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Department of Physiology, Sahlgrenska Academy, Göteborg University, Goteborg, Sweden
Submitted 28 May 2007; accepted in final form 4 September 2007
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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7 min as determined by field excitatory postsynaptic potential recordings. Thus as for the expression of long-term potentiation (LTP), recovery from this depression is susceptible to whole cell dialysis ("wash-out"). In contrast to LTP-induced unsilencing, the AMPA signaling after stimulus interruption was again labile, resumed stimulation resulted in renewed depression. The present study has thus identified a novel cycle for AMPA signaling in which the nascent glutamate synapse cycles between an AMPA silent state, induced by a small number of synaptic activations, and a labile AMPA signaling, induced by prolonged inactivity. |
INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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; Xiao et al. 2004). Thus in response to such stimulation AMPA signaling at a previously (experimentally) nonstimulated set of synapses is substantially reduced. Based on variance and failure analysis as well as on stable N-methyl-D-aspartate (NMDA) receptor (NMDAR)-mediated signaling, this reduction was explained by removal of AMPA signaling (AMPA silencing) at a subset (about half) of these synapses (Xiao et al. 2004). This AMPA silencing does not require NMDAR or metabotropic glutamate receptor (mGluR) activation for its induction and is thus distinct from conventional forms of long-term depression (LTD) (Abrahamsson et al. 2005; Xiao et al. 2004). Nevertheless, because AMPA silencing, and its counterpart AMPA unsilencing, are considered important elements in the expression of LTD and long-term potentiation (LTP) (Malinow and Malenka 2002), respectively, such test frequency induced AMPA silencing will naturally have implications for the ability of the synapses to express LTP/LTD.
When examined in the neonatal rat AMPA silence appeared to be a consequence of test stimulation only (Abrahamsson et al. 2005; Groc et al. 2002; Xiao et al. 2004), i.e., not being present prior to stimulation, and LTP-inducing stimulation resulted merely in the recovery to the naive state (Xiao et al. 2004; unpublished data). However, the signaling state after LTP differed from the naive signaling state in that test frequency stimulation no longer reduced AMPA signaling. Thus after LTP, AMPA signaling may only cycle between silent/unsilent states via conventional plasticity mediated via NMDAR and/or mGluR activation. The question then arises whether AMPA signaling also prior to LTP can cycle between silent/unsilent states or whether LTP is the sole cause for unsilencing. Considering that silencing prior to LTP is induced by such weak activity as a few synaptic activations, it would seem possible that synapses in the absence of such activity would tend to spontaneously recover its AMPA signaling. However, when test stimulation was interrupted for several minutes, no such tendency was observed (Xiao et al. 2004), suggesting that the AMPA silencing is not readily reversible even in the absence of synaptic activation. In analogy with the difficulty in inducing LTP using whole cell recordings (Malinow and Tsien 1990), an absence of experimentally observed recovery using whole cell recordings may, however, be explained by "wash-out" of the biochemical processes underlying AMPA unsilencing. This possibility of course also raises the question to what extent the phenomenon of test frequency induced AMPA silencing might be a consequence of the whole cell recording per se, this experimental procedure making AMPA signaling more labile.
In the present study, we have therefore used field and perforated patch-clamp recordings to examine whether a test frequency induced synaptic depression corresponding to that observed using whole cell recordings can be identified under more noninvasive conditions. It will be shown that such a synaptic depression exists and is reversed by inactivity within tens of minutes.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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Experiments were performed on hippocampal slices from 5- to 12- and 35- to 44-day-old Wistar rats. The animals were kept and killed in accordance with the guidelines of the Göteborg ethical committee for animal research. The rats were anesthetized with isoflurane (Abbott) prior to decapitation. The brain was removed and placed in an ice-cold solution containing (in mM) 140 cholineCl, 2.5 KCl, 0.5 CaCl2, 7 MgCl2, 25 NaHCO3, 1.25 NaH2PO4, 1.3 ascorbic acid, and 7 dextrose. Transverse hippocampal slices (300–400 µm thick) were cut with a vibratome (Slicer HR 2, Sigmann Elektronik, Germany) in the same ice-cold solution, and they were subsequently stored in artificial cerebrospinal fluid (ACSF) containing (in mM) 124 NaCl, 3 KCl, 2 CaCl2, 4 MgCl2, 26 NaHCO3, 1.25 NaH2PO4, 0.5 ascorbic acid, 3 myo-inositol, 4 D,L-lactic acid, and 10 D-glucose. After 1–8 h, typically 2–5 h, of storage at 25°C, a single slice was transferred to a recording chamber where it was kept submerged in a constant flow (2 ml/min) at 30–32°C. The slice was allowed to equilibrate in the recording chamber for 10 min before the recording started. There was no relationship between the amount of depression and the storage time (r = –0.19, n = 16, P > 0.05). The perfusion ACSF contained (in mM) 124 NaCl, 3 KCl, 4 CaCl2, 4 MgCl2, 26 NaHCO3, 1.25 NaH2PO4, and 10 D-glucose. Picrotoxin (100 µM) was always present in the perfusion ACSF to block GABAA receptor-mediated activity. All solutions were continuously bubbled with 95% O2-5% CO2 (pH 7.4). A cut between CA3 and CA1 and the higher than normal Ca2+ and Mg2+ concentrations were used to prevent spontaneous network activity. Under these conditions, the spontaneous activity in the slice preparation is very low, spontaneous EPSCs occurring at a frequency of 0.3–1 Hz (Groc et al. 2002; Hsia et al. 1998).
Recording and analysis
Electrical stimulation of Schaffer collateral afferents was carried out in the stratum radiatum. Stimuli consisted of biphasic constant current pulses (200 + 200 µs, STG 1004, Multi Channel Systems MCS Gmbh, Reutlingen, Germany) delivered through either a glass pipette (resistance: 0.5–1 M
) or an insulated tungsten microelectrode (resistance: 0.3–0.5 M). Stimulus intensity of 9–30 and 40–60 µA was used for slices from 35- to 44- and 5- to 12-day-old rats, respectively. Field EPSP recordings were made by means of a glass micropipette (1 M, filled with 1 M NaCl) in the s. radiatum. Whole cell patch-clamp recordings were performed on visually identified pyramidal cells, using infrared–differential interference contrast videomicroscopy mounted on a Nikon E600FN microscope (Nikon). The pipette solution contained (in mM) 130 Cs–methanesulfonate, 2 NaCl, 10 HEPES, 0.6 EGTA, 5 QX-314, 4 Mg-ATP, and 0.4 GTP or 130 KCl, 2 NaCl, 20 HEPES, 0.2 EGTA, 4 Mg-ATP, and 0.4 GTP (pH 7.3 and osmolality: 270–300 mosM). Liquid junction potential was both measured and calculated to be 8 mV (Cs-based solution) and 2 mV (K-based solution), and it was not corrected for. Patch pipette resistances were 2–6 M. For perforated-patch recordings, amphotericin B (240 µg/ml) was added to the pipette solution. Also, Lucifer yellow (0.05%) was always present in the perforating solution to detect possible membrane leakage using a fluorescence camera. If Lucifer yellow entered the cell, the experiment was discarded. Field EPSPs and EPSCs were recorded at a sampling frequency of 10 kHz and filtered at 1 kHz, using an EPC-9 amplifier (HEKA Elektronik, Lambrecht, Germany). For AMPA EPSC recordings cells were held in voltage-clamp mode at –70 mV. Series resistance was monitored using a 5-ms, 10-mV hyperpolarizing pulse, and it was not allowed to change >15% in whole cell and 20% in perforated-patch-clamp experiments, otherwise the recording was not included in the analysis. Field EPSPs and EPSCs were analyzed off-line using custom-made IGOR Pro (WaveMetrics, Lake Oswego, OR) software. Field EPSPs and EPSCs amplitudes were measured as the difference between the baseline level immediately preceding the stimulation artifact and the mean amplitude during a 2-ms time window around the negative peak between 3 and 8 ms after the stimulation artifact. Field EPSPs were also estimated by linear regression of the initial slope. Because our experimental design precludes adjustment of stimulation intensity (cf. RESULTS), experiments in which the field EPSPs exhibited signs of population spike activity were discarded. For the EPSPs not excluded by this criterion, initial slope and amplitude measurements gave the same results. Because the amplitude measurements were less noisy, these measurements were used for further analysis. Synaptic depression in the individual experiments was calculated as the percentage decrease between the first evoked EPSP/EPSC and the average EPSP/EPSC after 80–120 stimuli. Because of the large variation between individual EPSCs when recording the activity from a relatively small number of synapses, using whole cell (Fig. 4) or perforated-patch-clamp recordings (Fig. 5), recovery in those experiments was evaluated as the potentiation of the first six EPSCs after stimulus interruption. Recovery from the field EPSP depression (Fig. 3F) after stimulus interruption was calculated as percentage of the synaptic depression itself (i.e., depression as 100%). To reduce the noise inherent in constructing such a ratio, the average of the first three field EPSPs at the onset of stimulation and after stimulus interruption, respectively, was used. The presynaptic volley was measured as the amplitude of the initial positive-negative deflection and was not allowed to change >10%, otherwise the experiment was discarded. Data are expressed as means ± SE. Statistical significance for independent and paired samples was evaluated using Student's t-test.
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Chemicals were from Sigma–Aldrich (Stockholm, Sweden) except for D-AP5 and LY 341495 (Tocris Cookson, Bristol, UK) and QX-314 (Alomone Labs, Jerusalem, Israel).
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RESULTS |
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Test frequency induced field EPSP depression
In conformity with the results obtained using whole cell recordings (Xiao et al. 2004), stimulation of a naïve synaptic input in the neonatal rat at low-frequency (0.2 Hz) led to a rapid and considerable decrease in field EPSP amplitude with no change in the presynaptic volley (Fig. 1A). In contrast to results obtained using whole cell recordings, field EPSPs were always found to decrease, likely because of the larger number of synapses sampled using field than whole cell recordings. Nevertheless, the amount of depression varied among the experiments. When measured after the first 80–120 stimuli, when the depression had started to display a plateau, the field EPSPs had decayed 25–60% from the initial, naïve, value. On average the depression amounted to 37 ± 2.8% (n = 16; Fig. 1B). As indicated in the preceding text, the depression could not be explained by fewer activated axons because the presynaptic volley remained unchanged in these experiments (–1.0 ± 1.2%, n = 16; Fig. 1B). As shown in Fig. 1C, the variation in depression magnitude could not be explained by variation in naïve field EPSP magnitude or animal age.
Comparison between field EPSP and whole cell EPSC depressions
The whole cell EPSC depression was identified as AMPA silencing based on the analysis of changes in EPSC variance, changes in failure rate, and the stability of the NMDA EPSC (Xiao et al. 2004). Such tools are not available for field recordings, and our identification of the field EPSP depression as similar to the EPSC depression observed in whole cell recordings and, thus as being explained by AMPA silencing, thus rests on its similarity in properties to the depression observed for EPSCs. In agreement with the EPSC depression, the field EPSP depression commenced immediately on stimulation and displayed a similar development (compare e.g., Figs. 1 and 4). However, the average field EPSP depression observed (37%) was smaller than the corresponding average EPSC depression previously (60%) (Xiao et al. 2004) and presently (50%, Figs. 2 F and 4B) found after the same number of stimuli. It should be noted that this value of field EPSP depression (37%) may not represent the full extent of this depression because further stimulation appears to produce further depression (Fig. 2B).
We next examined whether the presently found EPSP depression exhibited stimulation dependence, input specificity, age dependence, and NMDA and mGluR independence, characteristic hallmarks of the EPSC depression (Abrahamsson et al. 2005; Xiao et al. 2004). In agreement with the EPSC depression, the field EPSP depression was found to be independent of stimulus frequency in that it was evoked to the same extent (per stimulus) by 0.05 Hz as by 0.2 Hz (36 ± 4.3%, n = 7 vs. 37 ± 2.8%, n = 16; Fig. 2A). To test for input specificity, field EPSP depression was first elicited in one pathway by 240 stimuli at 0.2 Hz after which stimulation of a second pathway was started. In agreement with input specificity, the depression elicited in this second pathway (41 ± 3.1%, n = 7) was indistinguishable from that in the first (42 ± 1.7%, n = 7; Fig. 2B). The field EPSP depression was also unaffected by the combined presence of the NMDAR antagonist D-AP5 (50 µM) and the broad-spectrum mGluR antagonist LY 341495 (20–100 µM; 35 ± 2.4%, n = 16; Fig. 2C). In whole cell experiments, EPSC depression was not observed in slices from rats >1 mo (Xiao et al. 2004). When examined in slices from 35- to 44-day-old rats using field EPSPs, a small depression was found (7.9 ± 3.1%, n = 10; Fig. 2D), which was also observed in the combined presence of D-AP5 and LY 341495 (10 ± 1.8%, n = 11, not shown). However, in general agreement with the whole cell result, the depression in these older animals was substantially smaller than that observed in slices from the young rats (P < 0.0001).
Occlusion between field EPSP and whole cell EPSC depressions
To further examine equivalence between the synaptic depression observed in intact cells using field recordings and that observed using whole cell recordings, we examined their interaction. One hundred twenty stimuli at 0.2 Hz were first given prior to the initiation of the whole cell recording while the recording electrode was kept in a cell-attached position. The cell membrane was then ruptured to obtain the whole cell recording, and stimulation was resumed within 2–3 min with an additional 120 stimuli. The EPSC depression was occluded after this prestimulation [11 ± 11%, average of binned values (3 consecutive EPSCs), n = 5; Fig. 2E)], and it was significantly different from that observed in interleaved control experiments [53 ± 8.8%, average of binned values (3 consecutive EPSCs), n = 5, P = 0.02] when no stimulation was given prior to the whole cell recording (Fig. 2F). Whereas the same stimulation strengths were used for the interleaved experiments shown in E and F, the EPSC magnitudes in the prestimulated cells were much smaller (122 ± 42 pA, n = 5) than those in the interleaved control cells (326 ± 95 pA, n = 5). This is to be expected because of the depression caused by the prestimulation, and this amplitude difference likely accounts for the larger variability in E than in F. Taken together, these results establish that the field EPSP depression is the same process as the EPSC depression observed using whole cell recording.
Recovery of the field EPSP depression after inactivity
To examine whether the maintenance of the field EPSP depression requires continued synaptic activation stimulation was interrupted for various time periods. Figure 3A shows an experiment in which stimulation was interrupted for 40 min, demonstrating a complete recovery of the depression. On the other hand, a 1-min stimulus interruption resulted in no recovery (–0.8 ± 6.7%, n = 6). The average recoveries after stimulus interruption for 2, 5, 20, and 40 min, respectively, are shown in Fig. 3, B–E. When plotting the relative amount of recovery against time of stimulus interruption, the recovery could be approximated by a single-exponential function with a time constant of 7 min (Fig. 3F). Although not statistically significant, there was a tendency for the recovery not to be complete, even after 40 min of stimulus interruption. After this long stimulus interruption (Fig. 3E), the volley was 96 ± 2.6% (n = 6) of the initial value, which would explain about half the lack of full recovery, suggesting that the recovery is likely to be a complete one. After the resumption of stimulation, the field EPSP decreased back to the level of depression obtained prior to the stimulus interruption (Fig. 3, A–E) with a similar time course as the initial depression (Fig. 3E, gray line). It can be noted that the recovery depended on stimulus interruption, and not on time, because continued stimulation at 0.2 Hz did not result in any recovery, rather some further depression (Fig. 2B).
This relatively rapid recovery presently observed would suggest that significant recovery should have been observed previously, using whole cell recordings and an 8-min stimulus interruption (Xiao et al. 2004). Nevertheless, we re-examined recovery in whole cell recordings using a substantially longer (20 min) period of stimulus interruption (Fig. 4A). In these experiments, the initial EPSC depression amounted to 45 ± 3.8% of the initial, naïve, value (Fig. 4B), but there was no significant recovery (n = 5, P = 0.43) after the 20-min stimulus interruption. However, using the perforated-patch-clamp technique and stimulus interruptions for 2 and 15 min, respectively, a recovery in agreement with the data obtained using field EPSP recordings was found. Thus although the 2-min stimulus interruption was not sufficient to produce any significant recovery (n = 5, P = 0.19) of the initial EPSC depression (44 ± 12%, Fig. 5C), the 15-min stimulus interruption produced significant recovery (n = 8, P = 0.015) of the initial depression (31 ± 12%, Fig. 5A). This result suggests that the lack of recovery using whole cell recordings is explained by wash-out. As shown in Fig. 5B, both the initial and the recovered AMPA EPSC depression were associated with corresponding changes in EPSC variance (1/CV2) (Abrahamsson et al. 2005). This result confirms previous studies using whole cell patch-clamp recordings that have associated the AMPA EPSC depression with a proportional decrease in the 1/CV2 value, a finding that links the AMPA EPSC depression to AMPA silencing in a subset of the activated synapses (Abrahamsson et al. 2005; Xiao et al. 2004).
A feature of the test frequency induced EPSC depression was that it was not associated with any change in paired-pulse facilitation (Abrahamsson et al. 2005; Xiao et al. 2004). Moreover, the depression produced by single or paired stimulation did not differ in magnitude (Abrahamsson et al. 2005; Xiao et al. 2004). These features could not be examined using field recordings because paired-pulse stimulation in this unclamped condition produces LTD the induction of which relies on NMDAR and T-type voltage-gated calcium channels and which is associated with an increase in paired-pulse facilitation (Wasling et al. 2002). However, using voltage clamp in the perforated-patch-clamp mode, both single stimulation and paired-pulse stimulation were used, and there was no distinguishable difference in depression magnitude (single: 39 ± 4.3%, n = 9; paired: 42 ± 6.1%, n = 10). Moreover, the depression was not associated with any change in paired-pulse facilitation (Fig. 5D). The average paired-pulse ratio in the beginning and at the end of the depression protocol (1st and last 5 binned data points) were 1.48 ± 0.17 and 1.46 ± 0.14 (n = 10), respectively. Thus using perforated-patch recordings, the depression not only resembles that observed using field recordings (magnitude and recovery) but also that observed in whole cell recordings (with respect to paired-pulse stimulation and facilitation), further establishing the equivalence between the field EPSP and EPSC depression.
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DISCUSSION |
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; Malinow and Malenka 2002; Montgomery and Madison 2004). The present results suggest that AMPA signaling in the developing synapse can also transit between silent/unsilent states in a manner not involving NMDAR and/or mGluR activation. It thus appears that glutamate released by single synaptic activations can cause rapid dispersal of AMPARs from the synaptic membrane; these receptors then slowly reappearing in the absence of glutamate release. Internalization and recycling of receptors in response to exogenous agonist exposure is a well-established phenomenon (Perez and Karnik 2005). For example, prolonged (>5 min) AMPA application (in culture) leads to a reversible AMPAR dispersion (and internalization) and to the transient creation of NMDAR-only synapses where none existed before (Lissin et al. 1999). The present study is, to our knowledge, the first in which a brief physiological stimulus has been suggested to evoke such cycling of ionotropic receptors.
A transient potentiation of synaptic transmission after a prolonged stimulus interruption has previously been described for the CA3–CA1 synapses (Niu et al. 1999). However, that potentiation seems distinct from the presently described inactivity-induced AMPA unsilencing in that it largely develops after the resumption of the stimulation (and not by the inactivity per se). Moreover, the experiments by Niu et al. used composite EPSPs (AMPA/NMDA) in a low (0.1 mM)-Mg2+ solution, and both the potentiation and its subsequent decay were largely NMDAR dependent.
The field recordings used in this study cannot by themselves reveal what underlies the activity-induced depression of AMPA signaling. However, in conformity with the AMPA silencing previously observed using whole cell recordings (Abrahamsson et al. 2005; Xiao et al. 2004), the field EPSP depression was input specific, commenced immediately on stimulation (and developed with a similar time course with stimulation), developed to the same extent by 0.2- and 0.05-Hz stimulation, was unaffected by NMDAR and mGluR antagonists, and was downregulated with age (Fig. 2, A–D). Moreover, prior induction of field EPSP depression largely occluded later induction of depression in the whole cell recording mode (Fig. 2, E and F). In contrast to the field EPSP depression, the AMPA silencing observed using whole cell recordings was not reversed by stimulus interruption, as also verified in the present study (Fig. 4). However, using perforated-patch recordings, reversal was observed (Fig. 5), suggesting that inactivity-induced AMPA unsilencing is susceptible to "wash-out." This susceptibility is shared with the induction of LTP in the whole cell configuration (Malinow and Tsien 1990), although the diffusible factors might not necessarily be the same. It thus seems safe to conclude that the field EPSP depression presently observed is the same process as that previously observed using whole cell recordings and thus explained by AMPA silencing.
The fact that the inactivity-induced unsilencing is blocked by wash-out suggests that the AMPA silencing/unsilencing takes place in the postsynaptic cell rather than being explained by kiss-and-run fusion (Choi et al. 2003) or by glutamate spill-over (Kullmann and Asztely 1998). A postsynaptic AMPA receptor based explanation is consistent with experimental data from glutamate-induced internalization of AMPA receptors, these receptors reappearing into the synaptic membrane during a time period comparable to the presently observed inactivity-induced unsilencing (Ehlers 2000; Passafaro et al. 2001). Moreover, after irreversible blockade of synaptic NMDARs (Tovar and Westbrook 2002) and GABAARs (Thomas et al. 2005), most of these nonfunctional receptors are replaced by naïve receptors within ten minutes. It thus seems plausible that the cycling of the nascent glutamate synapse between an AMPA signaling (but labile) state, and an AMPA silent one is explained by a rapid glutamate-induced AMPA receptor dispersion (and internalization) followed by a slow recovery given by AMPA receptor insertion.
In the preceding scenario for cycling between an AMPA labile and an AMPA silent state, the kinetics of AMPA receptor re-insertion is explained by constitutive exocytosis of receptors into the membrane or, possibly, by lateral diffusion of preexisting extrasynaptic receptors. However, none of these explanations may hold. Receptor insertion via constitutive exocytosis has been suggested to take a much longer time (hours) (Adesnik et al. 2005) than the tens of minutes observed, whereas a lateral diffusion by itself would be much faster (Choquet and Triller 2003). Moreover, in contrast to exocytosis, and the presently observed recovery, lateral diffusion of AMPARs is not affected by whole cell related wash-out (Adesnik et al. 2005). A possible explanation could then be that the re-insertion kinetics is determined not by the supply of AMPARs but by the AMPAR binding capacity of the synaptic membrane. The inactivity-induced unsilencing should then reflect the rebuilding of this binding capacity, whereas silencing should reflect the disruption of this binding capacity.
Interestingly in this context, key proteins involved in the reversible anchoring of AMPARs to the postsynaptic density change substantially during development (Tomita et al. 2003), raising the possibility that there is an immature expression pattern that could be more conducive toward the silencing/unsilencing cycle now described. Thus TARP 
8, a major transmembrane AMPA receptor regulatory protein (TARP) in the hippocampus that allow AMPARs to interact with various scaffolding proteins in the postsynaptic density (Rouach et al. 2005), starts to be expressed toward the end of the second postnatal week and may be absent in AMPA silent synapses (Tomita et al. 2003). TARPs interact with membrane associated guanylate kinase (MAGUK) proteins in the postsynaptic density (Chen et al. 2000), and the expression pattern of these proteins also change. Thus before postnatal day 10 SAP-102 is the dominating MAGUK (Elias et al. 2006; Sans et al. 2000), and between postnatal day 10 and 35 there is a dramatic increase in the expression of PSD-95 and PSD-93 (Elias et al. 2006; Sans et al. 2000). The expression of PSD-95 has been suggested to drive synaptic maturation and stabilization (Beique et al. 2006; Ehrlich et al. 2007; El-Husseini et al. 2000; Elias et al. 2006) and knock-out of PSD-95 results in an increased proportion of AMPA silent synapses (Beique et al. 2006). However, because stabilization of AMPA signaling in the developing synapse, at least in the short term, can be achieved via LTP in the neonatal rat, the immature expression pattern of TARPs and MAGUKs does not preclude AMPA stable synaptic transmission. On the other hand, the presence of the mature expression pattern of TARPs and MAGUKs in the synapse seems inconsistent with AMPA labile/silent transmission.
The synaptic depression described here can of course be seen as an extreme variant of novelty detector mechanism, only providing for at most a few activations before a several minutes silence. However, considering that it largely exists only in the developing brain, it may seem more useful to view it from a developmental perspective and as the behavior of a glutamate synapse not yet stabilized within a neuronal network. It is a common notion that the glutamate synapse is born without AMPA receptors, this state being maintained until the synapse eventually is exposed to the appropriate correlated pre- and postsynaptic activity, and AMPA signaling is added (Durand et al. 1996; Isaac et al. 1995; Liao et al. 1995). Because this addition of AMPA receptors occurs essentially momentarily, it seems reasonable that as indicated by present and previous results (Xiao et al. 2004), the whole machinery for AMPA signaling, including AMPA receptors, is rather present beforehand, the AMPA signaling, however, being labile until the synapse is exposed to the proper activity (Groc et al. 2006). Sporadic and noncorrelated activity will cause such synapses to temporarily lose its AMPA signaling but will regain it either momentarily by correlated pre- and postsynaptic activity or more slowly via inactivity.
Thus besides the fact that this test frequency induced synaptic plasticity is a prerequisite for the ability of the developing synapse to demonstrate LTP (unpublished data), it should perhaps not be seen as having a functional role as for example short-term plasticity in neural computation. In fact, it does not conform to conventional categorizations of synaptic plasticity. The depression part, although appearing prolonged, distinctly differs from LTD in that it needs to be maintained by synaptic activity albeit at low frequency. A potentiation part induced by the absence of synaptic activation is obviously remote from LTP. And because it is specific for a given synapse, not scaling the efficacy of a population of synapses in response to activity, it cannot be categorized as homeostatic plasticity. Nevertheless, because it involves expression mechanisms (AMPA silencing/unsilencing), albeit in a more labile form, thought to be involved in LTP/LTD, its interaction/noninteraction with these processes may be helpful in further understanding of the machinery underlying LTP/LTD.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Address for reprint requests and other correspondence: T. Abrahamsson, Dept. of Physiology, Göteborg University, Box 432, Medicinaregatan 11, 405 30 Göteborg, Sweden (E-mail: Therese.Abrahamsson{at}physiol.gu.se)
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and 
, from experiments on 5- to 8- and 10- to 12-day-old rats, respectively.
= 7 min).
