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Human Molecular Genetics Pages 839-846  

Impaired synaptic plasticity in mice carrying the Huntington's disease mutation
Introduction
Results
   Baseline synaptic function in HD mutant mice
   Impairment in induction of long-term potentiation (LTP)
   Post-tetanic potentiation and paired pulse facilitation
   Involvement of the presynaptic terminal
Discussion
Materials And Methods
   Mouse strains and hippocampal field recordings
   Intracellular recordings
Abbreviations
Acknowledgements
References

Impaired synaptic plasticity in mice carrying the Huntington's disease mutation

Impaired synaptic plasticity in mice carrying the Huntington's disease mutation

Martine T. Usdin1,4, Peggy F. Shelbourne3, Richard M. Myers1 and Daniel V. Madison2,4,*

1Department of Genetics and 2Department of Molecular and Cellular Physiology, B111 Beckman Center, Stanford University School of Medicine, Stanford, CA 94305, USA, 3Division of Molecular Genetics, University of Glasgow, 56 Dumbarton Road, Glasgow G11 6NU, UK and 4Neurobiology Course, Marine Biological Laboratory, Woods Hole, MA 02543, USA

Received December 2, 1998; Revised and Accepted February 4, 1999

Cognitive impairment is an early symptom of Huntington's disease (HD). Mice engineered to carry the HD mutation in the endogenous huntingtin gene showed a significant reduction in long-term potentiation (LTP), a measure of synaptic plasticity often thought to be involved in memory. However, LTP could be induced in mutant slices by an `enhanced' tetanic stimulus, implying that the LTP-producing mechanism is intact in mutant mice, but that their synapses are less able to reach the threshold for LTP induction. Mutant mice showed less post-tetanic potentiation than wild-type animals, and also showed decreased paired pulse facilitation, suggesting that excitatory synapses in HD mutant mice are impaired in their ability to sustain transmission during repetitive stimulation. We show that mutants, while normal in their ability to transmit at low frequencies, released significantly less glutamate during higher frequency synaptic activation. Thus, a reduced ability of Huntington synapses to respond to repetitive synaptic demand of even moderate frequency could result not only in a functional impairment of LTP induction, but could also serve as a substrate for the cognitive symptoms that comprise the early-stage pathology of HD.

INTRODUCTION

Huntington's disease (HD) is a member of a family of dominant, inherited late-onset neurodegenerative diseases that are characterized by an expansion in an expressed polyglutamine tract. Given the common factor of the expanded glutamine repeat, it is likely that a similar pathological mechanism may underlie all of these triplet expansion diseases. Individuals carrying the mutation for HD have such an expanded repeat in huntingtin, a 350 kDa protein of unknown function. Huntingtin is widely expressed throughout the brain and in many peripheral tissues (1).

Cognitive defects, including memory and information-processing deficits, mood changes, aggressive behavior and disruptions in spacial working memory, are among the earliest symptoms of HD, occurring before other symptoms, such as the movement impairments associated with later stages of the disease (2-4). Terminal HD often manifests with severe neuronal loss, mainly in the basal ganglia and cortex (5). However, it is not clear whether the neuron loss is a direct cause of HD, or whether it is a consequence of other effects of the mutant protein. For example, mice expressing exon 1 of huntingtin with 115-151 glutamines develop end-stage HD-like symptoms, including tremor, motor abnormalities, reduced brain size, body wasting and seizures (6). Some of these mice die within 6 weeks of birth. Pathological analysis showed no evidence of neuronal cell death, although these mice were found to have large intranuclear inclusions comprised of ubiquitinylated huntingtin degradation products that accumulate with age. These mice show neurological symptoms before detectable neuron loss.

We have investigated directly whether the presence of the expanded HD protein, in a form that molecularly most closely mimics the mutation in humans, can cause a neurological phenotype in the absence of neurodegeneration, using a `knock-in' mouse model. Mice expressing full-length mutant huntingtin protein were generated by targeted modification of the endogenous mouse Hdh gene in embryonic stem cells by homologous recombination, as described by P.F. Shelbourne et al. (7). The seven glutamine-encoding repeats normally present in the mouse gene were replaced with an expanded stretch of up to 80 CAG repeats, leaving the mutant gene under the control of the endogenous mouse transcriptional regulatory sequences. These mice express normal levels of mutant huntingtin containing 72 or 80 glutamine residues, a length corresponding to that seen in juvenile-onset HD in humans. These mice do not develop detectable nuclear inclusions, but show striking hyperaggressive behavior reminiscent of the behavioral abnormalities of early-stage human HD patients (7). These findings suggest that neurodegeneration and cell death, and perhaps even the formation of nuclear inclusions, are later-stage effects of the mutation, and are not necessarily correlated with all, in particular the early, symptoms of the disease.

These observations led us to search for pathological effects of the mutant HD protein other than cell death. To this end, we investigated the synaptic physiology of hippocampal slices from these knock-in mice, looking for changes in synaptic function and plasticity that might underlie early cognitive deficits seen in HD. The hippocampal preparation was chosen because: (i) normal synaptic transmission in the CA3-CA1 pathway described herein has been studied extensively, allowing discrimination between normal synaptic events and abnormal ones; (ii) the lamellar organization of the hippocampus allows the production of reproducible and stereotyped synaptic potentials; and (iii) while the exact function of the hippocampus remains unclear, it is thought to be involved in cognitive and memory processing, functions that are disrupted in HD (3). In addition, the HD protein is present in high levels in pyramidal cells (8,9), and these cells are reported to be lost in late-stage HD (10). These factors support the use of the hippocampal preparation to study the effect on synaptic plasticity of the expanded HD allele.

RESULTS

Baseline synaptic function in HD mutant mice

Hippocampal slices were stained with hematoxylin and eosin to test for general developmental abnormalities (data not shown). Slices showed no obvious anatomical abnormalities, in contrast to what is seen with some other targeted mutants (11), suggesting that gross hippocampal architecture is not disrupted by the mutation. To test for general deficits in synaptic function, we examined the input-output relationship of Schaffer collateral-CA1 synapses in response to single electrical stimuli. After placement of stimulating and recording electrodes in the stratum(s) radiatum in area CA1 of a hippocampal slice (Fig. 1A), we turned down the stimulus strength until no field excitatory post-synaptic potential (fEPSP) was evoked. The stimulus was then increased in increments, with four responses collected and averaged at each increment. We continued to increase the stimulus current until the size of the resulting fEPSP had clearly saturated. Data were averaged across all animals in each group (mutant and wild-type) to construct input-output curves (Fig. 1B). There was no significant difference between mutant and wild-type animals in this measure. Input-output curves for fEPSPs can vary for a number of reasons, such as differences in synaptic density or altered strength of individual synapses within the population. A lack of difference between mutant and wild-type animals indicates that these two populations have roughly the same density of synapses within the stratum radiatum of CA1 and that, as a population, these synapses are equally functional in response to single stimuli. Thus, there appear to be no gross differences in synaptic organization or baseline function between mutant and wild-type animals that might confound interpretation of other measures of synaptic function.


Figure 1. Input-output curves do not differ between mutant and wild-type mice. (A) The position of the stimulating and recording electrodes in the stratum radiatum CA1 region of the hippocampus. The Schaffer collateral (SC) fibers were stimulated by an electrode placed in the position indicated, or in an alternate stimulating position marked with an X. Recordings were made in mid stratum radiatum. (B) The mean (±SEM) evoked EPSP across all mice is plotted as a function of stimulus strength for 16 wild-type and 17 mutant animals. There was no significant difference between wild-type and mutant animals anywhere along the input-output curve, indicating that basic synaptic density and function are not affected by the mutation.


Impairment in induction of long-term potentiation (LTP)

Despite our finding that synaptic transmission at its most basic level was normal in HD mutant mice, the strong association of HD with cognitive and memory disturbances prompted us to examine the effects of the mutation on a measurement of synaptic plasticity, namely LTP. LTP is the sustained increase in synaptic strength obtained after a high-frequency conditioning stimulus, and is a compelling model for a synaptic mechanism underlying some forms of learning and memory (12). Stimulus-evoked fEPSPs were recorded in the stratum radiatum of area CA1 of hippocampal slices prepared from either wild-type or mutant mice (Fig. 2). We obtained at least 15 min of stable baseline transmission, testing once every 30 s. Following the baseline period, tetanic stimulation (100 Hz for 1 s, at test intensity, four trains, 30 s apart) was applied. Immediately after the tetanus, we resumed testing of synaptic strength by returning to the test stimulus of 1 per 30 s for at least 70 min. All experiments in wild-type or mutant slices were aligned relative to the time of tetanic stimulation, and the average amount of potentiation relative to baseline was determined at 70 min post-tetanus. Wild-type animals displayed potentiation of 132 ± 9.1% at 70 min post-tetanus, while mutant animals showed significantly (P < 0.05) less (112 ± 5.2%) (n = 16 wild-type, 17 heterozygotes).


Figure 2. LTP is impaired in slices from mutant HD mice. LTP, recorded for 70 min post-tetanus in wild-type (circle) and mutant (triangle) slices, following a 15 min baseline. Data points represent the mean response (±SEM) of 16 wild-type and 17 mutant animals. The insets show representative field recordings from a wild-type and a mutant animal at the time points indicated. In wild-type slices, the synaptic potential was elevated 132 ± 9.1% at 70 min, while the mutant potentials were elevated only 112 ± 5.2%. The difference between wild-type and mutant was significant at P < 0.05 for all points later than 15 min post-tetanus. Differences in post-tetanic potentiation were also significant (P < 0.05).

Despite the finding that LTP, on average, was significantly impaired in mutant compared with wild-type animals, we noted that a small number of mutant slices (four out of 32 slices, from four different animals) exhibited LTP that was indistinguishable from wild-type. It is possible that the mutation was not completely penetrant in those few slices, but that in those slices where the mutation was penetrant, it completely disabled LTP. However, a more likely explanation is that the mutation does not disable the LTP mechanism, but rather raises the threshold for inducing LTP or has some effect that makes tetanic stimulation less effective in reaching that threshold. Because LTP would be intact but more difficult to induce under the latter hypothesis, occasional successes in producing LTP would be expected.

To test the idea that the LTP mechanisms were intact in mutant animals, we attempted to produce potentiation in mutant slices using a stronger inducing stimulus. Slices that failed to show LTP to the first tetanic stimulation subsequently were subjected to an `enhanced' tetanic stimulation consisting of six 1 s long trains at 100 Hz (30 s apart), with the stimulus duration set to twice the test duration. Under these conditions, slices from mutant mice produced LTP that was indistinguishable from that of wild-type slices subjected to the same enhanced tetanic stimulation (Fig. 3). Although the standard tetanic stimulation (four trains at 100 Hz for 1 s) used in Figure 2 would not be characterized as `weak' compared with protocols from most other laboratories (e.g. refs 13,14; two trains of 25 pulses at 100 Hz or two 1 s trains at 100 Hz), it is below the threshold for inducing LTP in the majority of mutant slices. Thus, the HD mutation does not appear to act directly on the LTP mechanism. Rather, it appears to act by an indirect mechanism, making it more difficult to reach the threshold for LTP induction.


Figure 3. Normal LTP can be induced by an enhanced tetanus in HD mutant slices. Slices that failed to respond to the first standard tetanic stimulus (100 Hz for 1 s; four trains, 30 s apart) were subjected to a second, stronger tetanic stimulus (100 Hz for 1 s, six trains with stimulus pulse duration set at twice the test duration, 30 s apart). This second tetanus induced potentiation to the same extent in wild-type and in mutant slices [137 ± 20.9% potentiation in wild-type (n = 8 animals) at 70 min, 124 ± 5.0% in mutant (n = 7 animals); P < 0.27]. Insets are as described in Figure 2.


Post-tetanic potentiation and paired pulse facilitation

An additional observation arises from our data that might point toward a mechanism to account for the failure of mutant slices to achieve LTP with the standard inducing stimuli. Mutant animals show an impairment of the post-tetanic potentiation (PTP) immediately following tetanic stimulation (Fig. 2). Unlike LTP, this deficit is present with both the standard and enhanced tetanic stimulation, indicating that a deficit in PTP, unlike LTP, is probably not of a threshold nature. Following standard tetanization, slices from wild-type animals showed PTP of 231 ± 15.3%, while mutants showed only 178 ± 11.5% (n = 16 wild-type, 17 mutant animals; difference significant at P < 0.05). Following enhanced tetanization, wild-type slices again showed significantly greater PTP (233 ± 20.0%, n = 8 slices) than mutant slices (173 ± 13.78 %; n = 7 slices; difference significant at P < 0.05). The deficit in PTP persists even when LTP is unaltered, suggesting that an underlying change in LTP cannot account for the observed change in PTP. Since PTP is thought to arise from processes in the presynaptic terminal, this might indicate that the HD mutation is altering synaptic function at a presynaptic locus.

To examine potential presynaptic influences of the HD mutation, we examined paired pulse facilitation (PPF) in slices from mutant and wild-type animals. PPF occurs when two stimuli are delivered to synapses in rapid succession, resulting in the facilitation of the synaptic response to the second stimulus. PPF is represented as the ratio of the response to the second stimulus divided by the response to the first. PPF is a measure of presynaptic function, thought to result from an increase in transmitter release probability caused by calcium influx into the presynaptic terminal during the response to the first stimulus. Two stimuli were delivered to a slice in rapid succession, with the interpulse interval being varied in decrements from 1 s to 40 ms. In wild-type slices, significant PPF was observed at intervals from 40 to ~200 ms. In contrast, slices from mutant animals had less PPF than those from wild-type animals at all intervals (Fig. 4).


Figure 4. Paired pulse facilitation is decreased in the HD mutant slices. Facilitation is displayed as the ratio of the slope of the evoked EPSP of the second of a pair of pulses to the slope of the EPSP recorded from the first pulse. This ratio is plotted as a function of the interpulse interval; n = 16 wild-type and 17 mutant animals (mean ± SEM). *Points that show a statistically significant difference in a Student's t-test at P < 0.05. Traces (a) and (b) are typical paired pulse recordings from wild-type (a) and mutant (b) slices taken at an interpulse interval of 200 ms.

The depression of PPF seen in the mutants, and in particular a depression at longer interpulse intervals, could be explained either by a decrease in the facilitation itself or by an increase in synaptic inhibition. We therefore measured both the fEPSP and the population spike for a subset of experiments. Plots of fEPSP versus population spike showed that there was no difference in the amount of post-synaptic action potential discharge for a given EPSP between mutant and wild-type synapses (data not shown), suggesting that there is no difference in functional synaptic inhibition between the two types of animals, and thus that the defect is in PPF itself.

Involvement of the presynaptic terminal

The impairment of both PPF and PTP suggests that the presynaptic terminals in mutant animals, while responding normally to single stimuli, are less able to sustain neurotransmitter release with repetitive stimulation. However, neither PTP nor PPF is a direct measure of the transmitter release from the presynaptic Schaffer collateral terminals. To obtain a more direct measure, we took advantage of the unique properties of MK-801, an irreversible blocker of the N-methyl-d-aspartate (NMDA) receptor channel. MK-801 can enter the pore of the NMDA receptor only when the the channel is open, and its presence blocks subsequent ion flux through this channel. During each synaptic stimulation, those NMDA channels opened by glutamate will be blocked by MK-801 and will be unavailable to conduct current during subsequent synaptic stimuli. Thus, the rate of decline of the NMDA component of the synaptic potential in the presence of extracellular MK-801 is proportional to the rate of glutamate release during synaptic activation (15,16). We used this effect to test the hypothesis that excitatory synapses in mutant animals release glutamate normally at low frequencies, but are impaired at higher frequencies. This was achieved by comparing the rates of MK-801 blockade of NMDA EPSPs in wild-type and mutant animals, under conditions of low and high frequency synaptic demand. Hippocampal slices were bathed in the [alpha]-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) receptor antagonist CNQX (10 µM) in artificial cerebrospinal fluid (ACSF) with the magnesium removed. Under these conditions, NMDA-only EPSPs were recorded with intracellular recording. Application of MK-801 was followed by one of two different stimulation protocols, termed `slow' and `fast'. `Slow' stimulation consisted of single shocks delivered to the presynaptic Schaffer collaterals at a rate of 0.1 Hz. This rate was chosen because our earlier PPF experiments indicated that there was no interaction observed between stimuli delivered 10 s apart. `Fast' stimulation consisted of a single test pulse followed after 500 ms by a brief train of stimuli (10 Hz for 1 s). This test pulse-train protocol was repeated every 10 s. Both the `fast' and `slow' stimulation protocols were applied to mutant and wild-type slices until the MK-801-induced blockade of the NMDA EPSP reached an asymptote. Rates of decline of the EPSPs were then calculated and these rates were compared between mutant and wild-type animals (Fig. 5). When Schaffer collaterals were stimulated at low frequency (0.1 Hz), the rate of MK-801 blockade of NMDA EPSPs recorded in CA1 pyramidal cells did not differ between mutant and wild-type slices (mean tau, wild-type: 0.029 ± 0.004, n = 9; mutant: 0.025 ± 0.008, n = 9; difference not significant, P > 0.6 one-way unblocked ANOVA). However, when the slices were stimulated at a higher frequency (10 Hz), the rate of blockade was significantly slower in mutant than in wild-type slices (wild-type: 0.219 ± 0.031, n = 9; mutant: 0.102 ± 0.013, n = 8; P = 0.0038 one-way unblocked ANOVA). Thus, while the glutamatergic synapses in area CA1 can transmit normally in response to single stimuli, they are impaired in their ability to sustain normal levels of transmitter release at even moderate frequencies of activation. Extrapolating from the paired pulse data, where deficits could be detected at interpulse intervals as long as 1 s, we conclude that this HD-induced deficit extends to frequencies as low as 1 Hz.


Figure 5. Synaptic glutamate release is reduced in heterozygous Huntington mutants for moderate/high frequency transmission, but not low frequency synaptic transmission. (A and B) Each graph illustrates a representative example of the decline in the NMDA receptor-mediated EPSP following the application of 40 µM MK-801. The amplitude of the EPSP is plotted against the trial number, at one trial per 10 s. Stimulation at a rate of 0.1 Hz (`slow' protocol) resulted in equally slow declines in the EPSP in slices from wild-type (panel A1, WT) and heterozygous mutant (panel B1, Het) animals. During the `fast' protocol, a higher frequency train of stimuli (10 Hz for 1 s) was delivered between each test stimulus in both wild-type (panel A2) and mutant (panel B2) recordings. The 0.1 Hz test stimulus revealed a much faster MK-801-induced decline in transmission, which was significantly slower in slices from mutant animals. The arrowhead in each graph marks the time when MK-801 was added to the bath. At this time, stimulation was stopped for 10 min to allow the drug to reach concentration in the slice. The insets show representative traces of the NMDA EPSPs during the MK-801-induced blockade. (C) A bar plot showing the average rate of decay (tau) across all experiments in wild-type and mutant slices, for the slow and fast protocol. *Statistically significant difference (in mutant relative to wild-type; P = 0.038).


DISCUSSION

We have engineered mice to carry an expanded polyglutamine stretch inserted into the endogenous mouse HD gene. This construction most closely mimics the mutation found in patients with HD, in that the mutant allele is expressed under the control of the intact endogenous promoter and in tissues and at levels dictated by the endogenous regulatory elements. Thus, we hope to avoid confounding situations caused by over-, ectopic or abnormal expression of the mutant protein. In addition, the relative contributions of normal and wild-type alleles are maintained.

The mice used in this study have 72 or 80 CAG repeats, a length which in humans leads to juvenile-onset HD, where movement symptoms may occur as early as 6 years of age. Based on results with overexpression models of HD (e.g. ref. 6, discussed above), we would predict that the movement and cell-loss symptoms of HD are caused by a slow accumulation of polyglutamine-containing huntingtin degradation products, and would be seen in the mouse model used in this study were mice able to survive to 6 years of age. Furthermore, we suggest that the results reported here represent the earlier stages of HD, occurring before observable accumulation of degradation products, and which underlie the early, cognitive symptoms of HD.

We have presented evidence suggesting that presynaptic terminals in mutant animals are less able to sustain release during a tetanic stimulation. A model consistent with this hypothesis is that the HD protein acts in the presynaptic terminal, at or near a site in the synaptic vesicle trafficking pathway, to influence neurotransmitter release. Indeed, the wild-type HD protein has been seen associated with microtubules and synaptic vesicles, and is enriched at the nerve terminal (17-19). A deficit in vesicle release or recycling could account for the decrease in LTP induction seen in the slices from mutant animals, where decreased transmission during tetanization would lead to less post-synaptic depolarization and thus to weaker LTP induction. Rather than a change in the threshold for LTP, these data suggest that the threshold for LTP induction may be the same, but the synapse is less able to sustain transmitter output to surpass that threshold during tetanic stimulation in mutant animals.

Similarly, the mutation may work to impair PPF and PTP either directly or indirectly. A direct mechanism might, for example, have the mutation interacting with the calcium handling mechanisms of the presynaptic terminal to decrease both PPF and PTP. An indirect mechanism might leave the processes of PPF and PTP functionally intact, but would decrease their expression by impairing a common underlying process such as the cycling of synaptic vesicles to their release site. While our data do not rule out a direct impairment of PPF, PTP and LTP, the simplest hypothesis that accounts for all three deficits holds that the HD synapse is impaired in its ability to support these processes because of a single underlying deficit, such as an inability to move vesicles to the point of release as efficiently as in wild-type animals.

Impairment of synaptic transmission even at moderate frequencies could arise from a disruption of the vesicle recycling, docking or fusion machinery through a gain-of-function mechanism; for example, by abnormal aggregation of the HD protein or a portion thereof. Such aggregation has been reported in patients with HD (20,21) and in other polyglutamine diseases (22,23). Alternatively, impairment of synaptic transmission could be caused by a loss-of-function mechanism, whereby the mutation reduces the normal function of the protein. There is evidence that in patients with the polyglutamine disorder spino-bulbar muscular atrophy, the expansion in the androgen receptor gene leads to slight impairment of the wild-type function of that protein (24). The presence of the expanded polyglutamine stretch in the HD protein could similarly reduce its normal function, resulting in a reduction in the ability of neurons to sustain higher frequency synaptic vesicle release; for example, by altering the strength of its interaction with other proteins, or by sterically hindering the protein from adopting its normal conformation.

Regardless of whether the phenotype arises from a gain or loss of function, these studies indicate that the Huntington mutation results in an impairment in the ability of excitatory synapses in cortical areas to respond fully to activation rates even as low as 1 Hz, well within the range of normal physiological synaptic activation. Such a defect in the ability of synapses to transmit normally at such low frequency would disrupt not only LTP, but virtually every known manifestation of activity-dependent synaptic plasticity. Evidence of involvement of the HD protein in vesicle trafficking or release would suggest a possible cause of, and sites of therapeutic intervention for, the dementia and other cognitive symptoms of HD. Thus, these results identify a strong potential substrate for understanding the cognitive deficits that make up the major symptomatology of the early stages of HD.

MATERIALS AND METHODS

Mouse strains and hippocampal field recordings

The progeny of two different founder mice, containing 72 and 80 glutamines, were used in this study. RNA and western blot analyses of these mice indicate that they express the mutant huntingtin RNA and protein at levels comparable with those seen in tissues from individuals with HD. The mutation was maintained on C57Bl/6 and FVB backgrounds, and experiments were performed using heterozygous mutant animals from the third backcross generation, and either wild-type littermates or parental strain controls. Only four age-matched littermates were available for this experiment, so the remainder of the cohort was made up of parental strain controls. The mutant phenotype observed was not present in either parental strain, in the four wild-type littermates or in age-matched 129sv mice. The results have since been confirmed on a younger cohort using mutant mice and their wild-type littermates, both from the sixth and seventh back-cross generation. The findings reported here were observed in mutant animals from both backgrounds.

Transverse hippocampal slices (400 µm) were prepared by standard techniques from 8-14-month-old wild-type (FVB/N and C57BL/6; Charles River Laboratories, Wilmington, MA) and heterozygous mutant HD mice (C57BL/6x129 or FVB/Nx129, age and strain matched). Both strains behaved similarly in these experiments and the data were pooled. Slices were incubated for at least 1 h in a humidified 95% O2/5% CO2 atmosphere and then transferred to a submersion recording chamber and continuously perfused with ACSF (120 mM NaCl, 5 mM KCl, 1.3 mM MgCl2, 2.5 mM CaCl2, 1.25 mM NaH2PO4, 26 mM NaHCO3, 11 mM glucose; Fluka, Neu-Ulm, Switzerland) equilibrated with 95% O2/5% CO2. Electrodes were placed as shown in Figure 1. Schaffer collateral fibers were stimulated with a tungsten bipolar electrode. Constant current stimuli of 100 ms duration were delivered at a rate of 1 per 30 s, except during collection of input-output data, during tetanization and during collection of PPF and MK-801 data, when rates were higher, as specified. The baseline stimulus current was set at a value that produced an EPSP approximately one-third of the way up the input-output curve. Stimulating electrodes were placed midway between the stratum pyramidale and the hippocampal fissure, either at the CA2-CA1 border or in CA1 near the subiculum (Fig. 1). fEPSPs were recorded with glass microelectrodes filled with saturated NaCl. The recording electrode was placed in mid-CA1, half way between the stratum pyramidale and the hippocampal fissure. All recordings were performed at room temperature (24°C). Two slices were recorded from each animal. The data from both slices were averaged to give one measurement from each animal. For the purposes of reporting and significance testing, the `n' value was the number of animals, not the number of slices. All experiments were performed blind to the genotype of the animal. All data were collected and analyzed before the identity of the animals was revealed. For construction of input-output curves, the stimulation frequency was increased to 1 per 5 s. Four EPSPs were collected at each stimulus value and averaged. In paired pulse experiments, the stimulation frequency was 1 per 10 s. Two values were collected for each time interval and averaged. `Standard' tetanic stimulation consisted of four 1 s trains of stimuli, delivered at 100 Hz at test intensity and pulse duration, with 30 s between trains. The `enhanced' tetanic stimulation was the same as standard, except that six trains were delivered and stimulus pulse duration was doubled to 200 ms. All animal experiments were conducted in strict accordance with a protocol approved by the Stanford University Animal Use and Care Committee.

Intracellular recordings

Intracellular recordings were made with sharp microelectrodes (120-220 M[Omega]) in 350 µm slices made from 2-4-month-old FVB heterozygote mice or their wild-type littermates. Slices were incubated in circulating oxygenated ACSF for 30 min at 30°C and then maintained in the same solution at room temperature until use. Electrodes were filled with 2 M KMeSO4 and 50 mM QX314 (Alamone Labs, Jerusalem, Israel) (to block the action potential). Hippocampal slices were maintained in the presence of 10 µM CNQX (Tocris-Cookson, Bristol, UK) and ACSF with all magnesium removed. In these conditions, an NMDA-only EPSP was recorded in response to Schaffer collateral stimulation. Slices were stimulated at a rate of 0.1 Hz until a stable EPSP was obtained. Stimulation was then stopped, and 40 mM of the NMDA open channel blocker MK-801 (RBI, Natick, MA) was added to the bath. After 10 min of MK-801 perfusion in the absence of stimulation, stimulation was resumed, using either a low frequency (slow) or higher frequency (fast) protocol. The `slow' protocol consisted of 0.1 Hz stimulation of the Schaffer collaterals that was continued until the amplitude of the EPSP reached an asymptote. The `fast' protocol consisted of a series of 10 Hz stimulus trains of 10 pulses each (i.e. 1 s). Each train was preceded by a single test stimulus used to measure the EPSP. The test pulse-train sequence was applied every 10 s, until the EPSP reached asymptote. The rate of decay of the EPSP in the presence of MK-801 was calculated using IGOR software (Wavemetrics, Lake Oswego, OR) and average tau values were computed. Statistical significance for differences between wild-type and heterozygous animals was assayed for both the fast and slow protocols with one-way unblocked ANOVA.

ABBREVIATIONS

ACSF, artificial cerebrospinal fluid; fEPSP, field excitatory post-synaptic potential; HD, Huntington's disease; LTP, long-term potentiation; NMDA, N-methyl-d-aspartate; PTP, post-tetanic potentiation; PPF paired pulse facilitation.

ACKNOWLEDGEMENTS

We thank Lucia Ramirez for excellent technical assistance, and members of the Myers and Madison laboratories for useful discussions and support. This work was supported by an award from the Wills Foundation and NIH grant NS 262237 (to R.M.M.), and a National Institute of Mental Health Silvio Conte Center for Neuroscience Research grant no. MH48108, and the Harold G. and Leila Y. Mathers Charitable Foundation (to D.V.M.). Part of this work was performed at the Marine Biological Laboratory, Woods Hole, MA.

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*To whom correspondence should be addressed. Tel: +1 650 725 7563; Fax: +1 650 725 4628; Email: madison@leland.stanford.edu

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