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The Journal of Neuroscience, July 1, 2000, 20(13):5115-5123
Abnormal Synaptic Plasticity and Impaired Spatial Cognition in
Mice Transgenic for Exon 1 of the Human Huntington's Disease
Mutation
Kerry P. S. J.
Murphy1,
Rebecca J.
Carter1,
Lisa A.
Lione2, 3,
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, CB2 1QJ, United Kingdom, and 5 Division of
Medical and Molecular Genetics, GKT School of Medicine, Guy's
Hospital, London SE1 9RT, United Kingdom
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ABSTRACT |
Huntington's disease (HD) is an autosomal dominant progressive and
fatal neurodegenerative brain disorder caused by an expanded CAG/polyglutamine repeat in the coding region of the gene.
Presymptomatic Huntington's disease patients often exhibit cognitive
deficits before the onset of classical symptoms. To investigate the
possibility that changes in synaptic plasticity might underlie
cognitive impairment in HD, we examined hippocampal synaptic plasticity
and spatial cognition in a transgenic mouse (R6/2 line) expressing exon
1 of the human Huntington's disease gene containing an expanded CAG
repeat. This mouse exhibits a progressive and fatal neurological phenotype that resembles Huntington's disease. We report that R6/2
mice show marked alterations in synaptic plasticity at both CA1 and
dentate granule cell synapses, and impaired spatial cognitive performance in the Morris water maze. The changes in hippocampal plasticity were age dependent, appearing at CA1 synapses several weeks
before they were observed in the dentate gyrus. Deficits in synaptic
plasticity at CA1 synapses occurred before an overt phenotype. This
suggests that altered synaptic plasticity contributes to the
pre-symptomatic changes in cognition reported in human carriers of
the Huntington' disease gene. The temporal and regional changes in
synaptic plasticity within the hippocampus mirror the appearance of neuronal intranuclear inclusions, suggesting a
relationship between polyglutamine aggregation and dysfunction.
Key words:
Huntington's disease; long-term potentiation; long-term
depression; hippocampus; cognition; intranuclear inclusions; NMDA
receptor
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INTRODUCTION |
Huntington's disease (HD) is one of
a family of neurodegenerative disorders attributable to an unstable CAG
trinucleotide repeat expansion within the open reading frame of the
gene (Paulson and Fischbeck, 1996 ). The age at onset of HD is
determined by the length of the CAG repeat expansion (Becher et al.,
1998). In humans the symptoms, which usually appear in the third to
fifth decades of life, often include an impairment of cognitive
function that can eventually lead to dementia (Harper, 1996). The
primary sites of neurodegeneration are the striatum and cerebral
cortex; however, in later stages of the disease, neuronal cell loss is also evident in other brain regions, including the hippocampus (Vonsattel et al., 1985; Folstein, 1990; Hedreen et al., 1991; Spargo
et al., 1993; Utal et al., 1998). There is now considerable evidence
that early cognitive impairment can appear in patients before the onset
of the classical symptoms (Mohr et al., 1991; Foroud et al., 1995;
Lange et al., 1995; Lawrence et al., 1996, 1998). Furthermore,
postmortem studies (Vonsattel et al., 1985) suggest that the first
symptoms (both motor and cognitive) appear in the absence of overt
neuronal cell loss, suggesting that impaired cognition is likely to be
caused by a cellular dysfunction rather than a consequence of neuronal
cell death.
Cognitive processes such as learning and memory are believed to depend
on changes in synaptic efficacy in certain key brain regions, including
the hippocampus (Bliss and Collingridge, 1993). To assess the
importance of hippocampal-dependent forms of learning and synaptic
plasticity in HD, we examined spatial cognition and the ability of
hippocampal synapses to support both long-term potentiation (LTP) and
long-term depression (LTD) in the R6/2 transgenic mouse. These mice
express the N-terminal portion of human huntingtin, containing a highly
expanded polyglutamine repeat (147-155), and develop a progressive
neurological phenotype similar to HD (Mangiarini et al., 1996). At
birth, R6/2 mice are indistinguishable from their littermate controls
and develop normally until ~8 weeks of age, at which point an overt
phenotype becomes discernible on home cage observation. Early
neurological signs include stereotypical hindlimb grooming, dyskinesia,
and an irregular gait. These abnormalities slowly become more evident
until by 12 weeks all animals are affected. The animals continue to
decline further and invariably expire suddenly by 16-18 weeks of age
(the cause of death is unknown). Although an overt phenotype was not
commonly seen until 8-9 weeks of age, more stringent motor testing has
revealed motor deficiencies from as early as 5-6 weeks (Carter et al.,
1999). Similarly, cognitive impairment can also be observed from as
early as 3-4 weeks of age (Lione et al., 1999).
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MATERIALS AND METHODS |
R6/2 transgenic mice. Mice were taken from a colony
established in the Department of Pharmacology, University of Cambridge. The line was maintained by backcrossing to CBA × C57BL/6 F1
animals. The present study used 66 hemizygotic transgenic mice and 72 littermate control mice from the 9th to the 16th generation. Genotyping
was confirmed by PCR (Mangiarini et al., 1996). Blood glucose levels were measured for some animals used in this study.
Hippocampal slice preparation and electrophysiology.
Transverse 400 µm hippocampal slices were prepared from animals aged between 4 and 18 weeks as described by Murphy and Bliss (1999), maintained in an interface recording chamber, and perfused continuously with oxygenated artificial CSF (ACSF) of the following composition (in
mM): NaCl 124, KCl 4, NaH2PO4 1.25, NaHCO3 26, CaCl2 2, MgSO4 2, and D-glucose 10. During the
dissection, blood samples were taken from some animals, and blood
glucose levels were measured using an automated glucometer (Bayer,
Newbury, UK). Initial field recording experiments were performed under
blind conditions (see below) and at a temperature of 26°C. At 26°C
the metabolic load is reduced [a precaution taken because HD has been
associated with an impairment of energy metabolism; see Jenkins et al.
(1993)], thereby maximizing slice survival and viability, especially
after the trauma of dissection and slice preparation. All subsequent field experiments were performed at 26°C. A later series of
experiments was performed at the higher temperature of 32°C. Under
these conditions transgenic slices were viable (see Table 1),
suggesting that an impairment of energy metabolism may not be readily
evident in R6/2 mice.
Field recordings. Two slices prepared from the same
hippocampal hemisphere were taken from each animal and transferred to an interface chamber (P. E. Scientific Systems Design, London, UK). Field recordings were made from the cell body layer of one slice
to measure the population action potential (population spike) and from
the stratum radiatum of the other to measure the field EPSP (fEPSP)
using glass microelectrodes filled with 1 M sodium acetate
(impedence 2-5 M ). Potentials were recorded using AC preamplifiers
(Neurolog, Welyn Garden City, UK) and stored on a Macintosh computer
(using A/Dvance software; R. M. Douglas, Vancouver, Canada).
Monopolar tungsten stimulating electrodes (A-M systems, Carlsborg, WA)
were placed in the stratum radiatum of each slice to activate Schaffer
collateral-commissural fibers. Test shocks were applied at 30 sec
intervals, at an intensity that evoked responses that were either
~25% in LTP or 50% in LTD of the initial maximum response.
Conditioning tetani used to induce LTP at CA1 synapses consisted of
three trains of 100 shocks at 100 Hz with an intertrain interval of 10 sec (Nosten-Bertrand et al., 1996). LTD or depotentiation were induced
by application of 900 shocks at 1 Hz (Dudek and Bear, 1992). For slices
of the dentate gyrus, the bathing medium contained 4 mM
Ca2+ and Mg2+
and 100 µM picrotoxin (Hanse and Gustafsson, 1992). To
induce LTP, the medial perforant path was stimulated with two trains of
20 pulses at 100 Hz, with a 30 sec interval at twice test shock duration (Nosten-Bertrand et al., 1996). Test shocks were set to the
threshold of the population action potential, and field recordings were
made in the molecular layer. NMDA receptor-mediated potentials were
isolated pharmacologically using Mg2+-free
ACSF containing 10 µM
6-cyano-7-nitroquinoxaline-2,3-dione disodium (CNQX; Tocris, Bristol,
UK). In all cases, application of the NMDA receptor antagonist
D-( )-2-amino-5-phosphonopentanoic acid (AP5; Tocris)
abolished the synaptic potential.
Intracellular experiments. Intracellular recordings were
made from CA1 pyramidal cells as described by Murphy et al.
(1994) and maintained at 32°C. Briefly, cells were impaled
with microelectrodes filled with 3 M potassium acetate or
potassium chloride (impedence 70-100 M), and membrane potentials
were recorded using an Axoclamp 2B amplifier (Axon Instruments, Foster
City CA). Only those cells that exhibited a stable resting membrane
potential more than 60 mV over a 20 min period in the absence of
holding current were included in this study. Input resistances were
calculated by injection of hyperpolarizing current (square pulse, 150 msec duration, typically 0.2-0.4 nA), and action potentials were
evoked by the injection of depolarizing current.
Up until 10 weeks of age, all experiments were performed blind. All
animals killed before 12 weeks of age were genotyped postmortem. Animals aged >12 weeks were identified by phenotype. Approximately equal numbers of male and female mice were used in this study.
Unless stated otherwise, the significance of differences between groups
produced by conditioning stimuli was assessed by unpaired two-tailed
Student's t tests. All mean values are expressed as mean ± SEM.
Morris water maze. Thirty-one female mice aged 7 weeks of
age were tested by a blinded experimenter at the same time each day
using standard protocols as described by Stewart and Morris (1993).
Briefly, mice were trained in the water maze (diameter 100 cm, height
40 cm, water depth 25 cm) over a 10 d period, receiving four
trials per day. The submerged platform (diameter 11.5 cm, height 24.5 cm) was placed at a fixed location within the northeast quadrant. Each
trial was separated by 5-10 min. A mouse was placed in the bath facing
the wall of the pool at one of four randomly chosen starting positions
(north, east, south, west). The mouse was allowed to swim until it
located and climbed onto the submerged platform. If the mouse failed to
locate the platform within 60 sec, it was removed from the water and
placed on the platform. At the end of each trial, mice were left on the
platform for 15 sec. The latency to escape the water was recorded for
each trial. On day 10, the mice received a single probe test 5-10 min
after the last trial. Before the probe test the platform was removed from the bath. The swim path of each mouse was recorded over 60 sec
while it searched for the missing platform. The distance swum and time
spent in each quadrant of the maze, as well as the total path length,
were traced and measured from video recordings. Animals were identified
by genotyping. Unless stated otherwise, statistical comparisons were
undertaken by two-factor ANOVA.
Immunocytochemistry. Brains were prepared as described by
Reynolds et al. (1998). Briefly, brains were dissected, frozen rapidly on powdered dry ice, and stored at 80°C. Brains were then
cryosectioned (30 µm), and inclusions were visualized by staining for
ubiquitin using a rabbit polyclonal anti-ubiquitin antibody (1:2000;
DAKO, Ely, UK). A horseradish peroxidase-conjugated secondary antibody (1:1000; Vector Laboratories, Peterborough, UK) was used, and staining
was visualized using diaminobenzidine (Sigma, Poole, UK).
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RESULTS |
Synaptic properties and plasticity at CA1 synapses
Initial experiments were designed to examine the basal properties
of synaptic function in area CA1 of the hippocampus. Analysis of
synaptic transmission revealed little difference between transgenic and
control animals, regardless of the severity of the phenotype. Stimulation intensity was set to elicit responses ~25% of the maximum. Input/output curves for transmission at transgenic and control
CA1 synapses were indistinguishable (Fig.
1a-c).
Paired-pulse stimulation, a test of presynaptic function, also revealed
little difference between transgenic and control mice (Fig.
1d,e), suggesting that normal synaptic
transmission occurs in transgenic mice and that slice viability is not
affected by the transgene or the severity of the phenotype. Indeed, the
apparent near-normality of the slices, even when prepared from animals
in the terminal phase of the phenotype (12-18 weeks of age), was
demonstrated by a series of intracellular recordings made in transgenic
CA1 neurons. These cells had normal resting potentials, input
resistances, and firing thresholds (Table 1). However, the mean amplitude of the
action potential was significantly smaller than that for control
cells.
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Figure 1.
HD mice have near-normal synaptic physiology in
area CA1. a, Input/output relationships for control and
transgenic mice aged 5-18 weeks [control slices denoted by  (pooled data from 24 slices, from 17 animals); transgenic slices
denoted by  (pooled data from 27 slices, from 18 mice)]. Field
EPSPs were evoked by stimulation of the Schaffer
collateral-commissural pathway at 0.067 Hz and recorded in the stratum
radiatum. b, Transgenic synaptic responses are
unaffected by age and severity of the phenotype. Individual responses
evoked at 400 µA are plotted against age [control
(r2 = 0.051, p > 0.1) and transgenic
(r2 = 0.004, p > 0.5) responses denoted by and ,
respectively]. c, Analysis of the population action
potential also revealed a normal input/output curve for transgenic
responses. Data points are pooled values from nine control slices (9 animals, aged 5-18 weeks; ) and 13 transgenic slices (from 11 animals, aged 5-18 weeks; ). Potentials were evoked by stimulation
of the Schaffer-commissural pathway and recorded in the stratum
pyramidale. d, Paired-pulse facilitation of field EPSPs
was similar in both control and transgenic slices. The mean slope of
the paired EPSP (expressed as percentage change with respect to the
first response) is plotted against interpulse interval. Data points are
pooled values from nine control slices (9 animals, aged 5-18 weeks;
) and 26 transgenic slices (from 17 animals, aged 5-18 weeks; ).
e, Paired-pulse facilitation of population action
potential. Transgenic responses are enhanced at an interval of 20 msec
(p < 0.05) but otherwise are normal [9
control slices (from 9 animals aged 5-18 weeks; ) and 22 transgenic
slices (from 15 animals, aged 5-18 weeks; )]. f,
PTP is normal in transgenic slices. Experiments were performed in 25 µM D-AP5 and responses were evoked at 0.2 Hz.
Tetanic stimulation (3× 100 pulses at 100 Hz; denoted by  ) induced
a transient potentiation rapidly decaying to baseline within 90 sec (7 control slices from 7 animals and 16 transgenic slices from 12 slices,
aged 7-14 weeks, denoted by and , respectively).
g, NMDA receptor-mediated transmission is normal in
transgenic mice  12 weeks of age. Input/output curves are superimposed
for normal synaptic responses (round symbols) and NMDA
receptor-mediated potentials (square symbols) recorded
in the same afferent pathway [6 control and 6 transgenic slices
(open and filled symbols,
respectively)]. NMDA receptor potentials were isolated
pharmacological in nominally magnesium-free ACSF containing 10 µM CNQX. h, Analysis of the somatically
recorded EPSP and population action potential revealed a decrease in
the likelihood for a transgenic EPSP to generate an action potential at
lower stimulation intensities. Data points are pooled values of somatic
EPSP slope/population action potential ratio plotted against
stimulation strength [9 control slices (9 animals, aged 5-18 weeks;
) and 13 transgenic slices (11 animals, aged 5-18 weeks; )].
Points indicated by an asterisk are significantly
different compared with controls (p < 0.05 in each case; Mann-Whitney test). Comparison of the transgenic and
control input/output relationships of somatically recorded EPSPs
revealed no significant differences between the two groups [slope
values (V/s) at 50, 100, and 400 µA were 0.72 ± 0.1, 1.85 ± 0.15, 4.59 ± 0.39, and 0.79 ± 0.01 (p > 0.6), 1.41 ± 0.24 (p > 0.1), 4.7 ± 0.41 (p > 0.8) for transgenic and control
slices, respectively].
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We next investigated synaptic plasticity at CA1 synapses using a
high-frequency conditioning tetanus (3× 100 pulses at 100 Hz) and a
low-frequency conditioning tetanus (900 pulses at 1 Hz) to induce LTP
and LTD, respectively. Baseline responses were monitored for 10-30 min
before conditioning and were found to be stable. Tetanic conditioning
revealed a marked difference in the ability of transgenic slices to
support LTP, with potentiation of the EPSP being significantly reduced
in transgenic slices (p < 0.001) (Fig.
2a). Interestingly, LTP of the
population action potential was normal (Fig. 2b). However,
low-frequency conditioning applied 1 hr after the induction of LTP
resulted in depression (depotentiation) of both transgenic field EPSPs
and population action potentials, whereas the control responses showed
only a transient depression that recovered to the potentiated baseline (Fig. 2a,b). Furthermore, low-frequency
conditioning of naive transgenic slices induced LTD in both the EPSP
and population action potential but failed to do so in control slices
(Fig. 2c,d). The LTD was homosynaptic (second
pathway not shown) and was not attributable to afferent damage, because
a subsequent period of tetanic conditioning induced LTP (Fig.
2c). The changes in synaptic plasticity at transgenic CA1
synapses was seen in all mice aged 5-18 weeks and did not appear to be
affected by the severity of the phenotype (see Fig. 6a).
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Figure 2.
HD mice express abnormal synaptic plasticity at
CA1 synapses. a, Left, Transgenic
synapses show reduced LTP and exhibit activity-dependent synaptic
depression (depotentiation) of the field EPSP. EPSP slope is plotted as
percentage change against time and expressed as a pooled mean [13
control slices () from 12 animals, and 17 transgenic slices ()
from 15 animals; aged 5-18 weeks]; SEM was plotted for every fifth
datum. Tetanic stimulation (denoted by ) induced robust LTP
(56.5 ± 6.6%; measured 1 hr after induction over 5 min) in
control slices but a smaller LTP at transgenic synapses (26.8 ± 3.4%; p < 0.001, Welch t test). In
contrast, low-frequency conditioning applied 1 hr after the induction
of LTP failed to depotentiate the control slices (4.9 ± 1.7%;
measured 1 hr after conditioning) but induced depression at transgenic
synapses (18.5 ± 2.8%; p < 0.001).
Right, Representative traces showing
averages of five consecutive EPSPs taken immediately before tetanic
stimulation (indicated as control), 1 hr after
the tetanus (indicated as LTP), and 1 hr after
low-frequency stimulation (indicated as depot.) are
superimposed. b, Transgenic slices exhibit normal LTP of
the population action potential but show marked depotentiation.
Left, Tetanic conditioning induced LTP of similar
magnitude in control () and transgenic () slices [229.7 ± 36.6% (15 slices from 13 animals) and 246.1 ± 38.3% (18 slices
from 17 animals), respectively; aged 5-18 weeks; p = 0.76]. The mean population action potential amplitudes were similar
for control and transgenic slices before conditioning (2.23 ± 0.29 mV and 2.52 ± 0.29 mV for control and transgenic slices,
respectively; p > 0.4) and 1 hr later (6.79 ± 1.05 and 8.06 ± 0.94 mV for control and transgenic slices,
respectively; p >0.3). Low-frequency conditioning
applied 1 hr later failed to depotentiate control responses (7.0 ± 2.9%) but induced a profound depression in the transgenic potential
(46.9 ± 3.9%; p < 0.001).
Right, Representative traces showing averages of five
consecutive population action potentials taken immediately before
tetanic stimulation, 1 hr after the LTP, and low-frequency stimulation
are superimposed and indicated as in a.
c, LTD is only seen in transgenic slices. Low-frequency
stimulation (bar) induced LTD in transgenic () EPSPs
but not in control () responses (19.2 ± 1.2%, 7 slices, and
6.34 ± 4.9%, 5 slices, respectively; p = 0.0076) (Welch t test). Tetanic stimulation ()
applied 1 hr after low-frequency conditioning successfully induced LTP
in both control and transgenic slices. Note that for experiments in
c and d, the test shock was set to elicit
responses at 50% of maximum. d, Low-frequency
conditioning (bar) also selectively induces LTD of
transgenic population action potentials [56.2 ± 4.1%
(n = 7) and 3.7 ± 13.7%
(n = 6) for transgenic () and control ()
slices, respectively; p = 0.0087 (Welch
t test)]. Calibration (a,
b): 5 msec, 5 mV.
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It was noted that post-tetanic potentiation (PTP) of the EPSP was
smaller in transgenic slices (Fig. 2a). PTP is believed to
be an indication of presynaptic function, reflecting a period of
enhanced transmitter release caused by the loading of the presynaptic terminal with calcium ions during tetanic conditioning. It is possible
that the impairment in LTP of the transgenic EPSP is caused by a
reduction in transmitter release that is only apparent during a period
of intense synaptic activity such as that seen during tetanic
stimulation. To investigate this possibility further, tetanic
conditioning was applied to control and transgenic slices in which the
LTP inductive mechanism was blocked by the NMDA receptor antagonist
D-AP5 (Collingridge et al., 1983). Under these
conditions, the degree of PTP was similar for controls and transgenic
EPSPs (Fig. 1f), suggesting that impaired transmitter
release during the tetanus was not responsible for the failure in LTP.
An alternative explanation for the differences in LTP and PTP might be
modification of NMDA receptor function (Collingridge et al., 1983;
Bliss and Collingridge, 1993; Cochilla and Alford, 1999). However,
examination of NMDA receptor-mediated field potentials in slices
prepared from animals older than 12 weeks revealed no apparent
differences in NMDA receptor function (Fig. 1g). It is conceivable that molecular events downstream of the NMDA receptor, such
as postsynaptic intracellular signaling and/or retrograde messenger
generation, are dysfunctional in the R6/2 mouse and account for the
abnormal change in PTP seen when NMDA receptors are operative. In rat,
the induction of LTD in slices prepared from young animals (<4 weeks)
is sensitive to the blockade of NMDA receptors (Dudek and Bear, 1992).
We found that AP5 completely blocked the induction of LTD in transgenic
slices (see Fig. 6c). These data suggest that NMDA receptor
function is normal but that biochemical cascades associated with them
may be dysfunctional.
The observation that transgenic cells exhibited a reduced action
potential during somatic depolarization does not accord with the
finding that the input/output relationship for the transgenic population action potential was normal (Fig. 1c). However,
closer investigation of synaptically generated population action
potentials revealed a marked difference between transgenic and control
slices. Figure 1h shows the ratio of the somatically
recorded field EPSP and population action potential against
stimulation. At lower stimulation intensities, a transgenic EPSP is
less likely to generate an action potential than control potentials.
Alternatively, it is possible that the cells firing are those with
smaller action potentials. It is possible that this stimulus-dependent
effect on EPSP/action potential coupling might account for the
difference seen in LTP at the level of the transgenic EPSP and
population action potential (see Discussion).
Spatial cognition
We would expect dysfunctional synaptic plasticity in the
hippocampus to affect hippocampal-dependent forms of learning such as
spatial cognition (Morris et al., 1986, 1998; Chapman et al., 1999). To
address this possibility, 7-week-old animals were tested in a modified
Morris water maze (Stewart and Morris, 1993). Control mice rapidly
learned the location of a submerged platform, whereas transgenic mice
performed poorly (Fig. 3a)
(p < 0.001). After training, the platform was
removed, and a probe test was performed to examine the exploratory
behavior of the mice. Unlike control mice that repeatedly returned to
the location of the platform, the transgenic animals swam in a random
manner, with little or no reference to the location of the platform
(Fig. 3b). Probe test analysis revealed that the transgenic
mice spent less time than control mice in the quadrant that had
previously contained the submerged platform (Fig. 3c)
(p < 0.05). Although transgenic mice exhibited
a motor swimming deficit in that they swam more slowly than controls,
the comparison of swim paths taken (illustrated in Fig. 3b)
demonstrated that transgenic mice were cognitively impaired. Recent
analysis of younger mice with less developed motor impairment also
demonstrated a clear cognitive deficit in the water maze (Lione et al.,
1999).
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Figure 3.
Spatial cognition is impaired in HD mice.
a, Mean escape latency is plotted against day of
training in the Morris water maze, commencing at 7 weeks of age [22
control () and 9 transgenic () mice]. Mice did not differ in
initial escape latency, indicating that transgenic mice did not exhibit
a nonspecific sensory or motor impairment. Over the course of training,
control mice rapidly learned the location of the submerged platform,
whereas transgenic mice showed little improvement (ANOVA genotype × day interaction F(9,261) = 2.45, p < 0.02). b, Representative swim
paths illustrate the impairment of spatial cognition during the probe
trial in transgenic mice. Although the controls concentrated their
search in the location at which the platform had been placed during
training, the transgenic mice showed less focused swim paths.
c, Probe test analysis reveals that transgenic
(filled bar) mice spend less time in the platform
quadrant than controls (open bar; p < 0.02 using two-tailed t test to compare time spent in
platform quadrant).
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Intranuclear inclusions and synaptic plasticity
A hallmark of HD is the appearance of highly ubiquitinated
neuronal intranuclear inclusions (NIIs) (Fig.
4). These were first described in the
R6/2 mouse (Davies et al., 1997) and then later found in human
postmortem HD brain (DiFiglia et al., 1997). In HD, NIIs are insoluble
proteinacious aggregates that include the N-terminal fragment of mutant
huntingtin containing the expanded polyglutamine repeat (Davies et al.,
1997). Furthermore, NIIs now appear to be a common feature in most
triplet repeat disorders (Perutz, 1999). Although NIIs have been
reported previously in the hippocampus of R6/2 mice (Davies et al.,
1997; Ono et al., 1999), they have not been described in any detail. We
report here that the appearance of NIIs in the hippocampal formation of
the R6/2 mouse is age dependent and shows a marked regional
distribution. Inclusions were present in the principal cells of the CA1
region by 3 weeks of age (Fig.
5a,b,e,f),
several weeks before the onset of phenotypic behavior or the appearance
of NIIs in other hippocampal areas. In the dentate gyrus (Fig.
5c,d,g,h), inclusions are
present at 7 weeks but are not present in all neurons in the stratum
granulosum until ~10 weeks of age.
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Figure 4.
Photomicrographs of ubiquitinated NIIs in
CA1 neurons in a section of R6/2 mouse brain (13 weeks of age) under
bright-field (a, b) or fluorescence
(c, d) illumination. The areas
outlined in a and c are
shown at higher magnification in b and d.
Inclusions were immunostained for ubiquitin, and the section was
counterstained with the fluorescent dye Hoechst 33258 to visualize
nuclei. Small arrows in b and
d show that the same inclusions can be seen in both
fields. Numerous neuronal nuclei can be seen in the pyramidal cell
layer (c). At higher magnification, inclusions
can be seen clearly localized to the nucleus of CA1 neurons. The
large arrow in b and d
indicates an inclusion in a nucleus stained with Hoechst dye
(arrowheads). Scale bar (shown in a):
a, c, 100 µm; b,
d, 33 µm.
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Figure 5.
The temporal and regional pattern of NII
distribution in HD mouse hippocampus. Ubiquitinated inclusions are seen
in CA1 pyramidal neurons (a, b,
e, f) and granule cells of the
dentate gyrus (DG) (c, d,
g, h) in hippocampi of mice killed at 3 weeks (a, b, d), 7 weeks
(c), or 10 weeks (e,
f, g, h) of age. Nuclei in
b, f, and h were
visualized by staining with Hoechst 33258 (a,
e, g). Inclusions are clearly localized
to the nuclei of CA1 pyramidal cells (arrows in
a, b, e,
f) and dentate gyrus (g,
h). Inclusions are present in CA1 neurons, but not
granule cells, at 3 weeks of age. Some inclusions can been seen in the
dentate gyrus at 7 weeks but are not present throughout the stratum
granulosum until 10 weeks of age. Scale bars (shown in
d): a-f, 100 µm; (shown in
h): g, h, 100 µm.
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The role of NIIs in either the pathogenesis of HD or the decline in the
R6/2 mouse is not understood. However, the temporal separation of the
appearance of NIIs in the CA1 subfield and their appearance in the
granule cells of the dentate gyrus provided an opportunity to compare
synaptic plasticity in the presence and absence of NIIs in animals of a
similar age and phenotypic status. Experiments were performed to assess
LTP at perforant path-granule cell synapses in one group of animals
aged between 4-7 weeks and a second group aged 12 weeks or more (time
periods corresponding with low or widespread expression of NIIs in the stratum granulosum, respectively). PTP was normal in the 4-7 week group and LTP was not significantly impaired (p = 0.09), whereas the older transgenic mice (12 weeks) expressed
dramatically reduced LTP (p < 0.01) (Fig.
6b). In contrast, LTP and LTD
at transgenic CA1 synapses were significantly reduced at 5 weeks of age
(p < 0.05 and p < 0.01, respectively) (Fig. 6a). Together, these observations suggest that the temporal and regional pattern of altered plasticity within the hippocampus of R6/2 mice may be related to the appearance and distribution of NIIs.
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Figure 6.
Age- and region-dependent changes in
plasticity in the HD mouse. a, Left, The
magnitude of LTP expressed at transgenic CA1 synapses over three age
ranges is compared with that seen in the control slices. LTP is
significantly impaired in transgenic slices from 5 weeks onward [5-6
weeks, 26.2 ± 3.9% (n = 5); 7-9 weeks,
30.9 ± 7.2% (n = 5); 10 weeks, 22.9 ± 4.54 (n = 7); controls slices, 56.5 ± 6.6% (n = 13); level of significance determined
using Bonferroni multiple comparisons test]. Right,
Lasting activity-dependent synaptic depression is enhanced in
transgenic slices from 5 weeks onward [5-6 weeks, 38.8 ± 5.5% (n = 5); 7-9 weeks, 47.4 ± 11.4%
(n = 5); 10 weeks, 51.6 ± 4.2%
(n = 8); control slices, 7.0 ± 2.9].
b, The induction of LTP at granule cell synapses is
age-dependent in transgenic mice. Top, LTP was induced
in both control and transgenic slices in animals aged 4-7 weeks
[57.8 ± 15.7% (n = 8) and 30.0 ± 9.4% (n = 11), respectively; p < 0.05]. Bottom, LTP is absent at transgenic granule
cell synapses in animals aged 12 weeks [68.2 ± 13.4%
(n = 5) and 15.8 ± 5.4%
(n = 7) in control and transgenic slices,
respectively; p < 0.01]. c, The
induction of LTD at transgenic CA1 synapses is NMDA receptor-dependent.
Low-frequency conditioning (open bar) failed to induce
LTD in the presence of 25 µM D-AP5
(filled bar) (1.8 ± 0.1%, 3 slices
from 3 animals; measured 1 hr after conditioning). Subsequent
low-frequency conditioning after washout of AP5 successfully induced
LTD (31.8 ± 0.2%; p < 0.01, paired
t test).
|
|
| |
DISCUSSION |
We report that in a progressive transgenic model for HD, both
synaptic plasticity and spatial cognition are impaired at a time point
before the onset of an overt phenotype. The synaptic dysfunction is a
selective impairment of LTP coupled with activity-dependent depression
of synaptic transmission. These changes occur before the onset of
neuronal cell loss in the R6/2 mouse [which has been reported to be
detectable in several brain regions from 13 weeks of age (Davies et
al., 1999)]. Based on this evidence, we propose that altered synaptic
plasticity may contribute to the early cognitive deficit seen in
presymptomatic HD patients. Impaired LTP and cognitive dysfunction have
been reported in transgenic models of Alzheimer's disease
(Nalbantogluet et al., 1997; Chapman et al., 1999). In one study,
although LTP was impaired, LTD was not abnormal (Nalbantogluet et al.,
1997). Interestingly, in the R6/2 mouse, the conspicuous change in
activity-dependent plasticity is one of synaptic depression. Given that
LTP was normal at the level of the population action potential (Fig.
2b), and that LTP of the EPSP could be recovered if a
stronger stimulation intensity was used (Fig. 2c), it is tempting to suggest that, at least in part, the cognitive deficit seen
in the R6/2 mouse is attributable to abnormal synaptic depression. If
this is indeed the case, then this is the first time that LTD has been
implicated in cognitive dysfunction.
The finding that there is weakened coupling between the EPSP and
generation of action potentials in the R6/2 mouse was unexpected. Furthermore, the observation that in older transgenic mice the action
potential was reduced in a subset of cells suggests that the mechanisms
underlying the generation of action potentials requires further
investigation. The reduced population action potential at lower
stimulation intensities might account for the differences seen in LTP
expressed at the level of the dendritic EPSP and the somatic action
potential. However, it should be noted that experiments using a sodium
channel antagonist to block the propagation of action potentials still
expressed normal LTP (Gustafsson et al., 1987). The dissociation
between the EPSP and action potential may have a profound effect on the
passage of information through polysynaptic neural circuits; it is
tempting to suggest that this might be a factor underlying the
neurological and motor deficits seen in the R6/2 mouse. Recently, a
similar reduction in action potential amplitude has been reported in
R6/2 striatal neurons (Levine et al., 1999). However, these cells also
showed marked changes in resting membrane potential and input
resistance, phenomena absent in CA1 hippocampal neurons reported here.
In all other respects, basal transmission at CA1 synapses appears to be
normal. This contrasts markedly with changes reported in two other
mouse lines expressing a mutated murine HD gene (Hdh mouse)
(Shelbourne et al., 1999; Usdin et al., 1999) or a yeast artificial
chromosome (YAC) expressing mutant full-length human huntingtin
(YAC mouse) (Hodgson et al., 1999). Unlike the R6/2 mouse,
the Hdh mutant shows abnormalities in both PPF and PTP, whereas the YAC mutant exhibits NMDA receptor-mediated
hyperexcitability. In agreement with our study, both of these models
also show an impairment of LTP at CA1 synapses. Based on the deficit in
PTP and a reduced rate of MK801 binding to NMDA receptors, it was suggested that a frequency-dependent deficit in transmitter release might underlie the abnormalities in synaptic function seen in the
Hdh mutant. Indeed, normal huntingtin has been associated with vesicle trafficking and is known to be enriched at the presynaptic terminal (DiFiglia et al., 1995; Gutekunst et al., 1995; Sharp et al.,
1995). We also saw a decrease in PTP under conditions similar to those
used in the Hdh mutant study. However, when the experiment
was repeated in the presence of an NMDA receptor antagonist, PTP was
normal. It is therefore possible that the changes in PTP and MK801
binding in the Hdh mutant are not a direct consequence of
dysfunctional transmitter release but attributable to a modification in
NMDA receptor-mediated function (Chen et al., 1999) or possibly other
glutamate receptors such as metabotropic receptors (Cha et al.,
1998).
The changes in synaptic function reported in the YAC mouse
study are difficult to reconcile with our finding: first, because of
the different mouse strain used, and second, because their experiments
were performed in the absence of extracellular magnesium. Interestingly, unlike the R6/2 mouse, the YAC mouse
exhibited a marked increase in basal transmission mediated by NMDA
receptors. Recently, it has been shown that injection of full-length
mutated huntingtin into cells expressing functional NMDA receptors
induces a selective augmentation of receptor current in receptors
containing the NR2B subunit (Chen et al., 1999). Both NR2A and NR2B
subunits are expressed in the hippocampus, and it is possible that the difference seen between the R6/2 and YAC mouse lines may
reflect a differential distribution of receptor subunits.
Alternatively, NMDA receptor augmentation may represent a gain of
function attributable to the C-terminal portion of mutant huntingtin
(Chen et al., 1999), a portion of the protein that is absent in the
R6/2 mouse.
Activation of NMDA receptors appears to be an essential component of
the synaptic dysfunction reported here, with changes in both PTP and
LTD requiring functional NMDA receptors. Receptor expression and
binding profiles in striatum and neocortex of the R6/2 mouse show
normal expression of NMDA receptors but a marked decrease in
dopaminergic and certain subunits of metabotropic glutamate receptors
(Cha et al., 1998). Similar receptor changes in the hippocampus might
provide an explanation for impaired LTP and the novel LTD reported
here. Under certain conditions, the induction of LTP depends critically
on activation of postsynaptic metabotropic glutamate receptors
(Bortolotto et al., 1994). Furthermore, presynaptic metabotropic
receptors mediate increases in transmitter release associated with both
the induction and maintenance of LTP (Herrero et al., 1992;
Sanchezprieto et al., 1996). A reduction in receptor number would be
expected to raise the inductive threshold for LTP, a view consistent
with the data presented here. Dopaminergic receptors are also involved
in the induction (Blitzer et al., 1995) and maintenance (Frey et al.,
1991, 1993) of LTP, via cAMP activation of protein kinase A (PKA). The
role of PKA during LTP induction is to maintain the inactivation of
protein phosphatases (Blitzer et al., 1995) that otherwise would
facilitate the induction of LTD (Mulkey et al., 1993). If phosphatase
inactivation is compromised by a reduced number of dopaminergic
receptors, then one would expect an impairment in LTP similar to that
reported here. Furthermore, such an impairment would have a
postsynaptic locus and therefore could not be explained by
dysfunctional transmitter release as proposed for the Hdh
mutant. Moreover, an inappropriate pattern of phosphatase activation
might also account for the NMDA receptor-dependent form of LTD
expressed at R6/2 synapses.
It has been reported that R6/2 mice exhibit a progressive form of
diabetes (Hurlbert et al., 1999). Moderate cognitive impairment is a
complication of diabetes in man (Franceschi et al., 1984). Furthermore,
poor spatial cognition and impaired LTP have also been reported in rats
with streptozotocin-induced diabetes (Biessels et al., 1998). However,
we are confident that the changes in cognition and plasticity reported
here are not directly attributable to diabetes. First, blood samples
taken from (nonfasted) animals used in the preparation of slices for
this study, at a time when changes in synaptic plasticity at CA1
synapses were fully manifest (4-7 weeks of age), had blood glucose
levels within the normal range: 4.2 ± 0.7 mM
(n = 7) and 6.0 ± 0.3 mM
(n = 5) for transgenic and control mice, respectively.
Second, we did not see a change in maximal synaptic responses, unlike
diabetic rats, which show a marked decrease (Chabot et al., 1997).
The role of aggregate formation in the pathology of HD is widely
debated, with proposed roles ranging from the benign to the benevolent
or the malevolent (Saudou et al., 1998; Gutekunst et al., 1999;
Scherzinger et al., 1999). Inclusions have now been reported in several
transgenic mouse models (Davies et al., 1997; Reddy et al., 1998;
Hodgson et al., 1999; Schilling et al., 1999), with the notable
exception of the Hdh mutant (Shelbourne et al., 1999). In
the R6/2 mouse, the presentation of an overt phenotype follows the
appearance of NIIs detected using antibodies to ubiquitin. Furthermore,
manipulations that delay the appearance of the phenotype, such as the
inhibition of the apoptotic protease caspase-1, also delay the
appearance of the inclusions (Ona et al., 1999). The relationship
between the appearance of NIIs in the R6/2 hippocampus and alterations
in synaptic plasticity suggests that cells in which inclusions are
present are dysfunctional. However, a causal relationship has not been
established, and it should be noted that the Hdh
mouse, which exhibits a form of impaired LTP, does not develop
inclusions (Shelbourne et al., 1999).
The R6/2 mouse provides us with a useful tool to study changes in
cognitive and synaptic function related to HD. In particular, the
selective vulnerability of CA1 synapses provides us with a model for
investigating dysfunctional synaptic transmission that may underlie the
cognitive deficit seen in presymptomatic HD.
| |
FOOTNOTES |
Received Dec. 14, 1999; revised March 22, 2000; accepted March 28, 2000.
We thank M. A. Hickey, T. Humby, M. J. Hunt, and J. P. Spencer for their supporting contributions to this study. We also thank Roger Hart, Wendy Leavens, and Chris Riches for technical assistance.
Correspondence should be addressed to Dr. Kerry P. S. J. Murphy, Department of Biological Sciences, The Open University, Walton Hall, Milton Keynes, UK MK7 6AA. E-mail: k.murphy{at}open.ac.uk.
Dr. Dunnett's present address: School of Biosciences, Cardiff
University, Museum Avenue, Cardiff CK10 3US, UK.
| |
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ABSTRACT
INTRODUCTION
