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The Journal of Physiology logoLink to The Journal of Physiology
. 2007 Oct 11;585(Pt 2):429–445. doi: 10.1113/jphysiol.2007.142984

The development of synaptic plasticity induction rules and the requirement for postsynaptic spikes in rat hippocampal CA1 pyramidal neurones

Katherine A Buchanan 1, Jack R Mellor 1
PMCID: PMC2375477  PMID: 17932146

Abstract

Coincident pre- and postsynaptic activity induces synaptic plasticity at the Schaffer collateral synapse onto CA1 pyramidal neurones. The precise timing, frequency and number of coincident action potentials required to induce synaptic plasticity is currently unknown. In this study we show that the postsynaptic activity required for the induction of long-term potentiation (LTP) changes with development. In acute slices from adult rats, coincident pre- and postsynaptic theta burst stimulation (TBS) induced LTP and we show that multiple high-frequency postsynaptic spikes are required. In contrast, in acute slices from juvenile (P14) rats, TBS failed to induce LTP unless the excitatory postsynaptic potentials (EPSPs) were of sufficient magnitude to initiate action potentials. We also show that coincident individual pre- and postsynaptic action potentials are only capable of inducing LTP in the juvenile when given at a frequency greater than 5 Hz and that the timing of individual pre- and postsynaptic action potentials relative to one another is not important. Finally, we show that local tetrodotoxin (TTX) application to the soma blocked LTP in adults, but not juveniles. These data demonstrate that somatic spiking is more important for LTP induction in the adult as opposed to juvenile rats and we hypothesize that the basis for this is the ability of action potentials in the postsynaptic CA1 pyramidal neurone to back-propagate into the dendrites. Therefore, the pre- and postsynaptic activity patterns required to induce LTP mature as the hippocampus develops.

Hebbian forms of synaptic plasticity are induced by coincident presynaptic glutamate release and postsynaptic depolarization (Kelso et al. 1986; Sastry et al. 1986; Wigstrom & Gustafsson, 1986; Bliss & Collingridge, 1993; Magee & Johnston, 1997). The physiological mechanisms providing this postsynaptic depolarization are potentially numerous but a prime candidate is the back-propagating action potential (bAP) that is initiated in the soma of the postsynaptic cell and back-propagates actively into the dendritic tree (Spruston et al. 1995; Magee & Johnston, 1997; Markram et al. 1997). The precise timing of pre- and postsynaptic action potentials has been shown to be critical for the sign and magnitude of plasticity induction (Bi & Poo, 1998; Debanne et al. 1998) and these rules operate at a number of different synapses in the brain with notable exceptions and deviations (Feldman, 2000; Meredith et al. 2003; Tzounopoulos et al. 2004; Dan & Poo, 2006; Wittenberg & Wang, 2006).

The Schaffer collateral synapse in CA1 of the hippocampus is one such exception. Although spike timing-dependent plasticity (STDP) was originally characterized in hippocampal cultures (Bi & Poo, 1998) and slice cultures (Debanne et al. 1998) and subsequently in hippocampal slices (Nishiyama et al. 2000), it is now known that this only occurs under specific conditions (Golding et al. 2002; Wittenberg & Wang, 2006) and there is a requirement for multiple postsynaptic action potentials, or bursts, to induce plasticity (Thomas et al. 1998; Pike et al. 1999). This leads to a more complex picture than was previously envisaged.

Over the course of hippocampal development the mechanisms of induction and expression of synaptic plasticity at the Schaffer collateral synapse in CA1 change as the synapse matures (Dudek & Bear, 1993; Hsia et al. 1998; Palmer et al. 2004). This development is closely correlated to the ability to perform hippocampal-dependent memory tasks, both emerging in the third week of life (for rats) (Dumas, 2005). Therefore in juvenile animals (< P21) synaptic plasticity enables connections to be established whereas in the adult, synaptic plasticity enables connections to be potentiated and depressed in response to learning episodes. Since the role of synaptic plasticity is different at each stage of development the patterns of activity required to induce synaptic plasticity are therefore likely to be different.

Here we show the rules of STDP in the hippocampus are distinct from those reported in other brain regions and that as the hippocampus matures the activity patterns required to induce synaptic plasticity, and therefore learning, alter. This reflects the different functions of information transfer and synaptic plasticity at these two stages of development.

Methods

Ethical approval

All experiments were performed in accordance with Home Office guidelines as directed by the Home Office Licensing Team at the University of Bristol.

Slice preparation

Brain slices were prepared from juvenile (P13–15) or adult (P45–55) male Wistar rats following a lethal dose of anaesthetic (Isoflurane inhalation). Brains were dissected in ice-cold artificial cerebrospinal fluid (aCSF) containing (mm): 119 NaCl, 2.5 KCl, 1 NaH2PO4, 26.2 NaHCO3, 10 glucose, 2.5 CaCl2, 1.3 MgSO4 equilibrated with 95% O2 and 5% CO2. Para-saggital hippocampal slices 300–400 μm thick were cut using a vibratome (DTK-1000, DSK, Japan) and slices were incubated in aCSF at 36°C for 30 min and then stored at room temperature until use. Before being transferred to the recording chamber, a cut was made between CA3 and CA1.

Whole-cell patch clamp recordings

Recordings were made in a submerged chamber perfused with aCSF (as above) at room temperature with the addition of 50 μm picrotoxin to block GABAA receptor-mediated transmission. Qualitatively similar results were found when some key experiments were performed at 35°C (e.g. Figs 1 and 2). LTP washed out much faster at 35°C so these experiments needed very short baselines (< 3 min) and for this reason all experiments shown were performed at room temperature. CA1 pyramidal cells were visualized using infra-red DIC optics on an Olympus BX-50 microscope. Patch electrodes with a resistance of 4–5 MΩ were pulled from borosilicate filamented glass capillaries (Harvard Apparatus) using a vertical puller (PC-10, Narashige, Japan). Pipettes were filled with intracellular solution containing (mm): 120 KMeSO3, 10 Hepes, 0.2 EGTA, 4 Mg-ATP, 0.3 Na-GTP, 8 NaCl, 10 KCl, pH 7.4, 280–285 mOsm.

Figure 1. Coincident pre- and postsynaptic TBS induces LTP in adult hippocampal slices.

Figure 1

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A, subthreshold EPSPs induce no synaptic plasticity. Left trace, schematic of TBS protocol and example current clamp recording of single burst of 5 subthreshold EPSPs (scale bar, 2 mV, 10 ms). Middle graph, single example of TBS of subthreshold EPSPs experiment. Arrow indicates application of TBS stimulus to the test pathway. Control pathway receives no stimulation during TBS. Sample traces show average evoked responses during baseline (1–3 min) and after 30–35 min (scale bar, 20 pA, 20 ms). Right graph shows pooled data from 4 experiments showing no pathway-specific synaptic plasticity after TBS. B, postsynaptic action potentials induce no synaptic plasticity. Left trace, example current clamp recording of a single burst of 5 action potentials (scale bar, 20 mV, 10 ms). Middle graph, single example of postsynaptic action potentials TBS experiment (traces scale bar, 20 pA, 20 ms). Right graph, pooled data from 7 experiments showing no pathway-specific synaptic plasticity. Symbols and traces as above. C, pairing subthreshold EPSPs with postsynaptic action potentials induces LTP. Left trace, example current clamp recording of a single burst of paired subthreshold EPSPs and postsynaptic action potentials (black trace). Grey trace showing test burst of subthreshold EPSPs given before TBS (scale bar, 20 mV, 10 ms). Middle graph, single example of subthreshold EPSPs and action potentials TBS experiment (traces scale bar, 40 pA, 20 ms). Right graph, pooled data from 11 experiments showing pathway-specific LTP. Symbols and traces as above. D, distribution of synaptic plasticity induced in individual TBS experiments where subthreshold EPSPs are paired with postsynaptic action potentials. Left graph, cumulative probability plot of individual experiments showing the mean normalized EPSC amplitude at 30–35 min in the test (•) and control (○) pathways. Right graph, histogram of mean normalized EPSC amplitude at 30–35 min in the control and test pathways (open bars) overlaid by line graphs of individual experiments showing the relationship between the mean normalized EPSC amplitude at 30–35 min in the control (○) and test pathway (•).

Figure 2. Coincident pre- and postsynaptic TBS fails to induce LTP in juvenile hippocampal slices.

Figure 2

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A, subthreshold EPSPs alone induce no pathway-specific synaptic plasticity. Left trace, schematic of TBS protocol and example current clamp recording of a single burst of 5 subthreshold EPSPs (scale bar, 4 mV, 20 ms). Middle graph, single example of subthreshold EPSPs TBS experiment. Arrow indicates TBS stimulus. Sample traces show average evoked responses during baseline (1–3 min) and at 30–35 min (scale bars 10 pA, 20 ms). Right graph shows pooled data from 5 experiments showing no pathway-specific synaptic plasticity after TBS. B, postsynaptic action potentials alone induce no synaptic plasticity. Left trace, example current clamp recording of a single burst of 5 action potentials (scale bar, 20 mV, 10 ms). Middle graph, single example of postsynaptic action potentials TBS experiment (traces scale bar, 20 pA, 20 ms). Right graph pooled data from 4 experiments showing no significant change in EPSC amplitude. Symbols and traces as above. C, pairing subthreshold EPSPs with postsynaptic action potentials fails to induce pathway-specific synaptic plasticity. Left trace, example current clamp recording of a single burst of paired subthreshold EPSPs and postsynaptic action potentials (black trace). Grey trace shows test burst of subthreshold EPSPs given before TBS (scale bar, 20 mV, 10 ms). Middle graph, single example of subthreshold EPSPs and action potentials TBS experiment (traces scale bar, 20 pA, 20 ms). Right graph, pooled data from 14 experiments showing no significant pathway-specific synaptic plasticity. Symbols and traces as above. D, distribution of synaptic plasticity induced in individual TBS experiments where subthreshold EPSPs are paired with postsynaptic action potentials. Left graph, cumulative probability plot of individual experiments showing the mean normalized EPSC amplitude at 30–35 min in the test (•) and control (○) pathways. Right graph, histogram of mean normalized EPSC amplitude at 30–35 min in the control and test pathways (open bars) overlaid by line graphs of individual experiments showing the relationship between the mean normalized EPSC amplitude at 30–35 min in the control (○) and test pathway (•).

Recordings from CA1 pyramidal neurons were made with an Axopatch 200B or a Multiclamp 700A amplifier (Molecular Devices, USA), filtered at 4–5 kHz and digitized at 10 kHz using a data acquisition board and signal acquisition software (CED, Cambridge, UK). Cells were voltage clamped at −75 or −80 mV (after junction potential correction of −9 mV). Series resistance was monitored throughout the experiments and cells that showed a > 20% change were discarded.

Synaptic responses were evoked in control and test pathways with 100 μs square voltage steps applied at 0.1 Hz through two bipolar stimulating electrodes located in stratum radiatum with the test pathway more proximal to the pyramidal cell layer. The two pathways were tested regularly to ensure independence by paired-pulse protocols. Postsynaptic action potentials were initiated through somatic current injections (2 ms duration, 2 nA amplitude).

Induction of synaptic plasticity

EPSCs were recorded in voltage clamp from two independent pathways for a baseline period of 3–5 min. Spike timing and TBS protocols were applied after the neurones were switched into current clamp mode within 10 min of reaching the whole-cell configuration to prevent wash-out of plasticity. Under these conditions we can exclude the possibility that wash-out of LTP affected our results since we could induce LTP in both juvenile and adult slices. The resting membrane potential of the neurones was −75.0 ± 0.5 mV (n = 50). The TBS protocol consisted of a train of 10 bursts where each burst consisted of five stimulations at 100 Hz with the frequency of bursts set at 5 Hz. Three trains were given separated by 10 s intervals. The spike timing stimulation protocol consisted of four trains of 100 paired pre- and postsynaptic stimulations at various frequencies. Spike timing intervals were measured as the difference between the average baseline EPSC peak and the action potential peak.

Data analysis

Measurements were made from averages of six traces to give one data point per minute. Average data are presented as mean ± s.e.m. Data comparisons were made between test and control pathways at 30–35 min or within pathways between baseline and 30–35 min after LTP induction using Student's paired two-tailed t test with a significance level of P < 0.05. Baseline recordings that showed a greater then 20% change measured by simple linear regression were discarded. Where regression analysis was performed, significance was determined using the t statistic, testing if the slope of the line was significantly different from zero.

Results

TBS-induced plasticity in adult slices

We first looked at the ability of slices taken from adult (P45–55) rats to express synaptic plasticity in response to TBS (see Methods). This pattern of stimulation is used because it is believed to correspond to the type of activity found in vivo during exploration (Kelso & Brown, 1986; Hoffman et al. 2002; Watanabe et al. 2002; Frick et al. 2004) and has been shown previously to induce large pathway-specific LTP (Hoffman et al. 2002; Frick et al. 2004).

In agreement with previous reports (Magee & Johnston, 1997; Hoffman et al. 2002; Watanabe et al. 2002; Frick et al. 2004), TBS of the presynaptic input or the postsynaptic CA1 pyramidal neurone separately did not induce significant pathway-specific synaptic plasticity (Fig. 1A and B; 83 ± 24% versus 101 ± 16%, control versus test pathway, n = 4, P > 0.05 for presynaptic only and 135 ± 22% versus 158 ± 14%, control versus test pathway, n = 7, P > 0.05 for postsynaptic only). When both pre- and postsynaptic inputs were stimulated together a robust test pathway-specific LTP was induced (Fig. 1C; 131 ± 16% versus 286 ± 58%, control versus test pathway, n = 11, P < 0.05). Figure 1D shows the distribution of individual experiments in Fig. 1C. The distributions of control and test pathways are clearly different with the majority of experiments showing pathway-specific LTP.

We often noticed a small increase in the control pathway (Fig. 1B and C) which we attribute to postsynaptic action potential firing (see also Golding et al. 2002; Watanabe et al. 2002; Frick et al. 2004). Since this synaptic plasticity was not dependent on glutamate release we considered it to be outside the scope of the current study and focused on synapse-specific plasticity which we refer to as pathway-specific LTP.

During TBS CA1 neurones had a resting membrane potential of −75 ± 1 mV with a range of −79 to −61 mV. Care was taken in these experiments to make sure the EPSPs were subthreshold for action potential initiation. The average size of the EPSP was 2.3 ± 0.5 mV with a corresponding EPSC size of 59 ± 9 pA.

TBS-induced plasticity in juvenile slices

We now compared the situation in the adult hippocampus with the juvenile hippocampus. In slices taken from P14 rats, TBS of either the presynaptic input or the postsynaptic CA1 pyramidal neurone separately did not result in significant pathway-specific synaptic plasticity (Fig. 2A and B; 123 ± 23% versus 145 ± 20%, control versus test pathway, n = 8, P > 0.05 for presynaptic only and 99 ± 10% versus 117 ± 11%, control versus test pathway, n = 8, P > 0.05 for postsynaptic only). In contrast to the results previously described for mature hippocampal slices, coincident pre- and postsynaptic TBS also failed to induce pathway-specific LTP. A non-significant increase was observed in both the control and test pathways but there was no significant difference between the two pathways (Fig. 2C; 145 ± 16% versus 190 ± 41%, control versus test pathway, n = 14, P > 0.05). Figure 2D shows the distribution of the individual experiments in Fig. 2C. In contrast to the distribution found in the adult hippocampus (Fig. 1), the majority of cells (11/14) show overlapping distributions for control and test pathways. However, there are three cells that have a large potentiation of both control and test pathways.

During TBS CA1 neurones had a resting membrane potential of −75 ± 0.6 mV with a range of −79 to −70 mV and the average size of the EPSP was 0.8 ± 0.2 mV with a corresponding EPSC size of 17 ± 3 pA. Although we took great care to ensure summation of EPSPs was subthreshold (as demonstrated in Fig. 2A) it is possible that this was not always the case due to the masking effects of somatic action potential generation. Therefore, the potentiation seen for a minority of experiments in Fig. 2C could be due to suprathreshold EPSP summation. Analysis of the two experiments with the greatest LTP did reveal above average EPSP summation amplitudes (10 and 15 mV compared with an 8 mV average) suggesting that this could be the case.

These data suggested that different rules apply to the induction of LTP between adult and juvenile slices and we hypothesized that this could be due to the role of postsynaptic spikes. So we next investigated the requirements for postsynaptic spiking in the adult and juvenile slices.

Multiple postsynaptic spikes are required for LTP induction in adult slices

During TBS it was necessary to ensure summation of EPSPs was subthreshold because we found that suprathreshold EPSPs given on their own were capable of inducing LTP (Fig. 3A and B; 146 ± 15% versus 188 ± 17%, control versus test pathway, n = 25, P < 0.05).

Figure 3. TBS of suprathreshold EPSPs induces LTP in adult hippocampal slices dependent on the number of spikes initiated.

Figure 3

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A, TBS of suprathreshold EPSPs induces LTP. Left, example trace of suprathreshold EPSP burst (scale bar 20 mV, 20 ms). Middle graph, single example of suprathreshold TBS experiment. Arrow indicates TBS, traces show average baseline response (1–3 min) and average response at 30–35 min (scale bar 20 pA, 20 mV). Right graph, pooled data from 25 experiments showing pathway-specific LTP. B, summary bar chart. Values show mean normalized EPSC amplitude at 30–35 min in the test (filled bars) and control (open bars) pathways. * denotes P < 0.05. C, magnitude of LTP in the test pathway depends on which EPSP triggers the first spike. Experiments were pooled depending on which EPSP in the burst triggered the first spike. •, individual experiments; ○, average values. D, magnitude of LTP in the test pathway depends on total amount of firing. Individual experiments show a correlation between higher firing percentage and increased levels of LTP. E, magnitude of LTP in the test pathway depends on the amplitude of summated EPSPs. Individual experiments show a correlation between summated EPSP amplitude and increased levels of LTP.

The importance of the EPSP amplitude and number of EPSP-induced spikes was investigated by analysing the spikes within each theta burst. Experiments were pooled depending on which EPSP in the burst triggered the first spike (Fig. 3C) and what percentage of the EPSPs caused a spike (Fig. 3D), different measures of the amount of spiking induced by the EPSPs. This revealed an inverse correlation between where the first spike occurred in the burst and the amount of LTP in the test pathway (Fig. 3C, r2 = 0.18, P < 0.05). If the first action potential occurred during the first three EPSPs of the theta burst then LTP could be induced but not if it occurred on the 4th or 5th EPSP (Fig. 3C). We also found a positive correlation between the amount of LTP induced in the test pathway and the percentage of EPSPs that were suprathreshold (Fig. 3D; r2 = 0.25, P < 0.05). Finally, we also found a positive correlation between the amplitude of the five summated EPSPs and the amount of LTP induced in the test pathway (Fig. 3E; r2 = 0.28, P < 0.05). Therefore, in the adult hippocampus, induction of LTP depends on the size of the EPSP and also the number of postsynaptic action potentials.

To investigate this further we paired subthreshold TBS of the presynaptic input with either one or two postsynaptic action potentials given to coincide with the first one or two EPSPs (Fig. 4). When only one action potential was given during the TBS no significant pathway-specific LTP was induced (Fig. 4A and C; 153 ± 25% versus 171 ± 38%, control versus test pathway, n = 9, P > 0.05) but two action potentials were sufficient (Fig. 4B and C; 129 ± 16% versus 239 ± 36%, control versus test pathway, n = 11, P < 0.05) demonstrating that more than one postsynaptic spike is required to induce pathway-specific LTP in the adult hippocampus.

Figure 4. Postsynaptic action potential bursts are required for LTP Induction in adult hippocampal slices.

Figure 4

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A, TBS consisting of a single postsynaptic action potential paired with 5 subthreshold EPSPs induces no pathway-specific synaptic plasticity. Left, schematic of TBS protocol and example trace of single burst of 5 subthreshold EPSPs and single postsynaptic action potential (scale bar 40 mV, 10 ms). Middle graph, example of single experiment, arrow indicates application of TBS. Sample traces show average evoked responses during baseline (1–5 min) and at 30–35 min (scale bars 20 pA, 20 ms). Right graph, pooled data from 8 experiments showing a small increase in both the test and control pathways. B, TBS consisting of a burst of 2 postsynaptic action potentials paired with 5 subthreshold EPSPs induces pathway-specific LTP. Left, example trace of single burst of 5 subthreshold EPSPs and 2 postsynaptic action potential (scale bar 40 mV, 10 ms). Middle graph, example of a single experiment (traces scale bar, 100 pA, 20 ms). Right graph, pooled data from 11 experiments showing a pathway-specific LTP at 30–35 min. Symbols and traces as above. C, summary bar chart. Values show mean normalized EPSC amplitude at 30–35 min in the test (filled bars) and control (open bars) pathways. * denotes P < 0.05.

STDP in adult slices

The data so far indicate that single postsynaptic spikes will not induce pathway-specific LTP in adult slices. This predicts that STDP induction protocols (Bi & Poo, 1998; Debanne et al. 1998) will not induce LTP contrary to what has been shown (Nishiyama et al. 2000 but see Pike et al. 1999). The timing of pre- and postsynaptic spikes, or spike timing interval (STI), has been shown to be critical in STDP in CA1 pyramidal neurones of the hippocampus. If the presynaptic action potential precedes the postsynaptic action potential by less than ∼20 ms then synaptic potentiation results but if the order of pre- and postsynaptic action potential firing is switched then synaptic depression is the result (Bi & Poo, 1998; Debanne et al. 1998; Nishiyama et al. 2000). When we performed STDP using single postsynaptic spikes, in agreement with Pike et al. we found no evidence for pathway-specific synaptic plasticity at positive (defined as the peak of the EPSC occurring before the peak of the induced action potential) or negative spike timing intervals (Fig. 5A and C, positive intervals, 124 ± 12% versus 120 ± 17%, control versus test pathway, n = 7, P > 0.05; Fig. 5B and C, negative intervals, 124 ± 12% versus 119 ± 14%, control versus test pathway, n = 10, P > 0.05). This therefore confirms that multiple postsynaptic spikes within a burst are required to induce pathway-specific LTP in adult slices (Figs 3 and 4).

Figure 5. Paired EPSPs and postsynaptic spikes do not induce synaptic plasticity in adult hippocampal slices.

Figure 5

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A, positive spike timing intervals do not result in LTP. Left trace, example trace of single spike timing pair consisting of an EPSP and postsynaptic action potential with a positive spike timing interval of +4 ms (scale bar, 20 mV, 20 ms). Right graph, pooled data from 7 positive interval spike timing experiments at 10 Hz (STI of between +0.4 ms and +15.6 ms). Bar indicates application of spike timing stimulation (ST). No LTP was observed in the test pathway compared with the control pathway. B, negative spike timing intervals do not result in LTP. Left trace, example trace of single spike timing pair consisting of an EPSP and postsynaptic action potential with a negative spike timing interval of −8.6 ms (scale bar, 10 mV, 10 ms). Right graph, pooled data from 10 negative interval spike timing experiments at 10 Hz (STIs of between −1.8 ms and −14.1 ms). No pathway-specific LTP was observed but there was a consistent transient depression in the test pathway of unknown origin. C, summary graph of all spike timing experiments at 10 Hz. Data points show mean normalized EPSC amplitude of the test pathway at 30–35 min against spike timing interval (STI).

Multiple somatic spikes are not required for LTP induction in juvenile slices

We now looked in detail at the spiking requirements for LTP induction in juvenile slices to compare with the situation in the adult. The importance of keeping the EPSPs subthreshold during TBS was demonstrated once again because suprathreshold EPSP summation resulted in pathway-specific LTP when the presynaptic input was given on its own (Fig. 6A and B; 152 ± 12% versus 228 ± 24%, control versus test pathway, n = 20, P < 0.05) or with coincident action potentials (Fig. 6B; 102 ± 13% versus 260 ± 67%, control versus test pathway, n = 10, P < 0.05). To achieve suprathreshold summation, the EPSP amplitude was increased to 5.5 ± 0.8 mV (corresponding EPSC amplitude 76 ± 12 pA).

Figure 6. TBS of suprathreshold EPSPs is capable of inducing LTP in juvenile hippocampal slices.

Figure 6

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A, TBS of suprathreshold EPSPs induces LTP. Left, example trace of suprathreshold EPSP burst (scale bar 20 mV, 20 ms). Middle graph, single example of suprathreshold TBS experiment. Arrow indicates application of TBS, traces show average baseline response (1–3 min) and average response at 30–35 min (scale bars, 100 pA, 20 ms). Right graph, pooled data from 20 experiments showing pathway-specific LTP. B, summary bar chart. Values show mean normalized EPSC amplitude at 30–35 min for the test (filled bars) and control (open bars) pathway. * denotes P < 0.05. C, correlation between timing of the first spike within a burst and plasticity in the test pathway. Individual experiments were pooled depending on which EPSP in a burst triggered the first spike (•). Average values for each pool are also shown (○). D, individual experiments show no correlation between the percentage of EPSPs causing a spike and plasticity in the test pathway. E, individual experiments show no correlation between the amplitude of summated EPSPs and plasticity in the test pathway.

The importance of the EPSP amplitude and the number of EPSP-induced spikes was investigated by analysing the spikes within each theta burst. Experiments were pooled depending on which EPSP in the burst triggered the first spike (Fig. 6C), what percentage of the EPSPs caused a spike (Fig. 6D) and the amplitude of the summated five EPSPs (Fig. 6E). In contrast to the situation in the adult hippocampus, we found that there was no significant correlation between the amount of LTP in the test pathway and the position within the burst of the first spike (Fig. 6C; r2 = 0.002, P > 0.05). There was also no correlation between the overall level of spiking (Fig. 6D; r2 = 0.04, P > 0.05) or the amplitude of the summated five EPSPs (Fig. 6E; r2 = 0.03, P > 0.05) and the amount of LTP in the test pathway. Therefore, in the juvenile hippocampus, a critical level of depolarization (induced by EPSP summation or spiking) is required to induce LTP by TBS. Once this threshold is reached, further depolarization or spiking does not increase the amount of LTP.

Timing and frequency dependence for STDP in juvenile slices

Since these results argue against a role for precise spike timing requirements for plasticity in the juvenile hippocampus, we next performed experiments to investigate the requirements for STDP using single pre- and postsynaptic spike pairings. First we looked at the relationship between the induction of plasticity and the precise timing of individual coincident pre- and postsynaptic stimulation. We found that if the pre- and postsynaptic stimuli were given at a positive interval, a small pathway-specific LTP was induced at intervals up to ∼ +30 ms (Fig. 7A and C; 109 ± 7% versus 136 ± 9%, control versus test pathway, n = 50, P < 0.05). The same was true when the pre- and postsynaptic stimuli were given at a negative interval. Again, a small pathway-specific LTP was induced at intervals up to ∼−40 ms (Fig. 7B and C; 118 ± 6% versus 152 ± 9%, control versus test pathway, n = 45, P < 0.05). There was no significant correlation between spike timing interval and LTP (Fig. 7C, r2 = 0.004, P > 0.05). Previous reports have found that the amount of LTP produced by STDP is inversely proportional to the initial size of the EPSP (Bi & Poo, 1998) so we analysed the relationship between initial EPSC amplitude and LTP (Fig. 7D). We found that at positive spike timing intervals there was no significant correlation between baseline EPSC amplitude and LTP (Fig. 7D, r2 = 0.0002, P > 0.05). At negative STIs the EPSC amplitude was proportional to the amount of LTP (Fig. 7D, r2 = 0.2, P < 0.05).

Figure 7. Induction of synaptic plasticity in juvenile hippocampal slices does not depend on the spike timing interval.

Figure 7

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A, positive spike timing intervals result in LTP. Left trace, example trace of single spike timing pair consisting of an EPSP and postsynaptic action potential with a positive spike timing interval of +2.4 ms (scale bar, 10 mV, 10 ms). Right graph, pooled data from 50 positive interval spike timing experiments at 10 Hz (STI of between +0.2 ms and +25.0 ms). Bar indicates application of spike timing stimulation. LTP was observed in the test pathway but not in the control pathway. B, negative spike timing intervals result in LTP. Left trace, example trace of single spike timing pair consisting of an EPSP and postsynaptic action potential with a negative spike timing interval of −10.8 ms (scale bar, 10 mV, 10 ms). Right graph, pooled data from 45 negative interval spike timing experiments at 10 Hz (STIs of between −0.4 ms and −35.2 ms). Pathway-specific LTP was again observed. C, summary graph of all spike timing experiments at 10 Hz. Data points show mean normalized EPSC amplitude in the test pathway at 30–35 min against spike timing interval. D, correlation of baseline EPSC amplitude and plasticity. Data points show mean baseline EPSC amplitude in the test pathway (1–4 min) for positive (• and continuous line) and negative (○ and dashed line) spike timing intervals against the amount of LTP.

We also investigated the frequency dependence of STDP under these conditions since previous reports have shown plasticity to be dependent on the frequency which coincident pre- and postsynaptic stimuli are given (Sjostrom et al. 2001; Froemke et al. 2006). Using single presynaptic stimulation preceding postsynaptic action potentials by 0–25 ms during the induction protocol, we found that pathway-specific LTP could be induced if the frequency of presynaptic stimulation and postsynaptic action potential pairs was set at 10 or 20 Hz (Fig. 8A and D; 109 ± 7% versus 136 ± 9%, control versus test pathway, n = 50, P < 0.05 for 10 Hz; 92 ± 10% versus 140 ± 17%, control versus test pathway, n = 11, P < 0.05 for 20 Hz) but not if the frequency was set at 1 or 5 Hz (Fig. 8B and C; 116 ± 12% versus 101 ± 10%, control versus test pathway, n = 12, P > 0.05 for 1 Hz and 99 ± 19% versus 113 ± 18%, control versus test pathway, n = 8, P > 0.05 for 5 Hz) whilst keeping the number of stimuli constant (Fig. 8E). This agrees with previous reports (Tzounopoulos et al. 2004; Wittenberg & Wang, 2006 but see Meredith et al. 2003). Stimulation of the pre- or postsynaptic input on their own did not induce any pathway-specific LTP (presynaptic stimulation only, 108 ± 16% versus 104 ± 18%, control versus test pathway, n = 5, P > 0.05; postsynaptic stimulation only, 118 ± 18% versus 70 ± 10%, control versus test pathway, n = 6, P > 0.05).

Figure 8. Induction of synaptic plasticity in juvenile hippocampal slices depends on the frequency of stimulation.

Figure 8

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A, left trace, example of single spike timing pair of EPSP and postsynaptic action potential with a positive spike timing interval of +3.2 ms (scale bar, 10 mV, 10 ms). Middle graph, example of single spike timing experiment at 10 Hz. Bar indicates application of spike timing stimulation, traces show average baseline response (1–4 min) and average response at 30–35 min (scale bar, 40 pA, 20 ms). Right graph, pooled data from 95 experiments of spike timing stimulation (interval −35 ms to +25 ms) at 10 Hz showing pathway-specific LTP. B, pooled data from 4 experiments of spike timing stimulation at 1 Hz showing no plasticity. C, pooled data from 8 experiments of spike timing stimulation at 5 Hz showing no plasticity. D, pooled data from 11 experiments of spike timing stimulation at 20 Hz showing pathway-specific LTP. E, frequency dependency of spike timing plasticity. Values show mean normalized EPSC amplitude in the test pathway at 30–35 min after ST stimulation at various frequencies. F, LTP is correlated with the level of chronic depolarization during STDP induction. Left, example traces showing 10 paired stimulations during the STDP induction at 10 Hz (top) and 20 Hz (bottom). Scale bar 4 mV, 200 ms (top) or 100 ms (bottom). Right, the amount of LTP in the test pathway is correlated with the level of depolarization during STDP induction. ○, data from 10 Hz induction; •, 20 Hz induction. The line is a simple linear regression to all the data points.

The data on the induction of LTP in juvenile slices has so far argued against a role for somatic action potentials (Figs 2 and 6). Here, we wondered if the apparent role of somatic spikes could be due to a chronic depolarization that we saw during STDP induction at frequencies of 10 or 20 Hz. To investigate this we analysed the correlation between the chronic depolarization produced by pairing of EPSPs and somatic action potentials at 10 or 20 Hz and the amount of LTP induced in the test pathway (Fig. 8F). This revealed a positive correlation (r2 = 0.26, n = 61, P < 0.05) suggesting that it is indeed the amount of residual depolarization that is important and perhaps not the somatic spiking per se. Hyperpolarization of the membrane potential was also sometimes seen which we attribute to activation of GABAB receptors.

Taken together these data show that in juvenile slices the timing of pre- and postsynaptic spikes relative to each other is not critical for the induction of synaptic plasticity, rather, it is the frequency of stimulation that is important (Figs 7 and 8). Specifically, postsynaptic action potentials and EPSPs need to occur at a sufficiently high frequency to create a chronic level of depolarization in the dendrites to induce LTP.

Back-propagating action potentials control LTP induction in adult but not juvenile slices

We noticed during the TBS experiments that the amplitude of the somatically evoked action potentials was attenuated within each theta burst to a greater extent in the juvenile hippocampus than the adult (Fig. 9). The 5th spike in each burst was 17 ± 5% smaller than the 1st spike in the adult (n = 9) but 35 ± 3% smaller in the juvenile (n = 14, P < 0.05) (Fig. 9B). This potentially indicates that action potentials during a theta burst become less effective in juvenile CA1 neurones and therefore may back-propagate into the dendrites less efficiently.

Figure 9. Somatic spikes within a theta burst attenuate more in juvenile than adult hippocampal slices.

Figure 9

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A, example traces of theta burst spiking in adult (top) and juvenile (bottom) slices. Bursts were induced by 2 ms current injections repeated 5 times (scale bar 20 mV, 10 ms). B, mean normalized spike amplitude in juvenile (•) and adult (○) slices demonstrates a greater degree of attenuation in the juvenile slices. Each spike amplitude was measured as the difference between the membrane potential 1 ms before the 2 ms current injection and the peak potential.

In order to test the hypothesis that the back-propagation of action potentials from the soma to the dendrites is the critical difference between LTP induction in adults and juveniles we devised a set of experiments in which we blocked the generation of somatic action potentials with local TTX application (Fig. 10A). In control experiments performed in juvenile slices a single 800 ms puff of TTX (10 μm) blocked the somatic action potential in a temporary manner that lasted ∼30 s (Fig. 10B; n = 4). Subsequent bath application of 10 μm TTX blocked the action potential to the same extent leaving only the passive membrane response to the current injection. This was subsequently subtracted from the amplitude of the action potential for the entire experiment. The same puff of TTX caused only a small non-significant transient depression in the amplitude of the EPSP (Fig. 10C; EPSP amplitude was reduced by 13 ± 18%, n = 4, P > 0.05). We then applied this local TTX application to adult slices immediately prior to TBS using subthreshold EPSPs that would normally produce robust LTP (Fig. 1C). The local TTX application blocked somatic action potential generation and completely abolished pathway-specific LTP (Fig. 10D and F; 158 ± 20% versus 163 ± 15%, control versus test pathways, n = 8, P > 0.05) demonstrating that under these conditions bAPs are critical for LTP induction in the adult. We also applied local TTX to juvenile slices immediately prior to TBS of only the presynaptic input using suprathreshold EPSPs that again would normally induce robust LTP (Fig. 6). Under these circumstances somatic action potentials were blocked revealing putative dendritic spikes and pathway-specific LTP was still induced (Fig. 10E and F; 110 ± 8% versus 173 ± 7%, control versus test pathways, n = 7, P < 0.05) demonstrating that bAPs are not critical for LTP induction in the juvenile.

Figure 10. Somatic spikes are required for paired TBS-induced LTP in adult slices but not suprathreshold TBS-induced LTP in juvenile slices.

Figure 10

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A, schematic diagram of the experimental set-up. TTX was applied locally to the soma of the CA1 pyramidal cell and the flow of solution in the bath was from top to bottom. Two stimulating electrodes were placed in the Schaffer collateral pathway. B, local TTX application completely blocked the somatic spike but this recovered within minutes. Arrow represents time of single 800 ms puff of TTX (10 μm). Example traces above show responses to somatic current injection at the time points indicated on the graph (scale bar 20 mV, 10 ms). C, local TTX application caused a transient non-significant depression in the EPSP. Arrow represents time of single 800 ms puff of TTX (10 μm). Example traces above show EPSPs at the time points indicated on the graph (scale bar 2 mV, 40 ms). D, local TTX application blocks LTP induced by paired TBS in adult slices. Left trace, example recording of a single burst of postsynaptic current injections showing complete block of the somatic action potential (scale bar 10 mV, 10 ms). Middle graph, single example of subthreshold EPSPs and action potentials TBS experiment in adult slices with local TTX application. Arrow represents time of TBS and TTX application. Sample traces show average evoked responses during baseline (1–3 min) and after 30–35 min (scale bar 40 pA, 20 ms). Right graph, pooled data from 8 experiments showing no pathway-specific LTP. E, TBS of suprathreshold EPSPs alone induces LTP in juvenile slices despite local TTX application. Left, example trace of suprathreshold EPSP burst showing a putative dendritic spike but no somatic spike (scale bar 20 mV, 20 ms). Middle graph, single example of suprathreshold TBS experiment. Arrow indicates application of TBS and TTX, traces show average baseline response (1–3 min) and average response at 30–35 min (scale bars 100 pA, 20 ms). Right graph, pooled data from 7 experiments showing pathway-specific LTP. F, summary bar chart. Values show mean normalized EPSC amplitude at 30–35 min for the test (filled bars) and control (open bars) pathway. * denotes P < 0.05.

Discussion

Synaptic plasticity in the dendrites of CA1 pyramidal cells requires NMDA receptor activation by coincident presynaptic glutamate release and postsynaptic depolarization. The required postsynaptic depolarization was initially believed to result from AMPA receptor activation (Bliss & Collingridge, 1993) but it is now known that it can also come from a number of other sources such as bAPs (Magee & Johnston, 1997; Markram et al. 1997; Stuart et al. 1997), locally induced dendritic spikes (Golding et al. 2002; Gasparini et al. 2004) or longer lasting depolarizing conductances (Sjostrom et al. 2001; Sjostrom & Nelson, 2002; Lisman & Spruston, 2005). The duration or magnitude of the resulting calcium transient is thought to determine the amplitude and direction of synaptic plasticity (Ismailov et al. 2004; Nevian & Sakmann, 2006). Here we have specifically investigated the activity patterns required to activate NMDA receptors and produce the necessary postsynaptic rise in calcium to induce LTP.

Our experiments show that the activity patterns required to induce synaptic plasticity at the Schaffer collateral synapse in CA1 of the hippocampus change with development. Interestingly, this mirrors the developmental profile for the ability to perform hippocampal-dependent memory tasks (Rauch & Raskin, 1984; Green & Stanton, 1989; Dumas, 2005) and the development of different mechanisms underlying plasticity induction and expression (Dudek & Bear, 1993; Hsia et al. 1998; Palmer et al. 2004) as well as the maturation of NMDA receptor subunit complement (Barria & Malinow, 2002; Ritter et al. 2002). If this is the case, our data would suggest that in juvenile animals synaptic plasticity enables synaptic connections to be established and potentiated by high-frequency presynaptic activity without the need for any coherent postsynaptic activity pattern. Conversely, in adult animals synaptic plasticity is important for memory formation where the correlated patterns of pre- and postsynaptic activity are much more critical.

We show that in the juvenile hippocampus, postsynaptic action potentials initiated at the soma are not effective at inducing synaptic plasticity during TBS whereas synaptically induced spikes are (Figs 2 and 6). Further analysis of the timing and number of synaptically induced spikes observed during these experiments showed that they did not influence the amount of LTP observed (Fig. 6C and D) indicating that single synaptically induced spikes are sufficient to induce LTP. Interestingly, dendritic spikes are known to propagate poorly and therefore act as an ideal localized signal for LTP induction (Golding et al. 2002; Gasparini et al. 2004; Letzkus et al. 2006). The lack of influence of somatic activity on LTP in the juvenile hippocampus could be due to a failure of somatic action potentials to back-propagate effectively and the attenuation of somatic action potentials seen in Fig. 9 would suggest this. Furthermore the induction of LTP in the absence of somatic action potentials (Fig. 10E) also supports this conclusion. Alternatively, developing dendrites may lack the ability to interpret the bAP signal.

Further evidence that LTP induction in the juvenile hippocampus requires postsynaptic depolarization above and beyond somatic action potentials is shown in Figs 7 and 8. We found that in the juvenile hippocampus single pairs of coincident pre- and postsynaptic spikes were able to induce plasticity only when pairs of stimuli were repeated at 10 Hz or greater (Fig. 8). We also observed that the plasticity induced at 10 Hz showed no timing dependence for the pre- and postsynaptic activity (Fig. 7). An average increase in synaptic strength was induced regardless of the order of pre- and postsynaptic spikes. Therefore, the chronic dendritic depolarization produced by 10–20 Hz action potential firing is more important for the induction of plasticity than the precise timing of pre- and postsynaptic spikes (Fig. 8) (Sjostrom et al. 2001) which may explain why we do not see any consistent LTD in our experiments. It is also possible that the non-specific synaptic potentiation induced by action potential firing could mask or override specific LTD induction. These data support previous evidence that the classic rules of STDP described for hippocampal dispersed or slice cultures (Bi & Poo, 1998; Debanne et al. 1998) do not apply at the Schaffer collateral CA1 pyramidal cell synapse in acute slices (Wittenberg & Wang, 2006).

The requirement for temporal electrical integration of action potentials to supply sufficient dendritic depolarization for LTP induction, such as that seen in Fig. 8 and at cortical synapses (Markram et al. 1997; Sjostrom et al. 2001), is superficially contradictory to the data in Fig. 2C which shows that high-frequency bursts are unable to induce plasticity when paired with presynaptic bursts. Dendritic recordings have shown that back-propagating action potentials undergo potent frequency-dependent attenuation (Callaway & Ross, 1995; Spruston et al. 1995; Tsubokawa & Ross, 1997; Frick et al. 2004). We also show that somatic action potentials attenuate more in the juvenile hippocampus than the adult (Fig. 9). Therefore there needs to be a balance between temporal integration and spike attenuation.

In summary, in the juvenile hippocampus the critical dendritic depolarization comes from either summation of EPSPs leading to a dendritic spike (Figs 6 and 10E) or from summation of EPSPs and somatic spikes when given above a critical frequency (Fig. 8). These observations imply that the pattern of activity that will be most suited to producing LTP will be presynaptic bursts of activity leading to temporal EPSP summation above a local dendritic spike threshold (Golding et al. 2002). This may reflect a greater reliance on dendritic spikes rather than somatic activity in the induction of LTP in younger animals, and future use of dendritic recordings may shed more light on the nature of dendritic spike initiation during plasticity induction.

In the adult hippocampus, the requirements for plasticity induction are shifted to a greater reliance on the coincident activity of pre- and postsynaptic elements. Somatically evoked action potentials were able to induce LTP when paired with subthreshold presynaptic stimulation unlike in the juvenile hippocampus (Figs 1 and 2). Synaptically evoked spikes also induced LTP, and the amount of LTP induced was correlated with the degree of spiking, contrary to the situation in the juvenile hippocampus (Figs 3 and 6). LTP was only induced when spiking occurred at the beginning of the burst, and as the percentage of spikes increased so did the amount of LTP observed (Fig. 3C and D). Coupled with the observations that multiple somatically evoked action potentials are required for LTP (Fig. 4) and that inhibition of somatic spikes blocks LTP (Fig. 10D), this demonstrates that somatic action potentials have a clear influence on LTP induction in adult animals. This may reflect the ability of action potential bursts to back-propagate in the adult suggested by the minimal attenuation seen at the soma (Fig. 9). Therefore, in the adult hippocampus the dendritic depolarization required to induce LTP comes from bursts of postsynaptic spikes (Figs 1 and 3) (Thomas et al. 1998; Pike et al. 1999; Wittenberg & Wang, 2006).

As the hippocampus matures, dendritic conductances have been shown to change (Santos et al. 1998; Chen et al. 2004; Kip et al. 2006). The expression and distribution of voltage-gated calcium and potassium channels may alter the ability to induce dendritic calcium spikes and the ability of action potentials to back-propagate (Hoffman et al. 1997; Kortekaas & Wadman, 1997; Tsubokawa & Ross, 1997; Magee & Carruth, 1999; Tsubokawa et al. 2000; Chen et al. 2005). This may reduce the reliance on dendritic spikes in the adult hippocampus and allow the CA1 pyramidal neurones to interpret coincident pre- and postsynaptic activity. For example, changes in A-type potassium currents have been shown to lead to boosting of bAPs by coincident EPSPs (Frick et al. 2004). Furthermore, the development of GABAergic inhibition will also have a role in LTP induction by TBS (Davies et al. 1991; Meredith et al. 2003) although we note that we have pharmacologically blocked GABAA receptors in all our experiments.

It is clear from our data that multiple postsynaptic spikes are required to induce synaptic plasticity in the adult hippocampus and that therefore a burst of action potentials is necessary as a signal for synaptic enhancement. This is broadly in agreement with the emerging picture for how synaptic plasticity is induced in the hippocampus during learning episodes (Huerta & Lisman, 1993, 1995; Pike et al. 1999; Wittenberg & Wang, 2006) and illustrates the importance of rhythmic activity such as the theta band that is present during exploratory behaviour.

Acknowledgments

This work was supported by GlaxoSmithKline (K.A.B.), EU (ENI-NET, J.R.M.) and Medical Research Council, UK (J.R.M.). We thank A. D. Randall, J. G. Hanley and G. L. Collingridge for critical reading of earlier versions of the manuscript.

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