Dynamic synapses as archives of synaptic history: state-dependent redistribution of synaptic efficacy in the rat hippocampal CA1

Abstract

Plastic modifications of synaptic strength are putative mechanisms underlying information processing in the brain, including memory storage, signal integration and filtering. Here we describe a dynamic interplay between short-term and long-term synaptic plasticity. At rat hippocampal CA1 synapses, induction of both long-term potentiation (LTP) and depression (LTD) was accompanied by changes in the profile of short-term plasticity, termed redistribution of synaptic efficacy (RSE). RSE was presynaptically expressed and associated in part with a persistent alteration in hyperpolarization-activated I(h) channel activity. Already potentiated synapses were still capable of showing RSE in response to additional LTP-triggering stimulation. Strikingly, RSE took place even after reversal of LTP or LTD, that is, the same synapse can display different levels of short-term plasticity without changing synaptic efficacy for the initial spike in burst presynaptic firing, thereby modulating spike transmission in a firing rate-dependent manner. Thus, the history of long-term synaptic plasticity is registered in the form of short-term plasticity, and RSE extends the information storage capacity of a synapse and adds another dimension of functional complexity to neuronal operations.

Figure 1. Schematic drawing of various types of STP

A–C, each wave represents a synaptic response to a 10-pulse train at 40 Hz and is merged with a pseudocolour-scale image of STP ratios, which are calculated from the equation indicated below panel D. Based on the mean STP ratio of EPSP_8–10, synapses are classified into facilitating (A), balanced (B) or depressing synapses (C). D, the relationship of three synaptic states. The STP ratio usually becomes stationary for the 8th–10th pulses in a train, and therefore, unless otherwise specified, we referred to the STP ratio of EPSP_8–10 simply as ‘STP ratio’. RSE is defined as a change in the STP ratio after induction of synaptic plasticity.

Figure 2. Changes in the STP profiles (i.e. RSE) induced by LTP induction at Schaffer–CA1 synapses

A, time course of LTP monitored by single-pulse stimuli (every 30 s, red). LTP was induced by tetanic stimulation (100 pulses at 100 Hz) at time 0 min and maintained over 150 min. To monitor the response to burst firing, 10-pulse trains at 40-Hz were applied at times −20, −15, 145 and 150 min and every 5 min during time 0.5–120 min. AP5 was absent during the period from time −15 to 0 min. The right panels show burst responses at time −20 and 60 min. Note that the degree of potentiation was smaller in later responses in a burst (fEPSP8–10, blue) as compared to the initial response (fEPSP₁), which is indicative of RSE. B, traces of synaptic responses (the same data as the panel A) are superimposed onto the pseudocoloured images that show ratios of individual fEPSPs to fEPSP₁ at time −20 min (Ba), to the corresponding fEPSP_N at time −20 min (Bb), and to fEPSP₁ at each time point, i.e. the STP ratio (Bc). C, average data for each parameter in the panel Ba–c (n = 8 slices). The degree of a change in fEPSP_8–10 was smaller than that seen in fEPSP₁, that is, the STP ratio was reduced after LTP induction. This change was maintained over 150 min.

Figure 3. Spontaneously occurring RSE in the absence of AP5

A, in the presence of AP5, the responses to the bursts were stable, but after AP5 washout at time 30 min, fEPSP₁ exhibited gradual augmentation along application of the burst trains every 5 min (5 times), in which case the degrees of potentiation were smaller in later fEPSPs than fEPSP₁, that is, 10-pulse trains at 40 Hz alone induced RSE similar to that induced by LTP. RSE was preserved even after a 30-min period during which burst trains were absent. B, summary of STP changes spontaneously occurring in the absence of AP5. The top panel indicates synaptic responses evoked by the first (i.e. basal response, black) and fifth (red) application of burst trains. The bottom graph shows changes in fEPSP1 and STP ratio from the basal response as a percentage. *P < 0.05, **P < 0.01 versus basal response; Tukey's test after ANOVA (n = 5–8 slices).

Figure 4. Activity-dependent, bidirectional RSE

A and B, representative STP changes induced by 900 pulses at 1 Hz (A), or four 100 pulses at 100 Hz (B). Time courses of fEPSP slopes are plotted in the left panels. The right panels indicate 10 fEPSP slopes normalized to fEPSP₁ in each train on a pseudocolour scale, on which raw field responses were superimposed. The bottom-right panels merge two traces 20 min before and 30 min after LFS or tetanus. D, summary of bidirectional synaptic plasticity and RSE. Changes in fEPSP₁ (red) displayed a BCM-like sigmoid curve (Bienenstock et al. 1982), and they were correlated inversely with the mean changes in fEPSP8–10 relative to fEPSP₁ in each train (ΔSTP ratio, blue), except for four tetani (100 pulses at 100 Hz), which did not alter the STP ratio. In the presence of 1 μm CGP55845, however, four tetani decreased the STP ratio to a degree similar to that after one tetanus-induced LTP. In contrast, one tetanus-induced RSE was blocked by 100 μm SQ22536. AP5 blocked the induction of both LTP and RSE. Data were obtained 15 min before and 30 min after tetanus. *P < 0.05, **P < 0.01 versus basal response; Tukey's test (n = 5–8 slices).

Figure 5. Synaptic states are discriminated by RSE

A–B, representative RSE after depotentiation (A) and dedepression (B). A, depotentiation was induced by LFS (900 pulses at 1 Hz) applied 5 min after tetanus (100 pulses at 100 Hz). Only fEPSP₁ was returned to the baseline level, but later fEPSPs were kept augmented after depotentiation. The right panels merged raw traces with pseudocolour images of STP ratios (for details, see Fig. 3 legend). B, weak tetanus (50 pulses at 100 Hz) 5 min after low-frequency stimulation was given to induce dedepression. Again, only fEPSP₁ was returned to baseline. C, artificially normalized LTP preserves the level of RSE. Potentiated synaptic responses (grey) were adjusted to pretetanus baseline by reducing the intensity of test stimulation. Even though fEPSP₁ returned to the pretetanus level, synapses preserve the level of RSE. n = 8 slices. D, summary of RSE induced by various types of long-term plasticity.

Figure 6. Input-frequency dependence of RSE

A–C, representative STP evoked by burst trains with various frequencies of inputs before (Control) and after induction of LTP (A), LTD (B) and depotentiation (C). LTP and LTD were induced by stimulation consisting of 100 pulses at 100 Hz and 900 pulses at 1 Hz, respectively. Depotentiation was induced by applying LFS 5 min after tetanus of 100 pulses at 100 Hz. Data were obtained 15 min before and 30 min after plasticity induction. RSE was more evident at higher input frequency, but the direction of RSE was presented across frequencies. D, summary of the frequency dependence of RSE. *P < 0.05, **P < 0.01 versus basal response; Tukey's test (n = 4 slices).

Figure 7. STP has presynaptic origins

A–C, effects of low-dose CNQX (A), and low (B) and high concentrations of external Ca²⁺ (C) on 10 fEPSPs evoked by 40-Hz trains. Left traces are typical field recordings. Right panels show responses relative to fEPSP₁ (STP ratios) in each train. D, summarized data of panels A–C. *P < 0.05, **P < 0.01 versus control response; Tukey's test (n = 4–7 slices).

Figure 8. I_h activity contributes to the expression of RSE

A, effect of 30 μm ZD7288, an I_h channel blocker, on STP under basal conditions. Aa, the time course of changes in fEPSP₁ slopes following ZD7288 perfusion. Representative recordings at time −20 and 20 are shown in the inset. Ab, the STP ratio of 10 successive fEPSPs, which were normalized to each fEPSP₁. B, effect of 30 μm ZD7288 on STP after LTP induction. Ba, the time course of changes in fEPSPs slopes following ZD7288 perfusion 30 min after tetanus (100 Hz, 100 pulses). Bb, the STP ratio was reduced after LTP induction, and no additional decrease in STP ratios was induced by application of ZD7288, that is, the effects of LTP and ZD7288 on STP were occlusive. C, comparisons of the effects of ZD7288 and Cs⁺ before and after various synaptic experiences. The same protocol as shown in panel B was used. ZD7288 and Cs⁺ became ineffective at synapses that experienced LTP and depotentiation, but not LTD or strong LTP. *P < 0.05, **P < 0.01 versus control; Tukey's test (n = 5–7 slices).

Figure 9. ZD7288 reduces STP ratios by acting on presynaptic sites, but facilitates fEPSP₁ by acting on postsynaptic cells

A, voltage steps from −60 mV to −70 ∼−120 mV produced inward currents, in which the slow component, i.e. I_h current, was reduced by extracellular treatment with 30 μm ZD7288 under control conditions (Aa), whereas this effect was occluded when 100 μm ZD7288 was loaded into a patch pipette (Ab). Insets show typical raw traces. B, representative responses to 40-Hz trains without (Ba) or with intracellular ZD7288 (Bb) before (Control) and after extracellular treatment with 30 μm ZD7288. A and B indicate that intracellular loading of ZD7288 selectively blocks postsynaptic I_h activity. C, summary of the effect of extracellular ZD7288 on burst responses. EPSC₁ (grey) and STP ratios (black) were differentially affected by extracellular ZD7288 application. Note that the effect of extracellular ZD7288 (Extra ZD) in the presence of intracellular ZD7288 (Intra ZD) was similar to that obtained by field recordings (see Fig. 8). *P < 0.05, **P < 0.01 versus data without extracellular ZD7288; Tukey's test (n = 6 slices).

Figure 10. RSE obtained with whole-cell recordings

A–D, representative time courses in changes in EPSC sizes evoked by single-pulse test stimulation with voltage clamp at −60 mV. LTP (A), LTD (B), strong LTP (C), and depotentiation (D) were induced by a combination of current clamp of postsynaptic cells and the same stimulation of presynaptic cells as used in field potential recordings. Burst trains (40 Hz) were applied in the presence of AP5 every 5 min during time from −30 to −15 min and from 15 to 30 min. E, summary of data. The direction and level of plasticity and RSE were similar to those observed in field recordings (see Fig. 5). n = 4–7 slices.

Figure 11. RSE modifies a frequency preference in spike responses

A, upper trace: typical spiking activity generated by a CA1 pyramidal cell in response to a stimulus train with a natural temporal pattern (middle trace) sampled from a CA3 pyramidal cell in a free-moving rat. Bottom trace: extracted spikes. B–C, representative firing responses 20 min before and 30 min after induction of LTP (B) or depotentiation (C). Ba and Ca show the time courses of changes in EPSP1 evoked by single-pulse test stimulation in a current clamp mode. Rasterplots (Bb and Cb) show timings of spikes evoked by the same natural stimulus trains. The trains were applied 8 times every 60–120 s during the periods indicated by the hatched bars in the panels Ba and Ca. D, quantification of information transmitted from presynaptic to postsynaptic sites before and after induction of LTP and depotentiation. Mutual entropy enhanced by LTP was retained after depotentiation. E, frequency-dependent information transmission. At depotentiated synapses, the mutual entropy was increased in a frequency-specific manner (grey) whereas synapses with LTP displayed a broad increase (black). *P < 0.05, **P < 0.01 versus basal response; Tukey's test (n = 3–6 slices).