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REPORT
Department of Neurobiology and Anatomy, W.M. Keck Center for the Neurobiology of Learning and Memory, The University of Texas Medical School at Houston, Houston, Texas
Submitted 8 December 2004; accepted in final form 19 March 2005
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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). In previous studies, the cellular mechanisms that underlie these forms of learning have been analyzed by probing the synapse with a single presynaptic spike. However, mechanical or electrical stimuli sufficient to evoke a reflex elicit brief (1–2 s) bursts of spikes at moderate frequencies (10–30 Hz) (Antonov et al. 1999; Byrne et al. 1974, 1978; Phares et al. 2003; Walters et al. 1983). These observations raise the question of whether probing synaptic plasticity with a single spike reveals the full extent of the underlying mechanisms. Probing synaptic plasticity with brief bursts might expose novel mechanisms contributing to that synaptic plasticity. The interactions of activity-dependent short-term plasticity (e.g., depression or facilitation of a synapse during a burst of presynaptic action potentials) with the effects of a modulatory transmitter are difficult to predict from the effects of the modulator on isolated postsynaptic responses. For example, Hjelmstad (2004) found that dopamine differentially inhibits excitatory and inhibitory synapses onto medium spiny neurons in the rat nucleus accumbens during bursts. Although dopamine inhibited only the first few post synaptic responses of excitatory synapses, the modulator reduced inhibitory responses throughout a burst (Hjelmstad 2004).
Given that 5-HT is known to facilitate sensorimotor synapses probed with single presynaptic spikes, does 5-HT lead to a uniform increase in postsynaptic potential (PSP) amplitude during a burst (i.e., no change occurs in the short-term, activity-dependent dynamics of synaptic efficacy), or are the PSPs differentially facilitated (i.e., the short-term, activity-dependent dynamics of synaptic efficacy are altered so that facilitation is greater during one part of the response than another)? A uniform increase in the gain of synaptic efficacy might result from an increase in the size of the releasable pool of synaptic vesicles, activation of silent synapses, or a combination of modulatory effects such as an increase in release probability coupled with enhanced mobilization of vesicles to release sites (e.g., see Brager et al. 2002; Buonomano 1999; Phares et al. 2003; Selig et al. 1999). In contrast, differential modulation might occur with an increase in the fractional release due, for example, to an increase in release probability or prolongation of spike duration (Brager et al. 2002; Buonomano 1999; Markram and Tsodyks 1996; Phares et al. 2003; Tsodyks and Markram 1997; Wang and Kaczmarek 1998). These distinct forms of modulation can lead to differences in information transfer across the synapse as well as the output pattern of the postsynaptic neuron (Abbott and Regehr 2004; Buonomano 1999; Phares et al. 2003).
Protein kinases A and C mediate short-term facilitation at Aplysia sensorimotor synapses in a time- and state-dependent manner (see Byrne and Kandel 1996). These kinases would be expected to contribute to facilitation of the first postsynaptic response of a burst as they do for isolated responses. However, facilitation of postsynaptic responses throughout a burst raises the question of whether different kinase cascades contribute to the different phases of facilitation. For example, extracellular signal-regulated kinase (ERK) has been implicated in many examples of synaptic plasticity (Casey et al. 2002; Chi et al. 2003; Koh et al. 2002; Martin et al. 1997; Mazzucchelli et al. 2002; Morozov et al. 2003; Opazo et al. 2003; Purcell et al. 2003; Thiels et al. 2002; Watabe et al. 2000; Watanabe et al. 2002; Winder et al. 1999; Zhang et al. 2003a), but ERK does not seem to be involved in the 5-HT–induced facilitation of the sensorimotor PSP when probed with a single spike (Martin et al. 1997; Purcell et al. 2003). Might a role for ERK be revealed by probing with a burst of spikes?
Indeed, recent results raise the possibility that ERK might also contribute to short-term facilitation under conditions that more strongly challenge the release process (Angers et al. 2002; Chin et al. 2002). 5-HT leads to a rapid, ERK-dependent phosphorylation of synapsin that is associated with the dispersion of synapsin-like immunoreactivity at putative release sites in sensory neurons, which may contribute to vesicle availability for recruitment into the releasable pool (Angers et al. 2002). In addition, transforming growth factor-
1 produces an ERK-dependent dispersion of synapsin-like immunoreactivity and a reduction in short-term homosynaptic depression at sensorimotor synapses stimulated at 1 Hz (Chin et al. 2002). These results suggest that, although ERK may not contribute to the enhancement of transmitter release in response to a single spike, it may participate in facilitation during bursts.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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Aplysia californica (75–350 g) were obtained from Alacrity Marine Biological Specimens (Redondo Beach, CA) and Marinus (Long Beach, CA) and were maintained in an aquarium containing artificial seawater (ASW) at 
15°C. Animals were anesthetized by injecting isotonic MgCl2 (50% body weight).
Pleural-pedal ganglia were removed from the animal and pinned to the Sylgard-coated floor of a recording chamber. To reduce synaptic transmission during dissection, ganglia were bathed in low Ca2+/high Mg2+ ASW (composition in mM: 380 NaCl, 10 KCl, 1 CaCl2, 80 MgCl2, 20 MgSO4, 2.5 NaHCO3, and 10 HEPES; pH 7.7). All dissections and experiments were performed at 15°C. The connective tissue sheath was surgically removed from each ganglion. To suppress spontaneous and polysynaptic inputs without affecting the amplitude of evoked monosynaptic excitatory PSPs (EPSPs) (Trudeau and Castellucci 1992), the bathing medium was exchanged with high Ca2+/high Mg2+ ASW (in mM: 386 NaCl, 8 KCl, 13.8 CaCl2, 90 MgCl2, 20 MgSO4, 2.5 NaHCO3, and 10 HEPES; pH 7.7). The volume of saline in the recording chamber was adjusted to 600 µl, and the ganglia were allowed to rest a minimum of 1 h before an experiment.
Electrophysiology
Tail sensory and motor neurons were identified based on their location, size, and electrical properties. Standard electrophysiological techniques were used to stimulate intracellularly tail sensory neurons and to measure EPSPs in tail motor neurons (Phares et al. 2003; Sugita et al. 1992). To ensure the accurate measurement of depressed EPSPs/excitatory postsynaptic currents (EPSCs), only synapses with initial EPSP amplitudes 
3 mV were used. Motor neurons were hyperpolarized to –80 mV to prevent the EPSPs from triggering spikes. The sensory neuron was stimulated for 1 s at 10 Hz (10-ms pulses, 100-ms interpulse interval) with a current that was 1.3 times threshold. After recording one burst in current-clamp mode to test the initial EPSP amplitude criterion, the amplifier was switched into two-electrode voltage-clamp mode with a holding potential of –80 mV. Three additional bursts were elicited with an interburst interval of 10 min. This interburst interval allows the synapse to recover from any homosynaptic plasticity that may have been evoked by the preceding burst (Phares et al. 2003).
Pharmacological treatments
Three experimental groups were examined: control, 5-HT, and 5-HT + U0126. For each group there was a 1-h pretreatment with either DMSO (0.2% final concentration) or U0126 (Promega, 20 µM final concentration, dissolved in DMSO), an inhibitor of MEK, the kinase that activates ERK (Davies et al. 2000; Favata et al. 1998). In preliminary experiments, neither DMSO nor U0126 appeared to affect basal synaptic transmission. Therefore the control group was pretreated with U0126 (control group), and two 5-HT groups were included: one pretreated with DMSO (5-HT group) to probe facilitation during bursts and another pretreated with DMSO + U0126 (5-HT + U0126 group) to probe for the involvement of ERK in facilitation during bursts. The concentration of U0126 used for these experiments was previously shown to completely block the phosphorylation of synapsin by ERK in pleural-pedal ganglia treated with 5-HT (Angers et al. 2002) and reduce basal ERK activation (Chin et al. 2002; Purcell et al. 2003).
Short-term facilitation was produced using 5-HT. A 0.2 mM stock solution of 5-HT (creatine sulfate salt, Sigma) dissolved in high Ca2+/high Mg2+ ASW was prepared daily. A 30-µl bolus of either 5-HT (final bath concentration 10 µM) or high Ca2+/high Mg2+ ASW (control) was applied and mixed into the bath 5 min before the onset of the fourth burst. The experimenter was blind to both the pretreatment and treatment.
Data analysis
Electrophysiological data were sampled (3 kHz), stored using custom software (HPVEE 4.0, Hewlett-Packard, Palo Alto, CA), and transferred to Microsoft Excel or OriginLab Origin for analysis. Facilitation ratios were calculated for the initial EPSC and for the EPSCs during the steady-state phase of the response (EPSCs 6–10) by dividing the peak amplitude of each EPSC of the burst after treatment (posttest) by the corresponding EPSC of the burst that was elicited just before treatment (pretest). Facilitation ratios during the steady-state phase of the burst were averaged. The level of steady-state depression was measured as the average normalized amplitudes of EPSCs 6–10.
The time to peak and decay time constant (
) of initial and final EPSCs within bursts were compared before and after treatment. Time to peak was calculated as the time for the EPSC to traverse from baseline to its peak amplitude. To determine , the decay phase of the EPSC from 80% of the peak to the return to baseline were fit in Origin using the following equation: EPSC = A x e(–t/) + baseline.
All values are reported as means ± SE. Facilitation ratios were analyzed by two-factor ANOVA with repeated measures using Sigmastat 2.0 (Jandel Scientific). The first between-subject factor (i.e., treatment) had three levels: control, 5-HT, and 5-HT + U0126. For facilitation ratios, the second within-subject factor (i.e., phase, the repeated measure) had two levels: the initial and steady-state phases of the burst. Statistical analyses of the time to peak and the of decay were performed using SPSS version 10.1 by four-factor ANOVA with repeated measures. Each factor had two levels. Between-subject factors were 1) pretreatment with DMSO or U0126 and 2) treatment with ASW or 5-HT. Within-subject factors (repeated measures) were 1) first versus last EPSC of a burst and 2) before versus after treatment with ASW or 5-HT. Interactions of the pretreatment or treatment factors with each other and with each of the within-subject factors were also examined. For significant effects with more than two factors, Tukey posthoc tests were performed.
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RESULTS |
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The initial EPSC of each burst was characterized by its peak current, time to peak, and decay time constant (). Before treatment with ASW or 5-HT, no difference was observed in the amplitudes of the initial EPSC of bursts among the different groups [F(2,21) = 1.067, P = 0.362]. The average peak current of the initial EPSCs were 13.9 ± 1.5 nA for control (n = 6), 23.4 ± 5.1 nA for 5-HT (n = 12), and 16.2 ± 5.3 nA for 5-HT + U0126 (n = 6). The mean time to peak of the first EPSC before control treatment was 8.3 ± 0.6 ms (for values by group, Table 1) and averaged 12.1 ± 0.6 ms (for values by group, Table 1). Because sensorimotor synapses are located near the soma on neurites in the pedal ganglion neuropil (Zhang et al. 2003b), it is likely that voltage clamping the somata led to reasonable clamp of the synaptic region. Indeed, the EPSC decay was well fit by a single exponential (Fig. 1A), suggesting that the kinetics measurements presented in Table 1 are representative of the actual kinetics of the currents at the postsynaptic membrane (Johnston and Brown 1983).
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). This degree of depression of synaptic currents is also consistent with qualitative results from previous studies that have examined depression of synaptic potentials elicited by a burst of spikes (Antzoulatos et al. 2003; Buonomano and Byrne 1990; Eliot et al. 1993; Walters and Byrne 1983, 1984; Zhao and Klein 2002). When repeated at an interburst interval of 10-min, 10-Hz trains of presynaptic spikes resulted in comparable postsynaptic responses (Phares et al. 2003; see also Eliot et al. 1993). In the control group, the pretest and posttest bursts of EPSCs were similar (Figs. 2A and 3), indicating that the synapse had recovered from the depression that developed during the burst as well as other forms of activity-dependent plasticity (e.g., posttetanic potentiation).
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0.5 Hz (Edstrom and Lukowiak 1985). Because a single electrode was used to both inject current and record membrane potential of the sensory neuron and the sampling rate was low relative to duration of sensory neuron spikes (1–3 ms), we were unable to quantify spike durations. However, changes in spike duration can be inferred from changes in time to peak of the synaptic response. As shown Fig. 1 and Table 1, the time to peak of the last EPSC was longer than that of the first EPSC in a burst on average [F(1,21) = 14.4, P = 0.001]. The decay time constant, , of the 10th EPSC was also greater than that of the 1st [Table 1; F(1,21) = 20.1, P < 0.001], which suggests an overall slowing in EPSC kinetics during a burst. 5-HT enhanced synaptic efficacy throughout bursts
The facilitation ratios for both the initial and steady-state EPSCs recorded during bursts at sensorimotor synapses were analyzed by two-factor repeated measures ANOVA for three treatment groups (control, 5-HT, and 5-HT + U0126) and two phases of the bursts (initial and steady state). The analysis revealed a significant effect of treatment on the facilitation ratio [F(2,21) = 5.57, P = 0.012], but no significant effect of burst phase. Tukey posthoc analyses were performed to compare the three treatment groups. The 5-HT group (n = 12) was significantly different from the control group (n = 6; q = 4.89, P 
0.05). 5-HT produced a slight trend toward increased times-to-peak and slower decay time constants of the initial EPSC, but these effects were not statistically significant [time to peak: F(1,21) = 0.6, P = 0.46; : F(1,21) = 1.9, P = 0.18; Table 1]. Taken together, these analyses indicate that 5-HT facilitated synaptic transmission (the significant effect of treatment), and that the degree of enhancement was the same for the initial and steady-state phases of the response to a burst (the lack of significance in the effect for phase or of an interaction of phase with treatment; Figs. 2 and 3).
ERK does not contribute to 5-HT–induced facilitation during bursts
To test the hypothesis that ERK is involved in short-term 5-HT–induced facilitation of EPSCs during bursts, ganglia were treated with U0126, an inhibitor of MEK (the kinase that activates ERK), before treatment with 5-HT (see METHODS). Treatment of ganglia with U0126 did not affect the kinetics of EPSCs when analyzed by four-way ANOVAs comparing DMSO and U0126 pretreatments [Table 1; for time to peak: F(1,21) = 0.2, P = 0.69; for : F(1,21) = 1.62, P = 0.22]. Moreover, the facilitation ratios for the 5-HT group were not statistically different from the facilitation ratio of the 5-HT + U0126 group (Tukey posthoc analysis: q = 0.36, P > 0.05; Figs. 2, B and C, and 3). Thus the engagement of the ERK cascade does not seem to be necessary for 5-HT–induced short-term facilitation of synaptic transmission at sensorimotor synapses during 10-Hz bursts.
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DISCUSSION |
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). Although STF has been studied extensively, previous studies did not assess modulation during bursts of sensory neuron activity, which are more behaviorally relevant (Phares et al. 2003). Using bursts of action potentials to probe the voltage-clamped postsynaptic response, we found that 5-HT produced a uniform increase in the gain of sensorimotor synapses (Figs. 2 and 3). Simulations indicate that such a gain increase is likely to contribute to the prolongation of activity in the motor neurons and thereby enhance the ability of the motor neurons to drive a behavioral response (Phares et al. 2003).
A number of forms of plasticity are evoked by firing Aplysia sensory neurons in bursts. As seen in Fig. 2 and other published examples, bursts induce homosynaptic depression. At frequencies of 10 Hz and above, this homosynaptic depression differs from the depression that is evoked at lower frequencies in at least one mechanism: desensitization of postsynaptic receptors (Antzoulatos et al. 2003). The presence of desensitization suggests that the uniform gain increase observed after treatment with 5-HT may represent a relative increase in transmitter release that balances or compensates for the decreased receptor sensitivity. Despite the depression that occurs during a burst, trains of presynaptic spikes prevent or reverse the depression associated with low frequency stimulation (Jiang and Abrams 1998). However, this form of plasticity would not be detected in the protocol used in this study due to the long interburst interval. Aplysia sensorimotor synapses also exhibit posttetanic potentiation (PTP) (e.g., Clark and Kandel 1984; Walters and Byrne 1984). Because the stimulus used in this study are of lower frequency and shorter duration than used by others (Bao et al. 1997; Eliot et al. 1994; Jin and Hawkins 2003; Schacher et al. 1990; Schaffhausen et al. 2001), PTP is likely to have dissipated by the end of the 10-min interburst interval and thus unlikely to have contributed to the postsynaptic response. Indeed, we observed stable responses with repeated bursts of activity separated by 10 min (Fig. 2A).
The finding that 5-HT produced a uniform increase of synaptic strength is important because it constrains the type of mechanisms that contribute to STF. Both an increase in the fraction of vesicles released due to spike broadening and other mechanisms such as enhancement of action potential-secretion coupling and an increase in the size of the releasable vesicle pool have been suggested to contribute to STF (for review, Byrne and Kandel 1996). A uniform gain increase is unlikely to be due solely to mechanisms such as increased fractional release because such a change most often leads to greater depression and a lower level of steady-state synaptic transmission when a synapse is challenged with a burst of spikes (Brager et al. 2002; Brenowitz and Trussell 2001; Brenowitz et al. 1998; Tsodyks and Markram 1997; Wang and Kaczmarek 1998). Therefore our finding of uniform increase in synaptic gain indicates that there must also be an increase in pool size in agreement with theoretical models (Gingrich and Byrne 1985) and the experimental findings in sensorimotor synapses from cultured neurons (Zhao and Klein 2002). Furthermore, although there was a slight trend for 5-HT–treated synapses to have longer times to peak, we found no significant 5-HT–induced change in the time to peak of the synaptic current for either the first or last EPSC within bursts (Table 1). An increased time to peak would be expected if the modulation occurred through spike broadening (Augustine 1990; Castellucci and Kandel 1974; Gandhi and Matzel 2000; Gingrich et al. 1988; Hochner et al. 1986a,b; Klein et al. 1980). The amplitude of the postsynaptic response is linearly related to the duration of artificially (4-amino pyridine or tetraethyl ammonium) prolonged action potentials within the physiological range of spike durations (Gingrich and Byrne 1985; Klein 1994; Sugita et al. 1997). However, at the time we tested for STF (5 min after the onset of the 5-HT treatment), little broadening is expected (Sugita et al. 1997). Sugita et al. (1997) found that 5 min after the onset of 5-HT treatment, spikes broaden by about 25%. This degree of 4-amino pyridine-mediated spike broadening corresponded to only a small increase in EPSP amplitude (15%). Klein (1994) has shown that, in a soma-soma culture system, 5-HT produces the same level of facilitation postsynaptic responses whether it was elicited by a presynaptic spike that was free to broaden or by a spike-like waveform delivered by presynaptic voltage clamp to prevent broadening. Thus our data support the suggestion of Byrne and Kandel (1996) that a spike-broadening independent process is a central mechanism for STF at sensorimotor synapses that is not only important for facilitation after the synapse has been depressed, but also early in the response to 5-HT (Klein 1994; Sugita et al. 1997). 5-HT–induced spike broadening may contribute more significantly to plasticity, for example, after longer durations or at higher concentrations of 5-HT.
Another form of spike broadening, due to repetitive activity rather than 5-HT treatment, also occurs in pleural sensory neurons (Edstrom and Lukowiak 1985). As noted above, we could not directly measure spike durations; however, the occurrence of this phenomenon could be inferred from the increase in time-to-peak values during a burst (Table 1).
Not all STF may be due to presynaptic mechanisms. Application of 20 µM 5-HT for 10 min to isolated siphon motor neurons in culture leads to insertion of AMPA-like glutamate receptors into the membrane (Chitwood et al. 2001). Although such a mechanism would be likely to produce an increase in synaptic gain if it occurs in the presence of the presynaptic neuron, it is unlikely to have contributed to the gain increase we observed because of the time it takes to develop.
In contrast to our findings that 5-HT produced a uniform gain increase in synaptic transmission, differential effects of 5-HT on paired-pulse ratios at sensorimotor synapses in the abdominal ganglion have been reported (Gover et al. 2003; Jiang and Abrams 1998). At rested synapses, which often show paired-pulse facilitation at higher frequencies, as well as at synapses that had been strongly depressed by repeated low frequency stimulation, 5-HT facilitated the first response more strongly than the second using paired spikes at a frequency of 20 Hz. The discrepancy between these findings and those presented in Figs. 2 and 3 may arise from several sources. First, in our experiments, tail sensory and motor neurons were used rather than those that innervate the siphon. The different results may arise from yet unknown differences in the way these populations of neurons respond to bursts of presynaptic activity. Second, the sensorimotor synapses used in the present study had been repeatedly stimulated at 10 Hz. This repeated activation diminishes most of the facilitation of the first few postsynaptic responses and produces a state in which two presynaptic bursts yield nearly identical postsynaptic responses when separated by 3–10 min of inactivity (Fig. 2A; see also Eliot et al. 1993; Phares et al. 2003). In this state, the synapses are neither rested nor depressed. Therefore the affects of 5-HT on postsynaptic responses elicited by moderate to high-frequency stimulation might depend on the state of the synapse.
Based in part on its role in regulation of synapsin dynamics (Angers et al. 2002; Chin et al. 2002), we hypothesized that a role of ERK might be revealed when sensorimotor synapses were probed by bursts. Chin et al. (2002) also found that exogenous transforming growth factor 1 reduced homosynaptic depression of sensorimotor neuron synapses in culture stimulated with a 1-Hz train of presynaptic spikes. Not only was this effect blocked by U0126, but treatment with the MEK inhibitor also produced an increase in the extent of depression during the train without appearing to affect the amplitude of the initial EPSP. However, in this study, U0126 affected neither 5-HT–induced short-term facilitation nor homosynaptic depression at sensorimotor synapses (Figs. 2C and 3). These findings suggest that depression at 1 and 10 Hz may be due, at least partially, to different mechanisms, and that an ERK-dependent recruitment of vesicles from the synapsin-regulated pool may not contribute to transmission during brief, moderate frequency bursts such as those used in this study. However, the contribution of ERK-mediated modulation of synapsin or other proteins involved in the regulation of transmitter release may be revealed under other conditions such as different burst frequency, duration, or spike pattern.
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ACKNOWLEDGMENTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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FOOTNOTES |
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Address for reprint requests and other correspondence: J. H. Byrne, Dept. of Neurobiology and Anatomy, Univ. of Texas Medical School at Houston, 6431 Fannin St., MSB 7.046, Houston, TX 77030 (E-mail: john.h.byrne{at}uth.tmc.edu)
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