, 3, 6, and 7, and
dentatorubral-pallidoluysian atrophy (for references, see Paulson and
Fischbeck, 1997). The causative genes in each of these disorders are
different and unrelated in function, although the expansion of the CAG
repeats and the progressive neurological nature of these disorders
suggests that they may share a common mechanism of pathogenesis
(MacDonald and Gusella, 1996; Burright et al., 1997).
Over the past 20 years, many attempts have been made to generate animal
models of HD. Of particular importance have been the excitotoxic and
3-nitropropionic acid (3-NP) models that replicate many of the
histological features of HD in both rodents and primates (Beal et al.,
1986, 1993; Brouillet et al., 1995). 3-NP models in particular
reportedly model some of the motor symptoms of HD, including
abnormalities in gait and impairments in sensorimotor gating (Borlongan
et al., 1995; Brouillet et al., 1995; Kodsi and Swerdlow, 1997).
However, because both models are neurochemically induced, the
associated changes in behavior are not truly progressive. Thus they are
limited in their usefulness for testing treatments aimed at preventing
or slowing the motor dysfunction in HD. An animal model that exhibits a
progressive neurological phenotype is essential before such studies can
be usefully conducted.
A transgenic mouse model for HD (R6/2) that appears to have a
progressive phenotype has been developed recently (Mangiarini et al.,
1996). R6/2 mice, whose transgene contains the first exon of the human
HD gene carrying 141-157 CAG repeats, display a number of
the key neuropathological features of HD (Davies et al., 1997; Cha et
al., 1998). Critically, preliminary investigations showed that R6/2
transgenic mice develop several of the motoric characteristics of HD
(Mangiarini et al., 1996), including a progressive hypoactivity similar
to that seen in patients with HD (Carter et al., 1998; Dunnett et al.,
1998). However, so far the behavioral phenotype of this mouse has not
been analyzed in sufficient detail to determine its usefulness as a
progressive model of HD. Therefore, in this study we have characterized
the progressive motor deficits displayed by R6/2 transgenic mice. These
data will provide a baseline against which to assess (1) the relevance
of this mouse model to HD and (2) its potential usefulness for testing
therapies aimed at treating this devastating disease.
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MATERIALS AND METHODS |
Animals (R6/2 transgenic mice). The R6/2 line of
transgenic mice was generated as described previously (Mangiarini et
al., 1996). A colony of R6/2 transgenic mice was established in the Department of Pharmacology, University of Cambridge, and the line was
maintained by backcrossing to CBA × C57BL/6 F1 animals.
Genotyping was confirmed by PCR based on a modification of the method
of Mangiarini et al. (1996). The present study used 9 female
hemizygotic transgenic mice and 22 female wild-type littermate control
mice from six litters of the thirteenth generation, all born within 5 d of each other. Females were used because transgenic males were
used for breeding and were not available for behavioral testing. The
age of onset of overt symptoms in the R6/2 line is ~2 months, with
the severity of symptoms progressing rapidly over the following few
weeks, as reported previously (Mangiarini et al., 1996). Here, behavioral testing began at 5-6 weeks of age, when transgenic mice
were overtly phenotypically indistinguishable from their normal
littermates. Tests were conducted regularly (see below) over a 10 week
period to follow the progression of motor symptoms. One transgenic
mouse died during the final week of the study; data from this mouse
were included in the analysis.
Mice were housed together in numerical birth order in groups of mixed
genotype, and data were recorded for analysis by mouse number. Until
the appearance of the hindlimb grooming behavior, transgenic mice could
not be distinguished from normal mice in their home cage. Therefore,
until the grooming behavior appeared (between 8-9 weeks of age), the
experimenters were blind to the genotype of the mice. Although data
collected after the onset of an overt phenotype was not collected
blind, it should be noted that the home cage observations for overt
phenotype were performed and recorded separately from the behavioral
tests. Because the abnormal grooming in its early stage is difficult to
distinguish from normal grooming behaviors, this meant that until the
abnormal grooming movements occurred regularly, the experimenters did
not necessarily know the genotype of a particular mouse. Once the grooming behavior and other phenotypic changes became pronounced (usually between 10 and 14 weeks), it was impossible to conduct the
experiments blind.
Body weight. Body weight was measured twice per week.
Motor tests. Mice were trained on a battery of motor and
cognitive tests. Five motor tests of swimming, fore- and hindlimb coordination, balance, and sensorimotor gating are reported here. After
the establishment of stable baselines, animals were retested at weekly
intervals, with the exception of the acoustic startle test, in which
animals were retested every 2 weeks. The mean age of mice midweek of
each testing session was used for analysis and presentation purposes.
Swimming tank. To monitor swimming movements, mice were
trained to swim from one end of a water-filled glass tank to a visible escape platform at the opposite end (Perry et al., 1995). The glass
tank was 100 cm long and 6 cm wide and was filled to a depth of 20 cm
with water at a temperature of 23°C. The visible escape platform was
made from black perspex (6 cm square and 20.5 cm high), with the top
surface 0.5 cm above the water level. A vertical black line on the side
of the glass marked a horizontal distance 60 cm from the platform; this
served as the start line for recording swimming performance. During the
training period each mouse was placed in the water at one end of the
tank, and within a couple of trials learned to swim straight to the
visible escape platform at the opposite end. After training, mice were
given two trials per day for 3 consecutive days, by which time they
reached stable baseline performance levels. Mice were then given two
consecutive trials on a weekly basis. Mice were videotaped from both
sides, and the number of forelimb kicks, the number of hindlimb kicks, and the latency to swim the 60 cm distance were recorded. Analysis was
based on the mean scores of the two trials for each measure.
Beam walking. Motor coordination and balance of mice were
assessed by measuring the ability of the mice to traverse a graded series of narrow beams to reach an enclosed safety platform (Perry et
al., 1995). The beams consisted of long strips of wood (1 m) with a
28-, 12-, or 5-mm-square cross-section or a 28, 17, or 11 mm round
diameter. The beams were placed horizontally, 50 cm above the bench
surface, with one end mounted on a narrow support and the other end
attached to an enclosed box (20 cm square) into which the mouse could
escape. Two anglepoise lights (60 W) were positioned above and
to one side of the start of the beam. During training, mice were placed
at the start of the 12-mm-square beam and trained over 3 d (4 trials per day) to traverse the beam to the enclosed box. Once the mice
were trained (traversed the 12-mm-square beam in < 20 sec) they
received two consecutive trials on each of the square beams and each of
the round beams, in each case progressing from the widest to the
narrowest beam. Mice were allowed up to 60 sec to traverse each beam.
The latency to traverse each beam and the number of times the hind feet
slipped off each beam were recorded for each trial. Analysis of each
measure was based on the mean scores of the two trials for each beam.
Rotarod. The rotarod apparatus (Accelerating Model, Ugo
Basile, Biological Research Apparatus, Varese, Italy) was used to measure fore- and hindlimb motor coordination and balance. During the
training period, each mouse was placed on the rotarod at a constant
speed (24 rpm) for a maximum of 60 sec, and the latency to fall off the
rotarod within this time period was recorded. Mice received four trials
per day for 3 consecutive days, by which time a steady baseline level
of performance was attained. Mice then received two trials at 10 increasing speed levels, ranging from 5 to 44 rpm. The mean latency to
fall off the rotarod (for the two trials at each speed level) was
recorded and used in subsequent analysis.
Footprint test. The footprint test was used to compare the
gait of R6/2 transgenic mice with that of wild-type control mice. To
obtain footprints, the hind- and forefeet of the mice were coated with
purple and orange nontoxic paints, respectively. The animals were then
allowed to walk along a 50-cm-long, 10-cm-wide runway (with 10-cm-high
walls) into an enclosed box. All mice had three training runs and were
then given one run per week. A fresh sheet of white paper was placed on
the floor of the runway for each run. The footprint patterns were
analyzed for four step parameters (all measured in centimeters). (1)
Stride length was measured as the average distance of forward movement
between each stride. (2) Hind-base width and (3) front-base width were
measured as the average distance between left and right hind footprints and left and right front footprints, respectively. These values were
determined by measuring the perpendicular distance of a given step to a
line connecting its opposite preceding and proceeding steps. (4)
Distance from left or right front footprint/hind footprint overlap was
used to measure uniformity of step alternation. When the center of the
hind footprint fell on top of the center of the preceding front
footprint, a value of zero was recorded. When the footprints did not
overlap, the distance between the center of the footprints was
recorded. For each step parameter, three values were measured from each
run, excluding footprints made at the beginning and end of the run
where the animal was initiating and finishing movement, respectively.
The mean value of each set of three values was used in subsequent analysis.
Acoustic startle/prepulse inhibition (PPI). Acoustic startle
and PPI responses were measured in a startle chamber (San Diego Instruments) adapted for mice. The chosen paradigm was adapted from
Swerdlow et al. (1995) and assessed startle amplitude and PPI using
acoustic stimuli of 120 and 105 dB, a single prepulse interval (100 msec), and four different prepulse intensities [2, 4, 8, and 16 dB
above background noise (white noise, 65 dB)]. A mouse was placed in
the startle chamber and initially received a 5 min acclimatization
period with background noise alone. The mouse was then presented with
72 startle trials, each trial consisting of one of three conditions:
(1) a 30 msec 120 dB noise burst presented alone (S); (2) a 30 msec 120 dB noise burst preceded 100 msec by prepulses (30 msec noise bursts)
that were 2, 4, 8, or 16 dB above background noise (PP2, PP4, PP8, or
PP16, respectively); or (3) no stimulus (NS; background noise alone),
which was used to measure baseline movement in the chamber. These six
trial types (S, PP2, PP4, PP8, PP16, NS) were each repeated six times
in a pseudorandom order (36 trials), such that each trial type was presented once within a block of six trials. This block of 36 trials
was then repeated using an acoustic stimuli of 105 dB. Analysis was
based on the mean of the six trials for each trial type.
Statistical analysis. Behavioral data were subjected to
two-, three- or four-way ANOVA (SAS-RA software package) with one between-subject factor (genotype; transgenic or wild type) and with
repeated measures on one or more factors depending on the test used
(e.g., age, different beams, different rotarod speeds, etc.). Sidak's
test was used for multiple independent post hoc pair-wise
comparisons between transgenic and wild-type mice at each relevant
age and test level (Rohlf and Sokal, 1995). A critical value for
significance of p < 0.05 was used throughout the study.
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RESULTS |
Genotyping
In all cases, mice genotyped as transgenic were those that
exhibited a progressive deficit in the motor tests (see below).
Spontaneous appearance of motor deficits in R6/2
transgenic mice
At 5 weeks of age the home cage behavior of R6/2 transgenic mice
was indistinguishable from that of normal littermate control mice.
Overt signs of neurological abnormality were first evident by 8 weeks
(58 ± 0.5 d) of age, similar to that reported previously (Mangiarini et al., 1996). The initial abnormal neurological signs included stereotypical hindlimb-grooming movements, dyskinesia of the
hindlimbs when mice were suspended by the tail, and an irregular gait.
The frequency and severity of these abnormalities worsened slowly over
the following few weeks until by 12-13 weeks of age the animals showed
clear signs of irregular gait, resting tremor, stereotypical grooming,
abrupt and irregularly timed shuddering movements, occasional epileptic
seizures, and body weight loss (see below).
R6/2 transgenic and control mice gained weight at a similar rate until
10 weeks of age (Fig. 1). The body weight
of R6/2 transgenic mice stabilized at 10 weeks and then showed a
gradual decline, whereas their wild-type littermates continued to grow
throughout the study (genotype × age,
F22,638 = 47.80, p < 0.0001). A
significant decrease in total body weight in R6/2 transgenic mice was
evident by 13 weeks of age.
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Figure 1.
Body weights of wild-type and R6/2 transgenic
mice. Symbols indicate the means ± SEM body weight (gram) of
wild-type (n = 22) and R6/2 transgenic
(n = 9) mice. The body weight of R6/2 transgenic
mice gradually declines from 12 weeks of age. Asterisks
indicate significant differences between wild-type control R6/2
transgenic mice (**p < 0.01).
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Measurement of progression of motor deficits in R6/2
transgenic mice
To assess in more detail the neurological consequences of the
expression of the R6/2 transgene, R6/2 transgenic and wild-type littermate control mice were subjected to five tests of motor behavior.
Swimming tank
R6/2 transgenic mice displayed abnormalities in their swimming
movements from the onset of testing, and these became more marked over
subsequent weeks. When placed in the water, R6/2 transgenic mice often
floated temporarily, adopted a twisted posture, and kicked in a splayed
and uncoordinated manner with both hind- and forelimbs. In contrast,
control mice swam with vigor immediately after being placed in the
water, using mainly their hindlimbs to propel along. Although control
mice maintained a constant swimming latency throughout the study, R6/2
transgenic mice swam significantly more slowly at 5-6 weeks of age
(p < 0.0001) and swam even more slowly with an
increase in age (genotype × age: F8,232 = 13.48, p < 0.0001) (Fig.
2A). At 5-6 weeks of
age, R6/2 transgenic mice also exhibited a significantly greater number
of hind- and forelimb kicks to swim the 60 cm distance, compared with
controls [hindlimb: p < 0.01 (Fig.
2B); forelimb: p < 0.05 (Fig.
2C)].
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Figure 2.
Swimming performance of wild-type and R6/2
transgenic mice in the swimming tank. Wild-type (n = 22) and R6/2 transgenic (n = 9) mice were tested
in the swimming tank for two trials per day for 3 consecutive days at
5-6 weeks of age, retested at 8-9 weeks of age, and then weekly
thereafter. Separate measurements were made of the latency
(A), the number of hindlimb kicks
(B), and the number of forelimb kicks
(C) to swim 60 cm to a visible escape platform.
Vertical bars indicate means ± SEM of each measure
across all trials at each age. R6/2 transgenic mice display swimming
impairments at the earliest age tested, 5-6 weeks, which progressively
worsen over subsequent weeks. Asterisks indicate
significant differences between wild-type control and R6/2 transgenic
mice (*p < 0.05, **p < 0.01).
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The frequency of hindlimb kicking increased significantly with the age
of the R6/2 transgenic mice, in contrast with the control group, which
sustained a consistent number of hindlimb kicks over the 10 week period
(genotype × age: F18,232 = 2.24, p < 0.05). Although the number of forelimb kicks of
R6/2 transgenic mice was invariably significantly greater than that of
their wild-type littermates across sessions, no significant
genotype × age interaction was observed
(F8,232 = 2.02, p = 0.078),
because both groups increased the frequency of forelimb kicking across
sessions. The three-way interaction (genotype × limb × age:
F8,464 = 1.34, p = 0.25) failed to reach significance, suggesting that the ratio of forelimb to hindlimb kicks was comparable for R6/2 transgenic and control mice
(Fig. 2B,C). Swimming impairments, evident at 5-6
weeks of age, occurred at a time when the R6/2 transgenic animals were otherwise indistinguishable from their normal littermate controls.
Beam walking
Beam walking was used to compare the fine motor coordination and
balance capabilities of R6/2 transgenic and control animals. Different
levels of task difficulty were achieved by varying the shape and
cross-section of the beams (Fig. 3). At
the earliest age tested, 5-6 weeks, the control and R6/2 transgenic
mice walked along all the beam types with ease, although the R6/2
transgenic mice were significantly slower in traversing the narrowest
square beam (p < 0.0001) (Fig. 3C).
However, by 8-9 weeks of age (when home cage phenotypic abnormalities
first become apparent), R6/2 transgenic mice showed significant
difficulty in traversing all but the widest round beam, as measured by
their increased latency to traverse each beam, compared with control
mice. By 13-14 weeks of age, R6/2 transgenic mice took up to 12 times
as long as controls to traverse all the beams (p < 0.0001).
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Figure 3.
Balance and motor coordination on the
raised beams. Wild-type (n = 22) and R6/2
transgenic (n = 9) mice were trained to walk across
six progressively more difficult beams of square and round
cross-section to reach an enclosed safety platform. The latency to
cross (A-F) and the number of footslips made
(G-L) were recorded on each trial. All animals
were given two trials on each of the graded square and round beams, in
each case progressing from the widest to the narrowest, for 3 consecutive days at 5-6 weeks of age, retested at 8-9 weeks of age,
and then weekly thereafter. Individual symbols represent means ± SEM of the two groups on each test and age. R6/2 transgenic mice
exhibit a progressive decline in beam-walking ability with age and beam
difficulty. Asterisks indicate significant differences
between wild-type control and R6/2 transgenic mice
(*p < 0.05, **p < 0.01).
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At 8-9 weeks of age, R6/2 transgenic mice also made significantly more
footslips than control mice on all but the widest square and round
beams, the frequency of which increased with age and as the beams
became narrower. One obvious difference between R6/2 transgenic and
wild-type control mice was the manner in which the R6/2 transgenic mice
traversed the beams. At the onset of testing, R6/2 transgenic and
wild-type control mice adopted a stable upright posture, but by 10-11
weeks of age most R6/2 transgenic mice displayed ventral recumbence:
their thorax and abdomen were flattened against the upper surface of
each beam, their hind- and forelimbs were wrapped around the lateral
surface of each beam, and their forelimbs were used to drag themselves
along the beam while their hindlimbs became redundant. By 13-14 weeks
of age, some R6/2 transgenic mice failed to maintain balance on the beams and fell off. When this occurred on three consecutive trials the
animal was no longer tested. In subsequent trials, for purposes of
analysis, such animals were given a maximum latency of 60 sec and a
footslip score of 50, which equates to the highest number of footslips
before outright failure.
The significance of these observations was confirmed by ANOVA, which
indicated a significant effect of genotype on both the latency and the
number of footslips made while traversing the different beams
(F1,29 = 528.00 and 1441.06, respectively; both p < 0.0001) and a significant interaction between
genotype × age × beam (shape and size) for both measures
(latency: F16,1392 = 4.75; footslips:
F16,1392 = 8.69; both p < 0.0001).
Rotarod
Motor coordination and balance of mice were measured using a
rotarod. All mice used in this study showed learning of the rotarod test and reached a stable level of performance within 3 d, as measured by an increase in the mean duration time for mice to maintain
balance on the rotarod (data not shown). Throughout the study control
mice maintained balance on the rotarod for the maximum latency of 60 sec, on all rotation speeds, with the exception of 33 and 44 rpm, when
they would occasionally fall off (Fig. 4G,H).
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Figure 4.
Balance and motor coordination on the
rotarod. Wild-type (n = 22) and R6/2 transgenic
(n = 9) mice were subjected to eight different
speeds on an accelerating rotarod (5-44 rpm), receiving two trials per
speed. The means ± SEM of the duration of balance or latency to
fall (maximum trial length = 60 sec) for the two trials at each
speed level was recorded. Animals 5-6 weeks old were tested to
establish baseline performance, and animals were retested at 8-9 weeks
of age and then weekly thereafter. R6/2 transgenic mice 5-6 weeks old
exhibit difficulty maintaining balance on the rotarod at the highest
rotation speeds (G, H) and display
a progressive decline in performance on the rotarod with increasing
rotation speed and age. Asterisks indicate significant
differences between wild-type control and R6/2 transgenic mice
(*p < 0.05, **p < 0.01).
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R6/2 transgenic mice 5-6 weeks old had difficulty maintaining balance
on the rotarod at the highest rotation speeds of 33 and 44 rpm
(p < 0.0001) (Fig. 4G,H).
Thus these changes in rotarod rotation speeds identify significant
deficits in motor coordination and balance of R6/2 transgenic mice even
before any overt phenotype is detectable. There was a progressive
decline in performance of R6/2 transgenic mice on the rotarod at all 10 speeds over ensuing weeks, and by 13-14 weeks of age R6/2 transgenic
mice failed to maintain balance on the rotarod at any speed for >10
sec (Fig. 4A-H).
The significance of the difference between groups was confirmed by
ANOVA, which revealed a highly significant main effect of genotype
(F1,29 = 1868.70, p < 0.0001),
genotype × speed (F10,319 = 18.21, p < 0.0001), and genotype × age
(F6,174 = 350.54, p < 0.0001),
and a significant genotype × speed × age interaction (F60,1914 = 3.57, p < 0.0001),
reflecting a significant difference between the performance of R6/2
transgenic and control mice with an increase in rotarod rotation speed
and age.
Footprint test
Gait abnormalities were assessed by analyzing the footprint
pattern of mice while they walked along a narrow corridor. Footprint patterns of wild-type and R6/2 transgenic mice at 13-14 weeks of age
are illustrated in Figure 5. At all ages,
control mice walked in a straight line, with a regular even alternating
gait, placing the hindpaw precisely at the position where the
ipsilateral forepaw had been in the previous step (Fig. 5A).
By contrast, with increasing age, R6/2 transgenic mice progressively
weaved from side to side while walking along the runway, adopting
unevenly spaced shorter strides, staggering movements, and a gait that lacked a normal, uniform, alternating left-right step pattern (Fig.
5B).
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Figure 5.
Representative walking footprint patterns of 13- to 14-week-old wild-type (A) and R6/2 transgenic
(B) mice. Qualitatively, the generated patterns
clearly differ showing that R6/2 transgenic mice display irregularly
spaced shorter strides and an uneven left-right step pattern as
compared with the evenly spaced and accurately positioned footprints of
the wild-type control mice.
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The resulting footprint patterns were assessed quantitatively by four
measurements: stride length, hindbase width, frontbase width, and front
footprint/hind footprint overlap. Although R6/2 transgenic and control
mice exhibited comparable stride lengths at 5-6 weeks of age, these
gradually deviated with age (genotype × age:
F6,174 = 34.01, p < 0.0001)
(Fig. 6A). The stride
length of control mice increased significantly with age. By contrast, by 8-9 weeks, R6/2 transgenic mice displayed a significantly shorter stride length compared with control mice (p < 0.0001), and this effect became more pronounced as the mice got older
(Fig. 6A).
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Figure 6.
Quantitative analysis of the walking footprint
patterns produced by wild-type and R6/2 transgenic mice, based on
measurements of stride length (A), hindbase width
(B), frontbase width (C),
and distance between front and hind footprint placement or overlap
(D). At 5-6 weeks of age the footprint patterns
of R6/2 transgenic mice are indistinguishable from those produced by
wild-type control mice, but by 8-9 weeks of age, R6/2 transgenic mice
exhibit a significantly shorter stride length, a broader frontbase
width, and a greater distance between front footprint/hind footprint
overlap, as compared with wild-type control mice.
Symbols indicate means ± SEM by mice of each group
at each age on each measure. Asterisks indicate
significant differences in the performance of wild-type control and
R6/2 transgenic mice (*p < 0.05, **p < 0.01).
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The hindbase width of R6/2 transgenic mice did not differ from that of
their wild-type littermates throughout the study (genotype: F1,29 = 0.92, p = 0.345;
genotype × age: F6,174 = 0.97, p = 0.442) (Fig. 6B). In contrast,
the frontbase width of R6/2 transgenic mice was significantly broader
and more splayed than that shown by controls at 8-9 weeks of age, and
this difference was sustained over the five succeeding weeks
(genotype: F1,29 = 23.60, p < 0.0001; genotype × age: F6,174 = 2.88, p = 0.013) (Fig. 6C).
The distance from left or right front footprint/hind footprint overlap
provides an indication of uniformity of step alternation. As shown in
Figure 6D, R6/2 transgenic mice displayed a similar uniformity in step alternation at 5-6 weeks of age compared with controls, but by 8-9 weeks of age the regular left-right step pattern
began showing disruption, and they exhibited a progressively greater
distance between front and hind footprint placement (i.e., a reduced
overlap) as compared with controls. The progressive difference between
R6/2 transgenic and control mice with age was highly significant
(genotype × age: F6,174 = 8.06, p < 0.0001) (Fig. 6D).
Prepulse inhibition of the acoustic startle response
Acoustic startle is a motor reflex response to an intense loud
noise stimulus. As shown in Figure
7A,F, the acoustic startle response to 120 and 105 dB, respectively, did not differ between control and R6/2 transgenic mice over the first 10-11 weeks of age,
but did decline in the R6/2 transgenic mice at the final test at 12.5 weeks of age (genotype × age: F3,87 = 4.88, p < 0.01 and F3,87
=4.85, p < 0.007, respectively). It is noteworthy that the change in magnitude of acoustic startle responses during the course
of the study appeared to parallel the change in body weight of R6/2
transgenic and control mice (Fig. 1).
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|
Figure 7.
Prepulse inhibition of the acoustic
startle response in wild-type (n = 22) and R6/2
transgenic (n = 9) mice. Symbols indicate mean ± SEM of the response of the two groups at different ages to white
noise stimuli of 120 dB (A-E) and 105 dB
(F-J) with either the baseline startle
response recorded to the primary acoustic startle stimulus alone
(A, F, respectively) or with 100 msec prepulse warning
stimuli of rising intensities (2, 4, 8, and 16 in B-E
and G-J, respectively). R6/2 transgenic mice exhibit
impaired PPI by 8-9 weeks of age, and this impairment progressively
declines with age. Asterisks indicate significant
differences in performance between the two genotypes
(*p < 0.05, **p < 0.01).
|
|
The acoustic startle response is reduced when a prepulse stimulus is
presented before the main startle stimulus. The level of PPI, expressed
as a percentage reduction of the baseline startle response, obtained
with each of the four different prepulses in R6/2 transgenic and
littermate control mice at different ages of testing is shown in Figure
7B-E, G-J. At 5 weeks of age, R6/2 transgenic mice and
wild-type littermate control mice displayed comparable PPI at all
prepulse intensities. However, compared with control mice, a
significant reduction of PPI was apparent in R6/2 transgenic mice by
8-9 weeks of age at prepulse intensity levels of 2 and 4 dB. By 12-13
weeks of age PPI was significantly disrupted in R6/2 transgenic mice at
all four prepulse intensity levels.
Repeated-measures ANOVA of PPI to 120 and 105 dB startle stimuli
revealed significant effects of genotype (F1,29 = 23.23 and 35.96, respectively; both p < 0.001) and
genotype × age (F3,87 = 8.02 and 16.18, respectively; both p < 0.001), confirming that the
transgenic mice exhibited a significant progressively greater PPI
deficit as they aged. However, neither the genotype × prepulse intensity (F3,87 = 0.30, p = 0.828 and F3,87 = 0.22, p = 0.925, respectively) nor the genotype × prepulse intensity × age (120 dB: F9,348 = 0.82, p = 0.597; 105 dB: F9,348 = 0.60, p = 0.794) approached significance, confirming the
observation that the age-dependent deficit in the transgenic mice was
apparent and of similar magnitude at all prepulse intensities,
notwithstanding the fact that the higher intensity prepulses induced a
greater inhibition than lower intensity prepulses in the transgenic and
control mice alike.
| |
DISCUSSION |
Motor symptoms play a prominent role in the early stages of HD
(Harper, 1996), and R6/2 transgenic mice have been reported to display
a number of motor abnormalities reminiscent of those occurring in HD,
including dyskinetic movements, resting tremor, seizures, and locomotor
abnormalities (Mangiarini et al., 1996; Carter et al., 1998; Dunnett et
al., 1998). In this study we tested motor function in R6/2 mice and
showed that on all motor tests performed they display a marked and
progressive deterioration in performance, compared with wild-type
littermate control mice.
Behavioral testing commenced at 5-6 weeks of age. This age was chosen
as the starting point because it was several weeks before overt
symptoms first appear in R6/2 mice. However, even at 5-6 weeks it was
apparent that R6/2 transgenic mice exhibited difficulties in a number
of tasks (namely swimming, traversing the narrowest square raised beam,
and maintaining balance on the rotarod at the fastest rotating speeds).
For example, when R6/2 transgenic mice were placed in the swim tank,
their abnormal posture and inappropriate kicking movements contrasted
sharply with the coordinated, synchronized paddling movements shown by
wild-type mice. Thus from 5-6 weeks the R6/2 transgenic mice swam more
slowly and more inefficiently than wild-type control mice, although
there were no deficits seen in the other tests (gait, sensorimotor
gating, or motor performance on the lesser challenging wider beams and slower rotarod speeds). Furthermore, in their home cage at this age the
transgenic mice were indistinguishable from their wild-type littermates
by simple observation. There is therefore no clear "age of onset"
of neurological phenotype in R6/2 transgenic mice; the age at which a
phenotype is apparent depends on the sensitivity of the test and the
difficulty of the particular task used to characterize it. Even if a
mouse appears "normal" on inspection, a more sensitive test may
reveal significant deficits in fine motor control and motor coordination.
By 8 weeks of age, signs of neurological abnormality in R6/2 mice were
occasionally observed in the home cage, in particular stereotypical
hindlimb grooming movements. The stereotypical grooming increased in
frequency between 8 and 12 weeks, and at the same time, other deficits
in motor activity became apparent. In particular, balance and
coordination become increasingly impaired, and dyskinesia and resting
tremor ensued. The frequency and severity of these abnormalities
worsened gradually, until by 11 weeks of age the mice groomed
frequently, there were clear signs of a constant resting tremor, and
occasional epileptic seizures were evident. Concurrent with the onset
of severe motor deficits, and consistent with the findings of Davies et
al. (1997), R6/2 mice showed a progressive loss of body weight,
compared with littermate controls. In our study this was not until 12 weeks of age, nearly 2 months after motor deficits were first observed.
Therefore the motor deficits reported here cannot be attributed to loss
of body weight. This suggests that the onset of motor symptoms is a
consequence of the transgene rather than changes in body weight. It is
interesting that although they developed the overt neurological
phenotype at a similar time, mice in our colony in Cambridge began to
lose weight nearly 4 weeks later than reported previously (Davies et al., 1997). Because their genetic background is the same as the original colony, we attribute the differences between the two colonies
to changes in husbandry of our colony resulting in improved access to
food and water.
Between 8 and 14 weeks of age, the performance of R6/2 transgenic mice
in the swimming tank test worsened progressively. Performance on the
beam and rotarod also deteriorated over this time, with the mice taking
significantly longer to traverse all six beam types, exhibiting a
greater number of footslips, and failing to maintain balance on the
rotarod at all rotation speeds. Deficiencies in gait also became
apparent from 8 weeks of age. By 12 weeks these deficits were
pronounced; instead of walking in a straight line with evenly spaced
and accurately positioned footprints, R6/2 transgenic mice often weaved
from side to side, adopting staggering movements, irregularly spaced
shorter strides, and a gait that lacked a normal, uniform, alternating
left-right step pattern. Notably, these abnormalities were similar to
gait disturbances described in patients with HD (Koller and Trimble,
1985; Harper, 1996) and also in 3-NP treated rats (Guyot et al., 1997).
This latter observation is particularly interesting, because we have observed that the manner in which the R6/2 mice and 3-NP-treated rats
traversed the beams is also very similar (R. J. Carter and A. J. Morton, unpublished observations). Because 3-NP treatment is a
widely accepted model of the striatal pathology in HD, and the
behavioral changes shown by 3-NP-treated rats have been attributed to
selective striatal damage (Guyot et al., 1997), the striking similarities in the motor deficits of 3-NP-treated rats and R6/2 transgenic mice suggest that despite the absence of striatal neuronal loss, the motor deficits seen in R6/2 transgenic mice arise from striatal dysfunction.
R6/2 transgenic mice exhibited normal acoustic startle responses until
relatively late in the study when 12- to 13-week-old R6/2 transgenic
mice revealed a decline on both startle measures. In contrast, the
degree to which a prepulse inhibits the acoustic startle reflex was
significantly reduced in R6/2 transgenic mice at 8 weeks of age (at the
most sensitive, i.e., lowest, prepulse intensities). The impairment in
PPI in R6/2 mice increased with age, consistent with the progressive
impairment in PPI seen in patients with HD (Swerdlow et al., 1995). PPI
of the acoustic startle response has also been reported in rats after
quinolinic acid lesions of the striatum or systemic 3-NP treatment
(Kodsi and Swerdlow, 1995, 1997). Because the response of R6/2
transgenic mice to the basic acoustic startle only differed from that
of control mice at a relatively late age (and the analysis of PPI is
corrected for baseline level of startle), the loss of PPI in R6/2
transgenic mice is unlikely to be caused simply by a generalized muscular weakness but suggests that in R6/2 mice (as in humans) abnormalities in PPI are derived from sensorimotor deficits in the CNS.
There is at present no unequivocal neuropathological substrate for the
progressive deterioration in the motor performance of R6/2 transgenic
mice. Previous work has shown that although by 12 weeks of age the
brains of R6/2 transgenic mice weigh ~20% less than those of
wild-type control mice, there is no selective striatal cell loss
(Mangiarini et al., 1996; Davies et al., 1997). Recent studies,
however, show that R6/2 transgenic mice have neuropathological changes;
in particular they develop neuronal intranuclear inclusions (NIIs)
(Davies et al., 1997) and display a decreased expression of dopamine
(D1, D2) and mGluR1 receptor mRNA
in the striatum (Cha et al., 1998), from as early as 4-5 weeks of age.
Similar NIIs have been found in postmortem brains of patients with HD (Di Figlia et al., 1997), and postmortem changes in dopamine receptors in HD have been well documented (Harper, 1996). Thus, it seems possible
that the motor abnormalities we observed in R6/2 transgenic mice are
attributable to dysfunction of the striatum, despite the lack of
neuronal cell death in the striatum.
It is not yet known why neuronal loss is not seen in brains of R6/2
mice. The most likely explanation is that the early and sudden death of
these mice occurs before neuronal loss is evident. However, although at
first sight the lack of striatal neurodegeneration is a weakness of the
model, striatal dysfunction without cell death is also seen in HD. The
onset of motor symptoms in HD patients does not correlate well with
neuropathological grading, although this issue is complicated by the
enormous variation in the presentation of motor symptoms in HD.
Although few systematic studies relating clinical symptoms and
neuropathology in early stage HD have been performed, Meyers et al.
(1988) described five patients who died with clinical features of the
disease, including chorea and other involuntary movements, yet had no
discernible neuropathological abnormalities (Grade 0 pathology).
Notably, one of these patients had shown choreiform motor abnormalities
for 4 years before his death, yet still showed no neuronal loss. These
findings are similar to our findings in the mice and support the
suggestion that R6/2 transgenic mice may not only provide a relevant
genetic model of HD, but may also demonstrate a progressive
neurological phenotype that is directly comparable to that seen in
early HD.
Our study describes detailed motor and sensorimotor changes in R6/2
transgenic mice that progressively worsen with age and with test
difficulty. The quantifiable progression of these motor deficits makes
this R6/2 transgenic mouse model particularly suitable for assessing
the effectiveness of potential therapeutic agents and repair strategies
for treating the motor symptoms of HD. Moreover, this model of HD
offers a unique system in which the testing of experimental treatments
for HD can be performed even before an overt phenotype has developed.
Note
Since this work was submitted, we have become aware that diabetes
is present in R6/2 transgenic mice. We have tested the mice in
our colony and confirm that we have diabetic mice; indeed, diabetes is
common in R6/2 mice >14 weeks of age. However, we have found neither
elevated blood glucose nor urinary glucose to be present under a normal
feeding regime in mice <9 weeks of age. Furthermore, of the mice used
in this study, at 13 weeks only two of eight transgenic mice tested had
elevated blood glucose levels (14 mmol/l, 27.8 mmol/l) and glucose in
the urine (14 mmol/l, 27.8 mmol/l). The remaining six mice had normal
plasma glucose levels (4-8 mmol/l) and no glucose in their urine.
Therefore, during the critical testing period (5-10 weeks of age) in
our study, we believe that any deleterious effects that might be
associated with diabetes are unlikely to have contributed to the
behavioral phenotype we observed in R6/2 mice.
| |
FOOTNOTES |
Received Nov. 13, 1998; revised Jan. 26, 1999; accepted Feb. 8, 1999.
This work was supported by grants from the Hereditary Disease
Foundation and the Wellcome Trust (UK). R.J.C. is supported by the
Medical Research Council (UK); L.A.L. is supported by Parke-Davis Neuroscience Research (UK). We are grateful to Chris Riches for valuable technical assistance.
R.J.C. and L.A.L. contributed equally to this work.
Correspondence should be addressed to Dr. Jenny Morton, Department of
Pharmacology, University of Cambridge, Tennis Court Road, Cambridge,
CB2 1QJ, UK.
| |
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TOP
ABSTRACT
INTRODUCTION
