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REPORT
1Department of Pediatrics and 2Department of Pediatrics and Pharmacology, University of Colorado Health Sciences Center, Denver, Colorado; and 3Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
Submitted 14 December 2006; accepted in final form 8 February 2007
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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). In this network, periodic, synchronous neural activity resembling interictal EEG spikes occurs as a consequence of the synchronous activation of the entire population of CA3 pyramidal cells. This synchronous activity is driven by a positive feedback cycle composed of action potential–dependent glutamate release at recurrent collateral synapses and the generation of additional action potentials in postsynaptic pyramidal cells (Dingledine and Traub 1990). Given this robust positive feedback, it is a wonder that, once started, the CA3 pyramidal cells ever stop firing. One hypothesis is that transitions of the CA3 and similar networks from bursting to a quiescent state arise from activity-dependent short-term depression of the recurrent collateral synapses (Fedirchuck et al. 1999; Staley et al. 1998; Tsodyks et al. 2000). In this view, the probability of a subsequent burst is limited by the rate of recovery from short-term depression (Staley et al. 2001). Miles and coworkers added the important refinement that for lower levels of network excitability, bursts may not occur immediately after recovery from synaptic depression. Under these conditions, the probability of return to the bursting state is stochastic and dependent on sufficient random synaptic activity igniting the positive feedback cycle that initiates the next up state (Menendez de la Prida et al. 2006).
Activity-dependent depression of CA3 recurrent collateral synapses could occur by multiple mechanisms (Zucker and Regehr 2002). For example, activation of presynaptic adenosine A1 and 
-aminobutyric acid type B (GABAB) receptors modulate glutamate release probability and consequently the up-state duration as well as the probability of return to the up state from the down state (Cohen et al. 2006; Dulla et al. 2005; Masino et al. 2002; Staley et al. 1998). However, even when all known activity-dependent neuromodulators are blocked, the CA3 network continues to regularly oscillate between bursting and quiescent states, suggesting other mechanisms of synaptic depression. The limited number of identified releasable glutamate vesicles in CA3 axon terminals (Harris and Sultan 1995) and activity-dependent exhaustion of releasable glutamate at CA3–CA1 synapses (Dobrunz and Stevens 1997) led to the hypothesis that similar exhaustion of releasable glutamate at CA3–CA3 synapses was the most important determinant of synaptic depression and up-/down-state transitions in area CA3. Evidence to support this idea includes reduced osmotic release of glutamate at the end of a burst (Staley et al. 1998). Another line of evidence would be modulation of burst duration by altered glutamate release rates.
In this study, we tested the hypothesis that CA3 burst timing is determined by synaptic depression and recovery by reducing the rate of release of glutamate using substitution of extracellular Ca2+ with strontium (Sr2+) (Goda and Stevens 1994; Milledi 1966). Glutamate release in Sr2+ was slow and asynchronous, so that Sr2+ reduced the maximum rate of glutamate release at CA3 synapses. Sr2+ also reduced the rate of burst onset, reduced the rate of burst decay, and increased burst duration by more than an order of magnitude.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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Adult (4- to 6-wk-old) male Sprague–Dawley rats were anesthetized with 100 mg/kg pentobarbital and decapitated. The brain was quickly removed and placed into ice-cold high-sucrose solution containing (in mM) 87 NaCl, 2.5 KCl, 25 NaHCO3, 0.5 CaCl2, 7 MgCl2, 1.25 NaH2PO4, 25 glucose, and 75 sucrose. A Leica VT-1000E vibratome (Leica, Nussloch, Germany) was used to cut 400-µm-thick horizontal hemibrain slices that were submerged for recovery for 
90 min in a 50% high-sucrose and 50% artificial cerebrospinal fluid (ACSF) solution, containing (in mM) 126 NaCl, 2.5 KCl, 26 NaHCO3, 2 CaCl2, 2 MgCl2, 1.25 NaH2PO4, and 10 glucose (pH 7.4). Slices were then transferred to a submersion recording chamber, where they were superfused at 4 ml/min with ACSF solution containing (in mM) 126 NaCl, 2.5 KCl, 26 NaHCO3, 1.3 CaCl2, 2.0 MgCl2, 1.25 NaH2PO4, and 10 glucose (pH 7.4). All solutions were saturated with 95% O2-5% CO2 and the recovery chamber was maintained at 32.5°C. Experiments were approved by the University of Colorado Health Science Center Institutional Animal Care and Use Committee.
Electrophysiological recordings
Extracellular recordings were made at 32.5°C using glass pipettes pulled on a Narishige PP-83 electrode puller (Narishige, Tokyo, Japan) and filled with 150 mM NaCl. For recording spontaneous bursts, the recording electrode was placed under visual guidance in the stratum pyramidale of the CA3 region and adjusted so each burst was robust and significantly greater than noise. The placement of the recording electrode remained unchanged for the duration of the experiment. Recordings from Axoclamp 2B amplifiers (Molecular Devices, Union City, CA) were digitized at 2 kHz on a PCI-DAS 1602/16 Board (Measurement Computing, Middleboro, MA) using routines written in Visual Basic 6.0 (Microsoft, Seattle, WA).
For whole cell recordings, GABAA receptors were blocked with picrotoxin (100 µM) and GABAB receptors were blocked with CGP 5584 (1 µM). CA1 was separated from CA3 by knife cut to prevent burst-induced alterations in glutamate availability. CA1 pyramidal cells were visually identified and patch clamped at room temperature. Pipette resistance was 6–9 M
, measured by an Axopatch 200B amplifier (Molecular Devices). The internal patch solution contained (in mM) 135 CsMeSO4, 10 HEPES, 0.5 EGTA, 0.3 Na-GTP, 5 QX314, 4 ATP-Na2, and 4 MgCl2; pH was adjusted to 7.25 with CsOH. Neurons were voltage clamped at –70 mV and the series resistance was constantly measured by a –2-mV prepulse. Minimal stimulation of axons in the Schaffer collateral pathway was performed using a constant-current source (100 µA to 10 mA) every 5 s in the presence of extracellular Ca2+ (2 mM) and during wash-in of 10 mM Sr2+/0 Ca2+ to induce asynchronous release of glutamate onto dendritic spines. Recordings were terminated if changes in series resistance of >10% of baseline occurred. Responses were filtered at 2 kHz and digitized at 20 kHz (Clampex, Molecular Devices). Analysis was performed using Clampfit and responses were filtered using a Butterworth (eight-pole) low-pass filter (5,000 Hz).
Experimental design
Spontaneous network bursts in the CA3 region of the hippocampus were elicited by perfusion of the GABAA receptor antagonist picrotoxin (100 µM) and the GABAB receptor antagonist CGP 5584 (1 µM). After a period of stable bursting(>30 min) CaCl2 was removed from the perfusate by switching to Ca2+-free ACSF. Ca2+ was replaced with various concentrations of SrCl2 ranging from 2 to 10 mM using a Razel syringe pump (Razel, Stamford, CT) for 50 min at each Sr concentration. The number of bursts recorded therefore varied with burst frequency during the fixed 50-min recording time.
Data analysis
Burst characteristics were quantified using the following metrics: interburst interval, burst duration, peak amplitude, time-to-peak amplitude, and area under burst. All burst durations were measured as the time above an absolute threshold level set to threefold the baseline noise (Staley et al. 1998). When afterdischarges were present, they were included in the burst duration calculation. Interburst interval was measured as the period between the start of one burst and the start of the next burst (Bains et al. 1999; Staley et al. 1998). Peak amplitude and the area under burst were measured in relation to this threshold. Burst onset time was measured from burst onset to the peak burst amplitude and burst decay time was measured from the peak burst amplitude to burst termination.
When recording extracellular CA3 population bursts, peak amplitude, area under burst, and burst duration may vary with the distance from the site of burst initiation (Korn et al. 1987), the depth of the recording electrode, the conductivity of the slice (Traub and Miles 1991), or the location from which the slice was obtained in the septal–temporal axis (Staley et al. 1998). We calculated mean values for burst indices under control conditions for any given slice and position. All significances were determined using a one-way ANOVA. Data are plotted as means ± SE.
Model of glutamate release and replenishment
Goda and Stevens (1994) measured glutamate release rates in cultured hippocampal pyramidal cells in Ca2+ versus Sr2+ containing extracellular solutions. Release rates were described by biexponential decay
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A = 6.7 and B = 100 ms; and C = 0.006 releases/ms. For extracellular solutions containing 10 mM Sr2+ and 0.5 mM Mg2+, Ao = 0.69, Bo = 0.15, A = 25, B = 125, and C = 0.0096.
Replenishment of releasable glutamate is a first-order process with a time constant of several seconds for hippocampal pyramidal cell axon terminals (Dobrunz and Stevens 1997; Staley et al. 1998)
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RESULTS |
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We assessed the effects of replacing extracellular Ca2+ with Sr2+ on release of glutamate from CA3 axon terminals using whole cell recordings of excitatory postsynaptic potentials (EPSCs). Sr2+ (10 mM) desynchronized glutamate release as evidenced by a decreased amplitude of the initial EPSC and the appearance of multiple subsequent smaller EPSCs well after the stimulus (Fig. 1A; Goda and Stevens 1994; Milledi 1966). The charge transferred by the sum of the asynchronous releases in Sr2+ is roughly equal to the charge transfer during synchronous release in Ca2+ (Fig. 1, B and C). This indicates that over the time course of asynchronous release, Sr2+ functions primarily to reduce the synchrony rather than the probability of glutamate release at pyramidal cell synapses.
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), thereby reducing the probability of initiation of synchronous activity. Second, the reduced rate of glutamate release in Sr2+ should more closely match the rate of replenishment of glutamate, decreasing the degree of glutamate depletion (Fig. 1D), which could prolong synchronous activity. To evaluate the effects of desynchronization of glutamate release on CA3 network activity, we measured population burst activity in extracellular solutions containing either Ca2+ or Sr2+. Burst onset
Sr2+-induced reduction in the rate of glutamate release (Fig. 1) should reduce the peak amplitude of postsynaptic potentials and the probability of triggering postsynaptic action potentials. The consequent reduction in the positive feedback cycle that triggers bursts (Dingledine and Traub 1990) should be evident in the rate of burst onset. An increased latency from burst onset to peak burst amplitude was most evident at 2 mM Sr2+ (Figs. 2 and 3C). Time from the onset of the burst to peak amplitude increased significantly from control conditions versus 2 mM Sr2+ (n = 7, P < 0.001). At higher concentrations of Sr2+, the time to peak burst amplitude decreased to approximately control levels. This was most likely a consequence of the very large interburst interval at higher Sr2+ levels (Table 1), which were more than tenfold the control interval at Sr2+ concentrations >2 mM. At very long interburst intervals, there is complete recovery from burst-induced, activity-dependent, short-term depression at recurrent collateral synapses. Thus at long interburst intervals, it is much easier to initiate synchronous network activity (Staley et al. 2001).
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; Fig. 2; C and D). Typically afterdischarges occur within 1 s of the termination of the preceding burst. Supporting the idea that long interburst intervals and complete recovery from depression were responsible for the higher rate of burst initiation at higher Sr2+concentrations, the rates of onset of afterdischarges were much slower than the onset of the initial burst in Sr2+ (Fig. 2, C and D). Burst duration
Desynchronization of glutamate release should decrease the rate of activity-dependent depletion of releasable glutamate at recurrent collateral synapses (Fig. 1). If this depletion is the primary determinant of burst duration, then Sr2+ should also increase burst duration. Figure 3 and Table 2 demonstrate a robust increase in burst length in Sr2+. The increase in burst duration was correlated with Sr2+ concentration, with longer bursts at higher Sr2+ concentrations. A concentration of 8 mM Sr2+ had a mean burst length of 5,932 ± 1,101 ms, compared with 160 ± 10 ms for baseline (n = 9). The difference between baseline and wash was insignificant using a one-way ANOVA (n = 9, P < 0.001). The burst duration was associated with a reduced rate of burst decay: lower decay rates were associated with longer burst durations (Fig. 3C). This finding is consistent with the idea that reduced rates of glutamate release at CA3 axon terminals (Fig. 1) reduced the rate of depletion of releasable glutamate, thereby prolonging the burst duration.
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Desynchronization of glutamate release by Sr2+ perfusion (Fig. 1) should reduce the positive feedback cycle of action potential–dependent glutamate release at recurrent collateral networks and subsequent action potential generation in postsynaptic CA3 pyramidal cells. This should result in a decreased probability of bursting (Dingledine and Traub 1990). Table 1 and Figs. 2 and 4 demonstrate the reduced burst probability, manifest as an increased interburst interval. All concentrations of Sr2+ increased the burst interval. The maximum burst interval was observed at the Sr2+ concentration of 10.0 mM, which increased the interval between bursts by 3,663 ± 436% (n = 5) compared with that recorded in Ca2+-containing extracellular solution. The difference between baseline and wash was insignificant using a one-way ANOVA (P < 0.001). Figure 4, A and B shows changes in interburst interval during a single experiment. The mode of a frequency histogram for the baseline interburst interval was 21 events in the range 20–25 s. At 2 mM Sr2+ the mode was 13 events in the range 70–80 s and for 8 mM Sr2+ the mode was five events with interburst intervals ranging from 300 to 350 s. The bin size was increased at each concentration because of the dramatic increase in the interburst intervals. Figure 4B shows the increase in interburst interval as a cumulative probability distribution.
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, 2001). However, the time constant for recovery from synaptic depression is about 8 s (Dobrunz and Stevens 1997; Staley et al. 2001), so no significant effect of recovery would be seen for increases in interburst intervals >20 s. If Sr2+ reduced the rate of recovery from burst-induced synaptic depression, continued increases in synaptic recovery might be seen at interburst intervals >20 s but the increase in burst length resulting from recovery from depression should never exceed the initial burst length, which was never more than twice the average burst length in control conditions. As shown in Fig. 5, burst length continued to substantially increase at burst intervals >20 s, indicating that recovery from depression was not the primary determinant of the increase in burst length. This supports the idea that the increase in burst length at higher Sr2+ concentrations arose from concentration-dependent reductions in the rate of glutamate release at CA3 axon terminals.
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DISCUSSION |
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The replacement of Ca2+ with Sr2+ alters presynaptic function such that the fast synchronous component of glutamate release is replaced by slower asynchronous release (Fig. 1; Goda and Stevens 1994; Herrero et al. 1996; Milledi 1966). This was attributed to lower affinity and cooperativity for the sensors involved in synchronous release as well as higher residual Sr2+ from slower extrusion, resulting in asynchronous release (Xu-Friedman and Regehr 2000). Both the synchronous and asynchronous release components deplete the same vesicular pool (Bekkers and Clements 1999; Hagler and Goda 2001). Sr2+-induced reductions in the rate of synaptic glutamate release and depletion provide an opportunity to study the role of activity-dependent depression and recovery in the timing of synchronized network activity in hippocampal area CA3.
CA3 bursts are initiated when action potential–dependent glutamate release reaches a level that becomes self-sustaining (Dingledine and Traub 1991; Latham et al. 2000; Menendez de la Prida et al. 2006; Traub and Miles 1991; Wenner and O'Donovan 2001). The activity becomes self-sustaining by virtue of action potential–dependent glutamate release at recurrent collateral axon terminals, which triggers more action potentials in postsynaptic neurons and more action potential–dependent glutamate release. If synaptic strength is insufficient to generate action potentials, the probability that activity will die out before reaching a self-sustaining level is increased (Menendez de la Prida et al. 2006) and burst probability is proportionately reduced (Dingledine and Traub 1991; Staley et al. 2001). Synaptic strength can be reduced either by reducing glutamate release probability by activating GABAB or adenosine A1 receptors (Menendez de la Prida 2006; Staley et al. 1998), by blocking postsynaptic glutamate receptors pharmacologically (Dingledine and Traub 1990) or by long-term depression of synaptic strength (Bains et al. 1999; Staley et al. 2001, 2005).
When synaptic strength was reduced by decreasing glutamate release probability with GABAB agonists, a modest increase in burst length was observed (Staley et al. 1998). This suggested that lower glutamate release probability reduced the rate of onset of activity-dependent synaptic depression, thereby prolonging bursts. However, the reduced glutamate release probability prevented spontaneous bursts before burst length was substantially increased. Sr2+, by reducing the synchrony rather than the probability of glutamate release, provides a better way to assess the role of presynaptic glutamate in synchronous network activity. Spontaneous bursts could still be observed at Sr2+ concentrations that were high enough to increase burst duration to 37-fold the control value. This supports the idea that the supply of releasable glutamate is the limiting factor in burst duration. Sr2+ prolongs reverberatory synaptic activity in other neural networks (Lau and Bi 2005), suggesting that depletion of releasable transmitter may be a general means of limiting the duration of synchronous activation of neural networks.
The prolongation of burst duration by Sr2+ does not exclude contributions from other mechanisms of short-term activity-dependent depression, such as GABAB and adenosine A1 receptor-mediated reductions in glutamate release probability (Cohen et al. 2006; Dulla et al. 2005; Masino et al. 2002; Staley et al. 1998). However, the remarkable prolongation of burst length by Sr2+ supports the idea that depletion of releasable glutamate at some fraction of active synapses is an important and perhaps necessary step in burst termination. The increase in burst duration appears proportional to the increase in duration of glutamate release (Fig. 1 vs. Fig. 3). The longest time constant measured for asynchronous glutamate release was 125 ms (Goda and Stevens 1994), which is not sufficient to prolong bursts to the degree observed here. It is not necessary for asynchronous glutamate release to continue for 40 s for bursts to be prolonged to 40 s. At sufficiently low rates of glutamate release, the rate of replenishment of glutamate more closely matches the rate of depletion (Fig. 1D), so that activity-dependent synaptic depression will be substantially diminished. Further studies examining the rates of depletion and replenishment in Sr2+ and the interaction between A1 and GABAB antagonists and Sr2+ effects will clarify these issues.
Sr2+ could prolong bursts by other effects, such as by reducing calcium-dependent inactivation of high-voltage calcium channels (Lee et al. 1985), which might prolong dendritic plateau potentials. However, Sr2+ effects on the inactivation rates of neuronal high-voltage–gated calcium channels (Livneh et al. 2006; McNaughton and Randall 1997) are insufficient to explain the observed increases in burst duration. The nature of the plateau potential that occurs during CA3 bursts is controversial (Johnston and Brown 1986) and may include contributions from as-yet uncharacterized voltage-dependent calcium channels whose kinetics may be more substantially altered by Sr2+, so we cannot completely exclude an effect on calcium channels as a mechanism of burst prolongation, although at this time there is no evidence supporting this mechanism. Sr2+ might not support activation of calcium-dependent potassium channels, although block of these channels does not substantially alter CA3 burst duration (Staley et al. 1998).
Synchronous CA3 population bursts are capable of inducing long-term increases (Bains et al. 1999; Berhens et al. 2005) and reductions (Bains et al. 1999; Staley et al. 2001) in the strength of recurrent collateral synapses. This long-term synaptic plasticity is likely to occur as a consequence of the coincident glutamate release and dendritic depolarization that occurs during the burst. By desynchronizing glutamate release, Sr2+ perfusion should reduce the rate of coincident action potentials in pre- and postsynaptic neurons. The duration of bursts are hundreds of milliseconds, so the time constraints of spike timing–dependent synaptic plasticity are likely to be substantially relaxed during CA3 bursting. Nevertheless, the desynchronization of glutamate release by Sr2+ may reduce the coincidence of dendritic depolarization and glutamate release, resulting in long-term depression rather than long-term potentiation of recurrent collateral synapses. As mentioned earlier and demonstrated previously (Bains et al. 1999; Behrens et al. 2005; Staley et al. 2001), long-term depression of recurrent collateral synapses will decrease the likelihood that action potential–dependent glutamate release will trigger postsynaptic action potentials, thereby reducing the probability of burst initiation. Some evidence for long-term depression and consequent reduced burst probability is demonstrated in Table 1: after wash of Sr2+, burst probability remained reduced by a factor of 2. The return of the burst length to control values suggests that the increase in interburst interval after washing Sr was not attributable to incomplete removal of Sr. However, we cannot exclude this possibility, nor the possibility that replacement of Ca2+ with Sr2+ induced long-term depression independent of the timing of glutamate release. Further experiments using whole cell recordings during bursting may resolve these questions.
These experiments demonstrate that the supply of releasable transmitter can limit the duration of synchronous network activity and that when the release rate is diminished to approximate the rate of recovery, very prolonged episodes of network activity may occur. These findings may be important in understanding the pathophysiology of some forms of seizure disorders: reductions rather than increases in the probability of glutamate release may be proconvulsant.
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FOOTNOTES |
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Address for reprint requests and other correspondence: K. J. Staley, VBK 910, Neurology Department, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114 (E-mail: kstaley{at}partners.org)
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