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The Journal of Neuroscience, May 1, 1998, 18(9):3470-3479
Locomotor Activity in D2 Dopamine Receptor-Deficient Mice Is
Determined by Gene Dosage, Genetic Background, and Developmental
Adaptations
Michele A.
Kelly1, 2,
Marcelo
Rubinstein1,
Tamara
J.
Phillips3, 5,
Christina N.
Lessov3,
Sue
Burkhart-Kasch3,
Ge
Zhang4,
James R.
Bunzow4,
Yuan
Fang4,
Gregory A.
Gerhardt6,
David K.
Grandy4, and
Malcolm J.
Low1
Oregon Health Sciences University, 1 Vollum Institute,
Departments of 2 Cell and Developmental Biology,
3 Behavioral Neuroscience, and 4 Physiology
and Pharmacology, Portland, Oregon 97201, 5 Veterans
Affairs Medical Center, Portland, Oregon 97201, and
6 Department of Psychiatry, University of Colorado Health
Sciences Center, Denver, Colorado 80262
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ABSTRACT |
Locomotor activity is a polygenic trait that varies widely among
inbred strains of mice (Flint et al., 1995 ). To characterize the role
of D2 dopamine receptors in locomotion, we generated F2
hybrid (129/Sv × C57BL/6) D2 dopamine receptor (D2R)-deficient mice by gene targeting and investigated the contribution of genetic background to open-field activity and rotarod performance. Horizontal activity of D2R / mice was approximately half that of drug-naive, strain-matched controls but was significantly greater than
haloperidol-treated controls, which were markedly hypokinetic.
Wild-type 129/SvEv and C57BL/6 mice with functional D2 receptors had
greater interstrain differences in spontaneous activity than those
among the F2 hybrid mutants. Incipient congenic strains of
D2R-deficient mice demonstrated an orderly gene dosage reduction in
locomotion superimposed on both extremes of parental background
locomotor activity. In contrast, F2 hybrid D2R/ mice
had impaired motor coordination on the rotarod that was corrected in
the congenic C57BL/6 background. Wild-type 129/SvEv mice had the
poorest rotarod ability of all groups tested, suggesting that linked
substrain 129 alleles, not the absence of D2 receptors per se, were
largely responsible for the reduced function of the F2
hybrid D2R/ and D2R+/ mice. Neurochemical and pharmacological
studies revealed unexpectedly normal tissue striatal monoamine levels
and no evidence for supersensitive D1, D3, or D4 dopamine receptors in
the D2R/ mice. However, after acute monoamine depletion, akinetic
D2R+/ mice had a significantly greater synergistic restoration of
locomotion in response to SKF38393 and quinpirole compared with any
group of D2R+/+ controls. We conclude that D2R-deficient mice are not a
model of Parkinson's disease. Our studies highlight the interaction of
multiple genetic factors in the analysis of complex behaviors in gene
knock-out mice.
Key words:
D2 dopamine receptor; genetics; locomotor activity; C57BL/6 mice; 129/SvEv mice; dopamine; rotarod; gene knock-out mice
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INTRODUCTION |
Locomotor activity requires the
coordinated actions of cortical and subcortical structures (for review,
see Hikosaka 1991; Graybiel 1991; Mink and Thatch, 1993). The
basal ganglia, composed of corpus striatum, globus pallidus,
subthalamic nucleus, and substantia nigra (SN), play an important role
in modulating the final output of cortical motor neurons. The SN pars
compacta is the major source of ascending dopaminergic input to the
dorsal striatum. Striatal GABAergic neurons express dopamine receptors that belong to either the family of D1-like receptors (D1 and D1B)
linked positively to adenylyl cyclase or to the D2-like receptors (D2,
D3, and D4) that are inhibitory to adenylyl cyclase or coupled to
G-protein-activated ion channels (Civelli et al., 1993; Gingrich and
Caron; 1993, Sibley et al., 1993). Although in situ
hybridization studies indicated that largely segregated populations of
medium spiny neurons express the D1 and D2 receptors (Graybiel, 1991; Le Moine and Bloch, 1995), more recent work using mRNA amplified from
single cells demonstrated a high degree of overlap between D1- and
D2-like receptors (Surmeier et al., 1996).
Despite the differences in signal transduction mechanisms, the
contribution of D1- and D2-like receptors to locomotion through the
direct and indirect striatopallidal projections is generally considered
synergistic. Hypokinesia or akinesia can be induced pharmacologically
in the mouse by antagonists of either the D1-like (Rubinstein et al.,
1988; Cabib et al., 1991) or D2-like receptors (Fujiwara, 1992).
However, none of the available drugs has complete specificity for any
of the five known dopamine receptor subtypes. Administration of D2
antisense oligodeoxynucleotides to rats (Zhang and Creese, 1993) or
mice (Zhou et al., 1994) caused only a partial reduction in striatal D2
receptors but reduced spontaneous locomotor activity. Acute monoamine
depletion studies have demonstrated that stimulation of both D1- and
D2-like receptors is necessary for significant reversal of the
resulting akinesia (Jackson and Hashizume, 1986; Starr et al., 1987;
Rubinstein et al., 1988; Zarrindast and Eliassi 1991; Ferré et
al., 1994). In contrast, selective functional loss of the dopamine D1
receptor by gene targeting was reported to cause either an increase in
baseline activity (Xu et al., 1994) or no alteration in locomotion
(Drago et al., 1994). Much less is known about the contribution of the remaining dopamine receptor subtypes to locomotion or their capacity to
compensate functionally for the more abundant D1 and D2 receptors, although gene deletion studies (Accili et al., 1996; Xu et al., 1997)
and experiments using D3-preferring antagonists (Svensson et al., 1994)
indicated that the D3 subtype may be predominantly inhibitory. Our
laboratory also inferred a predominantly inhibitory role for the D4
subtype on spontaneous locomotion from a gene deletion study
(Rubinstein et al., 1997).
To investigate the selective physiological role of the D2 dopamine
receptor in locomotor activity, we have produced mice that lack
functional D2 receptors by gene targeting in embryonic stem cells
(Kelly et al., 1997). The following questions were addressed in the
present study. What are the specific components of locomotion that are
altered by the absence of D2 receptors? What is the contribution of
gene dosage at the D2 receptor locus to locomotion? What is the
interaction of the null mutation at the D2 gene locus and genetic
background on locomotion? Are there identifiable adaptations in other
molecular components of the nigrostriatal dopaminergic circuits in mice
lacking D2 receptors? Our results from a combination of behavioral,
neurochemical, and pharmacological assays emphasize the critical
contribution of genetic background to analysis of a complex phenotype
in the gene-targeted mice.
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MATERIALS AND METHODS |
D2 receptor-deficient mouse strains
The original F2 hybrid strain (129/Sv × C57BL/6J) containing the mutated D2 receptor allele was generated in
our laboratory as described previously (Kelly et al., 1997). To
establish an incipient congenic B6 strain, D2 dopamine receptor
(D2R)+/ mice were backcrossed to wild-type C57BL/6J for five
generations. The sex of the +/ mice was alternated between male and
female for each successive generation. After the fifth generation
backcross, the colony was expanded by inbreeding pairs of nonsibling
+/ male and female mice (all parents were N5,
making all pups N5 equivalents), and each mouse was
genotyped by Southern blot as described (Kelly et al., 1997). The
129/Sv strain mice that the D3 embryonic stem (ES) cells (Doetschman et
al., 1985) were derived from are no longer commercially available.
Therefore, to establish a substrain 129 line of mutant mice, the
original male chimeras derived from the gene-targeted ES cells were
bred to closely related wild-type 129/SvEvTac females (Simpson et al.,
1997) to produce substrain 129+/ mice. The colony was then expanded
as above. For simplicity these lines of mutant mice are referred to as
congenic B6 and congenic 129 in this report. Wild-type C57BL/6J mice
were obtained from The Jackson Laboratory (Bar Harbor, ME), and
129/SvEvTac mice were obtained from Taconic (Germantown, NY). Mice were
fed on the floors of the cages to assure easy access to food.
Approximately equal numbers of mice of both sexes were used for all
experiments, and the data collapsed across gender if the statistical
analyses revealed no gender interaction within a particular
measurement.
Assessment of postnatal development
F2 hybrid +/ mice were bred, and the resultant
pups were assessed from birth through postnatal day 20 when they were
weaned. Physical measurements were recorded daily, including weight,
eye opening, and pinnae opening. The righting reflex was assessed by
placing each pup on its back and timing the return to the upright position. The ages at which each pup was first observed to perform a
variety of locomotor skills, including crawling, walking, rearing, and
running, were also recorded. Video recordings of these same mice both
as young pups and as adults were made.
Neurochemical assays
D1 receptor saturation binding was performed on striatal
membranes (30-50 µg of protein) using the D1-selective antagonist [3H]SCH23390 (specific activity, 81.4 Ci/mmol;
DuPont NEN, Boston, MA) as a radioligand (Zhou et al., 1990) by methods
described previously (Bunzow et al., 1995; Zhang et al., 1996). The
saturation data were analyzed through a nonlinear regression fit of a
hyperbolic equation using Graph Pad (San Diego, CA) InPlot
software.
D1 receptor autoradiography was performed on 15 µm cryostat brain
sections using 1 nM [3H]SCH23390 in
the presence of 100 nM ketanserin to block 5-HT2 receptor
binding, as described in previous reports (Mansour et al.,
1990; Janowsky et al., 1992; LaHoste and Marshall, 1992). Nonspecific
binding was demonstrated on a separate set of slides by the addition of
5 µM (+)-butaclamol, a nonselective dopamine receptor
ligand.
Monoamines and their metabolites were determined using the methods
described previously by Hall et al. (1989). All tissue levels of these
compounds were determined as nanograms per gram wet weight of
tissue.
Measurement of locomotor activity
Omnitech Digiscan (Columbus, OH) model CCDIGI activity monitors
were used to quantify horizontal activity and rearing. All experiments
were performed between 8:00 A.M. and 4:30 P.M. using animals maintained
on a 12 hr light/dark cycle from 6:00 A.M. to 6:00 P.M. The 40 × 40 cm open-field chambers were enclosed in soundproof boxes that were
in turn enclosed in a quiet room separated from the colony area.
Horizontal distance was measured by the sequential breaking of infrared
beams, 5 cm on center, in the horizontal plane of the x- and
y-axes. Initiation of movement was incremented each time a
break in ambulatory activity occurred for >1 sec. Movement time was
incremented when a mouse was active for >1 sec. The average speed of
movement was obtained by dividing total horizontal distance by total
time in motion for each mouse in the 30 min testing period. Rearing
movements were counted each time an animal passed above and then below
the level of a sensor in the z-axis vertical plane (the
mouse must have remained below the level of a sensor for at least 1 sec
before it could score again).
Pharmacological experiments
Experiment 1. Mice were injected with either saline
or 0.3 or 0.6 mg/kg haloperidol (McNeil Pharmaceutical Co., Fort
Washington, PA), placed in a holding cage for 15 min, and then tested
in the open-field apparatus for 30 min. All drug treatments in
experiments 1 and 2 were administered intraperitoneally in a volume of
10 ml/kg.
Experiment 2. Drug-naive mice were pretested in an
open-field chamber for 15 min the day before the experiment to
habituate them to the apparatus. The day of the experiment, mice were
retested for 30 min to ascertain their pretreatment activity levels.
All animals were then depleted of monoamines by treatment with 200 mg/kg  -methyl-(dl)-p-tyrosine methyl
ester (AMPT) (Sigma, St. Louis, MO) followed 1 hr later by 5 mg/kg
reserpine (Sigma). One hour after reserpine treatment animals received
a second lower dose of 100 mg/kg AMPT. Similar regimens have been
documented to precipitously drop dopamine, norepinephrine, and to a
lesser extent, 5-HT levels (Starr et al., 1987). A total of 3 hr after the first AMPT dose, animals were tested in the open field for 30 min
to determine their monoamine-depleted activity levels. Mice were then
divided within genotype into three groups: saline, 6 mg/kg SKF38393, or
12 mg/kg SKF38393 (Research Biochemicals, Natick, MA) and received this
dose immediately before being placed in the open field for 1 hr. After
this 1 hr drug-treated trial, each group was retreated with its
original dosage of SKF38393 and the addition of 2 mg/kg quinpirole
(Research Biochemicals), except the saline group, which again received
saline. The animals were immediately returned to the open field for a
final 1 hr monitoring period and then killed by inhalation of
CO2. Four mice were dropped from the study (depletion
failures) because they scored >20% of their premonoamine depletion
distance and were >2 SD from the mean percentage scored by their
respective group. These four mice consisted of one each
F2+/, F2/, and wild-type parental
strains.
Rotarod test
Animals were placed in a neutral position on a stationary
6-cm-diameter cylinder. After 3 sec the rotarod was switched on to a
speed of 4 rpm, and the mice were timed until they fell from the
rotarod (or a maximum cutoff time of 120 sec). Mice that attained a
score of 120 sec were removed from the rotarod and returned to their
home cages; mice that fell were restarted for a total of three
consecutive trials per day for 4 d. Mice that could not remain on
the stationary cylinder for three trials scored zero. The highest of
the individual scores of each animal on each day were used for
analysis.
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RESULTS |
D2 receptor-deficient mice achieved age-appropriate
developmental milestones
All three genotypes of mice on the F2 hybrid
background grew normally from birth, with no differences in birth
weights and postnatal development, assessed by the timing of eye
opening or pinnae opening. Additionally, there were no differences
among the three genotypes in their age of acquisition of basic motor skills including the righting reflex, walking, running, rearing, and
grasping before weaning (data not shown). The mice had no tremor or
ataxia and did not display an abnormal stance or posture when assessed
directly in an open-field test or when the same test was reviewed on
videotape by observers blind to genotype (data not shown).
D2 receptor-deficient mice had decreased initiation of
spontaneous movement
Preliminary experiments demonstrated that both adult
F2/ mice and wild-type 129/SvEv mice displayed impaired
motor function relative to wild-type C57BL/6 mice. Consequently, we
performed a comprehensive analysis of spontaneous locomotor activity in an open-field on groups of drug-naive mice representing both parental strains as well as the three D2 receptor genotypes of F2
hybrid (129/Sv × C57BL/6) mice. Independent measures included
total horizontal distance traveled, number of initiations of movement,
total time spent in motion, and number of rearing events. The mice
ranked in order for total horizontal distance from high to low:
C57BL/6, F2+/+, F2+/, F2/,
and 129/SvEv (Fig. 1A).
The individual scores for each mouse were plotted on a frequency
histogram and showed five discreet populations with normal
distributions and a nearly complete lack of overlap between the
parental strains (Fig. 1B). Within each group of mice
there was a similar temporal pattern of habituation to the novel
environment of the open-field as demonstrated by higher activity counts
in the first time blocks compared with the later blocks (Fig.
1C). A statistical analysis demonstrated significant
differences by genotype or parental strain in several measures. ANOVA
(F(4,175) > 34; p < 0.0001)
followed by Tukey post hoc tests revealed that horizontal
distance, initiation of movement, time in motion (data not shown), and
number of rearing events (data not shown) were lower in
F2/ mice and wild-type 129/SvEv mice compared with
F2+/+ and wild-type C57BL/6 mice (p < 0.0001 for each comparison). F2+/ mice also had
significantly lower scores in these measures than F2+/+ or
wild-type C57BL/6 mice (p, <0.03-0.0001). Only
wild-type C57BL/6 mice had greater speed of movement than the other
groups (data not shown). The differences in horizontal distance
traveled could be attributed mostly to the differences in the absolute
number of movement epochs initiated by each genotype or strain (Fig.
1A). An ANOVA limited to the wild-type 129/SvEv and
F2/ mice demonstrated that the F2/ mice
actually had significantly higher scores for horizontal distance
(F(1,70) = 4.75; p = 0.03), time
spent in motion (F(1,70) = 5.47;
p = 0.02), and rearing (F(1,70) = 4.39; p = 0.04), but not initiation of movement.
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Figure 1.
Locomotor activity in drug-naive
F2 hybrid D2 receptor mutant mice and the wild-type
parental strains. A, Total horizontal distance traveled
(left) and initiation of movement (right)
over 30 min in a novel open field. Data are mean ± SEM.
White bars, Wild-type 129/SvEv (n = 35); gray bars, F2/
(n = 36); diagonal right bars,
F2+/ (n = 36); diagonal left
bars, F2+/+ (n = 37); and
black bars, wild-type C57BL/6 (n = 32). For statistical comparisons, see Results. B,
Frequency distribution histogram of total horizontal distance. The
fraction of each group scoring within a specified range is plotted. Bin
width is 1500 cm, such that the first bin represents mice scoring from
0 to 1500 cm centered on 750 cm. Groups of mice are the same as in
A. C, Time course of horizontal activity
in the open field during 30 min. Data are plotted as distance
traveled ± SEM in each time block of 5 min. p < 0.0001; F2/ compared with F2+/+ mice,
ANOVA followed by Tukey post hoc analysis. Open
squares, Wild-type 129/SvEv; open circles,
F2/; shaded triangles,
F2+/; shaded squares, F2+/+;
open triangles, wild-type C57BL/6.
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Because there were greater differences in every measure of locomotor
activity between the two wild-type parental strains than among the
F2 mice with varying numbers of D2 receptors, we produced congenic 129 and B6 strains of D2 receptor-deficient mice to better assess the contribution of the single gene product to a polygenic complex behavior. Locomotor activity measurements for the three D2
receptor genotypes on both congenic backgrounds are shown in Figure
2. Because of the passage of time and
seasonal differences in animal activity levels a direct comparison with
the data in Figure 1 is not appropriate; however, the overall rank
orders for total horizontal distance, rearing, and initiation of
movement were clearly unchanged. The B6 congenic / mice had
significantly lower scores for total horizontal distance
(p < 0.0001; ANOVA followed by Tukey post
hoc tests), initiation of movement (p < 0.0001), rearing (p < 0.0001), and duration of
horizontal movements (p < 0.0002) compared with
their +/+ siblings. The B6 congenic +/ mice also demonstrated reduced
total horizontal distance (p < 0.002) and
rearing (p < 0.001) compared with their +/+
siblings.
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Figure 2.
Locomotor activity in congenic 129 and B6 strains
of D2 receptor mutant mice. A, Total horizontal distance
traveled. B, Initiation of movement. C,
Vertical rears in 30 min by drug-naive mice in an open field. Data are
mean ± SEM. 129/, n = 9 (gray bars); 129+/, n = 20 (striped bars); 129+/+, n = 16 (black bars); B6/, n = 16 (gray bars); B6+/, n = 36 (striped bars); B6+/+, n = 19 (black bars). For statistical analysis see
Results.
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There were significant deficits in total horizontal distance
(p < 0.03; ANOVA followed by Tukey post
hoc tests) and initiation of movement (p < 0.0013) in 129 congenic / mice compared with 129 congenic +/+
siblings, whereas the +/ mice had a significant decrease only in
total horizontal distance (p < 0.05) when
monitored in a novel open-field environment. No significant differences were found in the number of rears of the three sibling groups. For both
sets of congenic mice, like the F2 mice, the D2 receptor genotype differences in total horizontal distance traveled can be
attributed primarily to differences in the initiation of movement and
not duration or speed of movement (data not shown).
Locomotion in D2 receptor-deficient mice was not affected
by haloperidol
To further assess the involvement of the D2 receptor and
contribution of genetic background to the multiple components of locomotor activity, mice of all five groups were treated acutely with
0.6 mg/kg haloperidol, a D2-like receptor antagonist.
F2+/, F2+/+, wild-type 129/SvEv, and
wild-type C57BL/6 mice demonstrated a drug-dependent decrease in many
locomotor parameters (Table 1). In marked
contrast to the other four groups, F2 D2R/ mice treated
with haloperidol were unchanged in all measured parameters. Total
horizontal distance scores for all other groups of mice treated with
haloperidol were actually significantly lower than the scores of
D2R/ mice (p < 0.0007; ANOVA followed by
Tukey post hoc tests). A 0.3 mg/kg haloperidol treatment
produced quantitatively smaller changes in all groups and also had no
effect on the F2/ mice (data not shown).
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Table 1.
Effects of haloperidol on locomotor activity in the
F2 hybrid D2 receptor mutant mice and the wild-type
parental strains
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The dose-dependent effects of haloperidol on locomotion in 129/SvEv
mice suggest that the low spontaneous activity in this strain is not
attributable to a coincidental absence of functional D2 dopamine
receptors. 129/SvEv mice also had significant increases in serum
prolactin secreted from the anterior pituitary gland in response to
haloperidol (data not shown) and had similar D2 binding sites on
striatal membranes compared with wild-type C57BL/6 mice measured by
saturation ligand binding to [3H]nemonapride as
described previously (Kelly et al., 1997). The Bmax was 347 ± 19 or 303 ± 5 fmol/mg
protein, and the Kd was 44 ± 11 or 37 ± 9 nM in 129/SvEv and C57BL/6 mice, respectively.
Functional D2 receptors did not correlate with
rotarod performance
The ability to balance and walk on a rotating cylinder is a test
of coordinated motor skills. Both F2/ mice and
wild-type 129/SvEv mice performed very poorly on the rotarod test with
little improvement over the four consecutive days of trials (Fig.
3A). ANOVA of the mean scores
by genotype on day 4 demonstrated that each of these two groups
differed significantly (p < 0.05, Tukey post hoc analysis) from F2+/,
F2+/+, and wild-type C57BL/6 mice. However, a frequency
histogram of the individual maximum scores revealed that the
F2+/ mice actually segregated into two distinct performance level populations (Fig. 3B): low performers
similar to wild-type 129/SvEv mice and high performers similar to
wild-type C57BL/6 mice. Rotarod score distributions of the other four
groups of mice were all consistent with single populations.
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Figure 3.
Rotarod testing of mutant mice and parental
strains. A, Rotarod performance in the F2
hybrid D2 receptor mutant mice and the wild-type parental strains. Data
are the maximal scores ± SEM on individual test days for each
group of mice. Open squares, Wild-type 129/SvEv
(n = 15); open circles,
F2/ (n = 18); shaded
triangles, F2+/ (n = 43);
shaded squares, F2+/+ (n = 31); open triangles, wild-type C57BL/6
(n = 15). B, Frequency distribution
histogram of maximal scores on day 4 of testing in the F2
D2 receptor mutant mice and the wild-type parental strains. The
fraction of each group from A scoring within a specified
range is plotted. Bin width is 20 sec, such that the first bin
represents mice scoring from 0 to 20 sec centered on 10 sec.
White bars, Wild-type 129/SvEv; gray
bars, F2/; diagonal right bars,
F2+/; diagonal left bars,
F2+/+; black bars, wild-type C57BL/6.
C, Rotarod performance in the B6 congenic strain of D2
receptor mutant mice. Data are maximal scores ± SEM on individual
test days for each group of mice. Open circles, B6/
(n = 17); shaded triangles, B6+/
(n = 49); shaded squares, B6+/+
(n = 20). B6/ mice scored significantly lower
than both other genotypes on days 2 and 3 but were indistinguishable
from them by day 4 (see Results).
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Because it was difficult to reconcile the unexpected finding of a
bimodal distribution of rotarod scores in the F2+/ mice with the unimodal distributions of spontaneous locomotor scores and the
50% reduction in D2 receptor sites compared with F2+/+ mice determined by saturation ligand binding (Kelly et al., 1997) (data
not shown) in the same group, we postulated that other polymorphic loci
between the substrain 129 and C57BL/6 parental strains of the
F2 hybrid mice might explain these data. Therefore we
repeated the rotarod study using congenic B6 mice carrying the mutated D2 receptor alleles. Congenic 129 mice were not tested because of the
floor effect already present in the wild-type 129/SvEv strain on this
test. The rotarod performance over 4 d of trials among the three
genotypes of congenic B6 mice differed markedly from the F2
hybrid mice (Fig. 3C). All the congenic B6 mice had similar
low scores on the first day of trials. On the second and third days the
/ mice scored significantly lower (p < 0.0001; ANOVA followed by Tukey post hoc tests) than both
+/+ and +/ siblings. The / mice, assessed within subjects, had
improved on days 2 and 3, and by day 4 they attained final performance scores indistinguishable from both +/+ and +/ congenic B6 siblings. Although the B6 congenic / mice learned how to avoid falling from
the rotarod with repeated trials, it was apparent from direct observation that they were never as facile at the task as their siblings with functional D2 receptors. Their qualitative behavior was
also very different from that of wild-type 129/SvEv mice, which
seemingly made no attempts at all of walking forward when the cylinder
began to rotate.
Adaptations of the nigrostriatal dopaminergic pathway in D2
receptor-deficient mice
Adult mutant mice lacking D2 dopamine receptors throughout
development consistently maintained ~50% of the spontaneous
locomotor activity of their strain-matched control siblings, moved with the same speed and duration as +/+ mice, and were significantly more
mobile than +/+ mice treated acutely with a relatively D2R-selective dose of haloperidol. This degree of locomotor impairment was not obvious on casual observation of the D2R/ mice and did not impose a
disability on the homozygous mutant mice in their controlled laboratory
environment. Therefore we hypothesized that some compensatory mechanism
was contributing to their relative normalcy.
One possibility was an increased production or turnover of dopamine in
the striatum and SN as a result of the loss of D2 autoreceptors. The
tissue content of dopamine and its metabolites, serotonin, 5-hydroxyindole-acetaldehyde, and norepinephrine were measured in the
dorsal striatum (Table 2) and SN (data
not shown) from congenic B6 mice of all three genotypes. Strikingly, no
significant differences were found in any of these measurements in
either anatomic location among genotypes.
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Table 2.
Tissue content of monoamines and their metabolites in
striatum from the B6 congenic strain of D2 receptor mutant mice
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We also characterized D1 receptor binding-sites in dorsal striatum from
the mutant mice by saturation ligand binding (Fig. 4). These data demonstrated that there
was a significant 20% decrease in Bmax
[273 ± 5 vs 345 ± 15 fmol/mg protein
(F(2,12) = 4.89; p < 0.05)],
but no change in Kd (0.27 ± 0.05 vs
0.32 ± 0.05 nM) between / and +/+ mice,
respectively. Autoradiography using [3H]SCH23390
revealed no qualitative, regional differences in the distribution of D1
binding sites in the brains of D2/ mice (Fig. 5), including ventral striatum and
frontal cortex.
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Figure 4.
Saturation binding of
[3H]SCH23390 to striatal membranes from the B6
congenic strain of D2 receptor mutant mice. Representative data were
derived from an experiment performed in duplicate, and similar results
were obtained from repeated experiments. Inset,
Scatchard plot of transformed saturation data.
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Figure 5.
Autoradiographic localization of D1 receptor
binding sites using [3H]SCH23390. Anatomically
matched sections including striatum, nucleus accumbens, and olfactory
tubercle from F2 hybrid D2 receptor +/+ (A,
B) and F2 hybrid / (C, D) mice
were incubated with 1 nM [3H]SCH23390
and 100 nM ketanserin. Nonspecific binding was revealed by
the addition of 5 µM (+)butaclamol (B,
D).
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To determine whether the locomotor compensation present in adult D2
receptor-deficient mice involved a functional supersensitivity of
D1-like receptors, changes in the D3 or D4 receptors, or pathways using
monoamines other than dopamine, we performed the following experiment.
Reserpine and AMPT treatment produced akinesia in all mice
Catecholamines and other monoamines were depleted from presynaptic
terminals using a combination of reserpine (a monoamine secretory
vesicle-depleting agent) (Hornykiewicz, 1966; Fujimiya et
al., 1994) and AMPT (a selective inhibitor of tyrosine hydroxylase activity) (Rubinstein et al., 1988). All five groups of mice (wild-type 129/SvEv, F2/, F2+/, F2+/+,
and wild-type C57BL/6) displayed significant decreases
(F(1,171) > 33; p < 0.0001)
within subjects in horizontal distance traveled compared with their
pretreatment levels (Fig. 6). An ANOVA
showed that the monoamine-depleted horizontal distance scores for
129/SvEv, F2/, F2+/, F2+/+
mice were significantly different from each other
(F(4,170) = 2.82; p = 0.03).
However, F2/ mice were only slightly more active than
the C57BL/6 mice (p < 0.05 by Tukey post
hoc test). These data suggest that functional monoaminergic
pathways are essential for the D2 receptor-deficient mice to maintain
their basal level of locomotor activity.
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Figure 6.
Reversal of monoamine depletion-induced akinesia
by D1-like and D2-like agonists in the F2 D2 receptor
mutant mice and the wild-type parental strains. Groups of
monoamine-depleted animals (see Materials and Methods) were treated
with either saline or 6 or 12 mg/kg SKF38393 and then assessed for 60 min in the open field apparatus. These data are represented by the
first three white bars for each group. In the next
section of the experiment the same groups of mice were retreated with
saline (data not shown because there was no change) or a combination of
SKF38393 and 2 mg/kg quinpirole. The latter data are represented by the
two striped bars for each group. All data are total
horizontal distance ± SEM; n, 8-10 per treatment
group for each genotype or parental strain. *Significantly higher than
all other groups for this dose (p < .0001).
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Monoamine-depleted D2/ mice responded to a D1-like agonist
The ability of mice lacking D2 receptors to move could be mediated
solely by the remaining D1 receptors. To address this question we
attempted to reverse the monoamine depletion-induced akinesia with
SKF38393, a D1-like selective receptor agonist (Setler et al., 1978).
Mice were injected with either saline or 6 or 12 mg/kg SKF38393 and
then placed immediately in the open-field apparatus for 1 hr. Analysis
of the total horizontal distance traveled revealed that there was a
significant genotype effect (F(4,170) = 10.23; p < 0.0001), with D2R/ mice scoring higher than
all other groups in response to SKF38393 and a treatment effect
(F(2,170) = 4.30; p = 0.015)
such that locomotor activity across genotypes was slightly stimulated
by either dose of SKF38393 compared with saline administration (Fig.
6). However, there was no significant genotype by drug interaction, perhaps because of the slightly higher baseline activity in the /
mice after monoamine depletion. An analysis of covariance using the
same data also failed to reveal a significantly greater response in the
D2R/ mice. These findings argue against D1 receptor supersensitivity as the major compensatory mechanism in the D2 receptor-deficient mice.
Monoamine-depleted D2/ mice did not respond to a
D2-like agonist
Because SKF38393 alone restored only a very small portion of
the original activity levels, we attempted a more complete reversal of
the akinesia with a combination of SKF38393 and quinpirole, a D2-like
receptor agonist (Koller et al., 1987). A preliminary experiment had
shown that 2 mg/kg quinpirole alone had no stimulatory effect on the
locomotion of monoamine-depleted mice (data not shown). After the
initial SKF38393 or saline injection trial, the same groups of mice
were treated with their original SKF38393 dosage combined with 2 mg/kg
quinpirole. Mice were then returned to the open-field apparatus for a
second 1 hr period of monitoring. A comparison of the total horizontal
distances scored after SKF38393 alone to the scores attained after
SKF38393 and quinpirole, revealed that wild-type 129/SvEv,
F2+/, F2+/+, and wild-type C57Bl/6 mice all
increased significantly (F(1,59) > 9.36;
p < 0.003). In contrast, the F2/ mice
had no additional response to the combination of drugs. Unexpectedly,
the F2+/ mice scored significantly higher (p < 0.0001 by Tukey post hoc tests)
for total horizontal distance measured compared with all other groups
at the lower (6 mg/kg) dose of SKF38393 plus quinpirole. A time course
of the locomotor stimulatory action of the combined D1-like and D2-like
agonists emphasizes the dramatic synergistic effect in the
F2+/ mice compared with all other groups (Fig.
7) and suggests that the differences in
total horizontal distance shown in Figure 5 were underestimated by
limiting the activity trial to 1 hr. A two-factor ANOVA comparison of
saline and both doses of SKF38393 plus quinpirole revealed significant
effects of genotype (F(4,170) = 19.8;
p < 0.0001), treatment
(F(2,170) = 53.11; p < 0.0001),
and a gene × drug treatment interaction
(F(8,170) = 5.97; p < 0.0001).
The saline groups were lower than quinpirole combined with either dose
of SKF38393 (p < 0.0001 by Tukey post
hoc test). Only mice with two functional D2 receptor alleles
showed a trend toward a greater response when given the combination of
the higher dose SKF38393 and quinpirole, suggesting that the +/ mice
had plateaued at their maximal possible response at the lower dose of
SKF38393. The control groups of monoamine-depleted mice of all
genotypes treated repeatedly with saline showed no spontaneous
recovery, whatsoever, of locomotor activity in the course of the
experiment.
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Figure 7.
Time course of locomotor recovery after the
combined administration of 6 mg/kg SKF38393 and 2 mg/kg quinpirole in
the F2 hybrid D2 receptor mutant mice and the wild-type
parental strains. Data are plotted as mean ± SEM of distance
traveled in each time block of 5 min. Drugs were administered at time
0. Open squares, Wild-type 129/SvEv; open
circles, F2/; shaded triangles,
F2+/; shaded squares, F2+/+;
and open triangles, wild-type C57BL/6.
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| |
DISCUSSION |
D2 receptor-deficient mice are not a model of
Parkinson's disease
Our data in the present experiments and a previous report (Kelly
et al., 1997) demonstrate that we have disrupted the D2 dopamine receptor gene in the mouse and confirm a role for the D2 receptor in
specific central components of locomotion: initiation of movement, time
spent in motion, and horizontal distance traveled. Rearing activity was
also strongly influenced by the D2 receptor. The absence of D2
receptors did not affect the speed of horizontal movement or
qualitatively alter the exploratory phase of locomotor activity in a
novel environment. Additionally, we observed no postural abnormalities,
catalepsy, tremor, or overt ataxia in the D2 receptor-deficient mice.
Therefore, other than the decreased initiation of movement, in most
respects the neurological syndrome of these mice differs considerably
from Parkinson's disease (Hornykiewicz, 1966); this finding is in
disagreement with the interpretation of Baik et al. (1995), who
analyzed an independently derived strain of F2 hybrid D2
receptor-deficient mice. It is not surprising that the presynaptic loss
of dopamine found in Parkinson's disease, or pharmacologically induced
by monoamine depletion, is associated with more profound neurological
deficits than the absence of a single subtype of dopamine receptor.
Acute antagonism of D2 receptors by haloperidol resulted in significant
decreases in the horizontal distance traveled, initiation of movement,
and time spent in motion for all genotypes except the D2
receptor-deficient / mice. Any possible antagonism of D3 (Freedman
et al., 1994) and/or D4 (Asghari et al., 1995) receptors by haloperidol
at the two doses used apparently had no net effect on locomotor
activity in the D2R/ mice. Rearing was also significantly decreased
by haloperidol, except in the D2R/ mice and wild-type 129/SvEv
mice, which exhibited virtually no basal rearing activity.
Gene dosage effects in heterozygotes
It is noteworthy that drug-naive and haloperidol-treated mice
heterozygous for the targeted D2 allele consistently demonstrated phenotypic measures that were intermediate to those of the +/+ and
/ mice. Scatchard analysis of [3H]nemonapride
binding indicated previously that the affinity of the D2 receptor for
this ligand was unchanged in +/ mice, but the total number of binding
sites was reduced by ~50% (Kelly et al., 1997). Therefore, it does
not appear that the loss of one allele and half of the receptor binding
sites caused a compensatory upregulation of the remaining normal
allele. If postsynaptic D2 receptors were present in excess on the cell
membrane it might be predicted that +/ mice with half the receptor
number would have no phenotype, but this was not the case. Therefore,
the decreased locomotor function displayed by +/ mice in this study
is consistent with a model for the nigrostriatal dopamine system that
includes no spare postsynaptic D2 receptors, similar to the conclusions drawn for the abundance of D2 receptors on pituitary lactotrophs (Meller et al., 1991). The D2 receptor +/ phenotype is also in agreement with antisense knock-down experiments in which moderate reductions in D2 receptors, as assessed by ligand-binding studies, led
to significant phenotypic effects (Zhang and Creese 1993; Zhou et al.,
1994; Silvia et al., 1994).
The decreased Bmax in the +/ mice may be
particularly relevant when considering dopamine transporter regulation,
downstream second messenger effectors, and regulation of dopamine
biosynthesis through dopamine D2R-like autoreceptors. We found no
evidence for altered dopamine biosynthesis in either the D2+/ or
/ mice based on the tissue content of dopamine and its major
metabolites. However, further studies of dopamine turnover and release
are warranted to more fully examine the issue of dopamine biosynthesis, particularly because recent studies provide little support for the
concept of compensatory D3 autoreceptors on SN dopamine neurons (Xu et
al., 1997). The unexpectedly high locomotor response of monoamine-depleted D2R+/ mice to the combined treatment by D1- and
D2-like agonists further emphasizes the importance of D2 receptor gene
dosage to motor function. The mechanism underlying this functional supersensitivity is unknown but probably occurs at a postreceptor level
and develops in response to continued dopamine signaling through a
chronically reduced number of D2 receptors. Further analyses of the
heterozygous mice may prove valuable in understanding the role of D2
receptor signaling in normal brain function and plasticity at
dopaminergic synapses.
Importance of genetic background in gene deletion experiments
Our study is a specific example of the importance of genetic
background in the evaluation of complex behavioral traits in mice
generated by targeted mutagenesis (Gerlai, 1996; Lathe, 1996; Banbury
Conference on Genetic Background in Mice, 1997). The vast majority of
gene knock-out experiments have used a diverse collection of ES cells
derived from substrain 129 mice (Simpson et al., 1997; Threadgill et
al., 1997), and the phenotypic analysis is often confined to
F2 hybrid mice derived by crossing the 129 ES cell-derived chimeras with another inbred strain, typically C57BL/6. This issue was
particularly germane in the present situation, because wild-type 129/SvEv mice with functional D2 receptors were a virtual phenocopy of
the predicted locomotor deficits caused by the loss of D2 receptors. In
particular, the 129/SvEv mice had markedly reduced scores for initiation of spontaneous movement, rearing, and rotarod performance compared with C57BL/6 mice. The low scores of the 129 parental strain
produced a floor effect confounding an interpretation of the
independent contribution of D2 receptors to the same measures. Therefore, a combined analysis of the parental strains and
congenic strains carrying the mutated D2 receptor allele was essential to discriminate between the phenotypes resulting from either the intentional mutation in the D2 receptor gene or other polygenic loci
contributed by the parental inbred strains (Flint et al., 1995).
This combined analysis revealed some surprising findings relevant to
motor coordination on a rotarod. Most wild-type 129/SvEv and
F2/ mice were unable to perform the rotarod test after
many trials, whereas wild-type C57BL/6 and congenic B6 D2R/ mice successfully learned to perform this task. Because the
F2/ mice have undergone only a small number of meiotic
crossover events on chromosome 9 (the location of the D2 receptor
gene Drd2 in mice), it is probable that many, but not all,
genes from the 129 parental chromosome 9 are still linked to the
targeted D2 receptor alleles, particularly in the differential segment
(Banbury Conference on Genetic Background in Mice, 1997). Consequently,
it is also probable that substrain 129 gene alleles other than
Drd2 are largely responsible for the poor rotarod
performance of F2/ mice and the bimodal distribution of
F2+/ mice scores. The fact that the congenic B6 D2R/
mice were able to learn the rotarod task, albeit with a lower aptitude
and a shallower learning curve than their siblings with intact D2
receptors, proves that the D2 receptor deficiency per se was not
responsible for the failure of the F2/ mice on the
rotarod, as concluded in a previous report (Baik et al., 1995). We
believe that a differential contribution of substrain 129 gene alleles
is the major reason for the apparent discrepancies in phenotypes
between that report and our own. By extension of these examples, it is
possible that background strain effects have influenced the
interpretation of other locomotor behavioral phenotypes described for
strains of mice with dopamine D1 and D3 receptor genes that have been
mutated by similar techniques (Xu et al., 1994; Drago et al., 1994;
Accili et al., 1996; Xu et al., 1997).
Developmental adaptations in D2 receptor-deficient mice
The net reduction in locomotor activity resulting from the chronic
absence of D2 dopamine receptors in the mutant mice was significantly
less than that induced by the acute pharmacological blockade of D2-like
receptors by haloperidol in wild-type mice, regardless of genetic
background. Therefore, we hypothesize that one or more adaptations have
occurred in the CNS of the mutant mice to account for their relatively
good locomotor function. D2/ mice were still dependent on the
function of monoaminergic neural circuits, because the combined
blockade of dopaminergic, serotoninergic, and catecholaminergic
synaptic activity with reserpine and AMPT produced akinesia.
Significant reversal of akinesia was readily accomplished in both
wild-type 129/SvEv and C57BL/6 mice by the simultaneous administration
of two subtype-selective, direct dopamine agonists, SKF38393 (D1 and
D1B) and quinpirole (D2, D3, and D4). Based on these observations, we
predicted that dopaminergic activation of the remaining D1, D1B, D3,
and D4 receptors in D2R/ mice would be sufficient to account for
their basal locomotor activity. If this prediction were true, the
combination of SKF38393 and quinpirole would have reversed the
reserpine-induced akinesia in D2/ mice. In fact, the D2/ mice
demonstrated only a small response to the D1-like agonist with no
additive or synergistic effect by the D2-like agonist, indicating that
the primary or sole adaptation in the D2/ mice is not the
upregulation of other components of central dopaminergic circuits.
There was actually a decrease in the number of D1 binding sites
assessed with a radiolabeled antagonist, similar to the downregulation
of D1 receptors in primate cortex, but not neostriatum, after chronic
treatment with D2-like receptor antagonists (Lidow et al., 1997). An
additional experiment with drug-naive mice administered 10 mg/kg of the
full D1R agonist SKF81297 also failed to demonstrate
D1R-supersensitivity, although the D2R/ mice responded to the
treatment with increased activity [60 min total horizontal distance
scores (mean ± SEM): saline-treated D2R/, 5824 ± 1278 cm; SKF-treated D2R/, 13,950 ± 1791 cm; saline-treated
D2R+/+, 9940 ± 682 cm; and SKF-treated D2R+/+, 20,730 ± 1329 cm].
Further studies are necessary to fully analyze the possible
contribution of nonD2 receptors and to determine the importance of
serotonin, catecholamine, or other nonmonoamine neurotransmitter systems in the compensatory mechanisms. One attractive hypothesis would
be a downregulation of adenosine A2A receptors that normally oppose the
function of dopamine D2 receptors at common postsynaptic sites
(Ferré et al., 1991; Svenningsson et al., 1997). In the future, a conditional gene-targeting system for the D2 receptor will
also clarify which adaptations to the absence of D2 receptors are
determined by irreversible organizational plasticity in the developing
brain and which occur activationally in the mature brain.
| |
FOOTNOTES |
Received Nov. 25, 1997; revised Feb. 13, 1998; accepted Feb. 19, 1998.
This work was supported by Public Health Service Grants DA07262
(M.A.K.), NS09199 (G.A.G.), AG06434 (G.A.G.), and DA09620 (D.K.G.), the
Department of Veterans Affairs (T.J.P.), Parke Davis Pharmaceuticals
(M.J.L.), and the Lucille P. Markey Charitable Trust (M.J.L. and
D.K.G.). We thank O. Rønnekleiv for assistance with D1 ligand
autoradiography, E. Johnston for help with behavioral studies, S. D. Dickinson for statistical analyses, and M. Geyer and N. Zahniser for
critical reading of this manuscript.
Correspondence should be addressed to Dr. Malcolm J. Low, Vollum
Institute, L474, Oregon Health Sciences University, 3181 Southwest Sam
Jackson Park Road, Portland, OR 97201.
Dr. Rubinstein's present address: Instituto de Investigaciones en
Ingeneria Genetica y Biologia Molecular, Consejo Nacional de
Investigaciones Científicas y Técnicas, University of
Buenos Aires, Argentina.
| |
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Top
Abstract
Introduction
