When we explore somewhere new, we activate a region of the brain that processes spatial information called the entorhinal cortex. This brain region stimulates the brain's memory-formation center, known as the hippocampus, which in turn forms a spatial memory of the new place. The process of forming these memories involves strengthening nerve connections, including those between the entorhinal cortex and the hippocampus.

Groups of neurons that produce synchronized electrical activity will naturally strengthen the nerve connections between them. This led scientists to predict that synchronized electrical activity between neurons in the entorhinal cortex and the hippocampus may contribute to the formation of spatial memories.

Previous research revealed that hippocampal neurons produced short bursts of electrical activity that are localized at specific sites along their branched nerve processes that extend out of the cell body and are where inputs from other neurons are received. These types of localized electrical activity have been associated with a strengthening of the nerve connections between the entorhinal cortex and the hippocampal neurons. Ion channels that allow calcium to flow through these neurons' cell membranes had been identified as a potential source of these local electrical activities, and calcium is responsible for the strengthening of nerve connections. But it remained unclear whether channels that allow only sodium ions to flow through might also be involved.

Kim, Hsu et al. have now investigated this question by devising a way to selectively block the electrical activity produced by sodium ion channels on the branched nerve processes of hippocampal neurons. Slices of rat brain were collected and an inhibitor that specifically affected the sodium channels was delivered to the brain slices. Electrodes were used to stimulate the inputs from the entorhinal cortex, and to monitor the resulting electrical activity in the hippocampal neurons.

Kim, Hsu et al. analyzed the results and reproduced them using computer simulations, which showed that sodium ion channels are essential for triggering brief electrical events within the individual branches of nerve processes. These local electrical events appeared to activate calcium channels to produce highly concentrated, short-lived calcium signals that are necessary for strengthening nerve connections. Future studies will determine whether local electrical activity mediated by sodium channels is also involved in strengthening nerve connections between other types of neurons, and how this mechanism affects the formation of memories.

Hebbian remodeling of neural circuits, encapsulated by the phrase ‘neurons that fire together wire together’, is the leading candidate mechanism for learning in the brain (Shatz, 1992; Cooper, 2005). Thus, the finding that synaptic plasticity often has properties compatible with Hebbian learning has been a powerful driver of experimental and theoretical studies of changes in synaptic weights. The simple idea is that coincident presynaptic and postsynaptic activity results in changes in synaptic strength such as long-term potentiation (LTP). Many in vitro studies support a model in which modifiable synapses detect presynaptic activity through glutamate binding to postsynaptic receptors and detect postsynaptic activity through depolarization, which relieves magnesium block of N-methyl-D-aspartate (NMDA) receptors (NMDARs) and activates voltage-gated calcium (Ca_v) channels. Both of these effects mediate postsynaptic calcium entry, which is believed to be a critical activator of the biochemical steps necessary for increases in synaptic strength (Madison et al., 1991; Bliss and Collingridge, 1993; Blackstone and Sheng, 2002; Cavazzini et al., 2005). Four decades of research have led to this general picture, but important questions about the events leading to the critical calcium entry remain unanswered.

Three distinct ideas have been considered for the type of postsynaptic depolarization required to produce the calcium entry leading to Hebbian LTP (Williams et al., 2007):

1. Postsynaptic axo-somatic action potential firing is necessary, and this signal reaches synapses in the form of backpropagating action potentials (bAPs),

2. Postsynaptic axo-somatic action potential firing is not necessary; rather, localized passive synaptic depolarization is sufficient,

3. Postsynaptic axo-somatic action potential firing is not necessary and passive synaptic depolarization is not sufficient; rather, localized synaptic depolarization must activate dendritic nonlinearities, such as locally initiated dendritic spikes (dSpikes).

At any given synapse at any moment in time, these three mechanisms of postsynaptic activity detection are mutually exclusive. However, all three mechanisms may exist in the brain, for example, in different cell types or even within the same cell at different synapses, different stages of development, or possibly in response to different activation patterns at the same synapse. Such heterogeneity would be consistent with the idea that LTP is not a single phenomenon, but rather a collection of mechanisms that can produce a long-lasting increase in synaptic strength (Malenka and Bear, 2004).

In each of the three cases above, the concerted action of multiple synapses is required—the so-called ‘cooperativity’ requirement for LTP (Feldman, 2012)—but the patterns of synaptic activation that result in LTP are quite different. In the first case, the synapses that drive action potential firing could be located anywhere in the dendritic tree and plasticity would occur at all synapses that experience significant depolarization as a result of the bAP. This is the most conventional interpretation of Hebbian LTP. In the second and third conditions, synapses have to be co-localized in the dendrites in order to depolarize each other sufficiently to produce Hebbian LTP. In these conditions, the postsynaptic axon does not have to ‘fire’ at all; the third condition additionally requires that the co-localized synapses produce enough depolarization to trigger a dSpike, which may occur with or without axonal firing. Although these conditions may still be classified as ‘Hebbian LTP’, because of the requirement for co-incident presynaptic and postsynaptic activation, the existence of LTP under these conditions would imply that Hebbian-like LTP occurs at finer spatial scales than the more cell-wide form that most current models employ. Thus, during behavior, neurons that fire may undergo LTP, but even a neuron that is synaptically activated but axonally silent during a behavioral event can be recruited to participate in the neural engram.

Interestingly, hippocampal place cells behave in a manner suggestive of a form of Hebbian LTP that may not require postsynaptic action potential firing: many cells are silent when the animal first goes to a new place, and then they are recruited to participate in the network representation of the spatial map (Frank et al., 2004). This suggests that if synaptic plasticity contributes to reshaping the network upon initial exposure to a new environment, it need not be conventional Hebbian plasticity, but rather a modified form of Hebbian plasticity that does not require axonal firing, such as the second and third conditions described above. Consistent with this idea, hippocampal neurons receive spatially tuned synaptic inputs even when they are silent (Lee et al., 2012). Understanding whether and how such inputs can drive synaptic plasticity will be an important step toward understanding how spatial memories are formed in the hippocampus.

If axonal action potential firing is required for synaptic plasticity, memories can only be stored in active neurons. On the other hand, if it is not required, memories can also be formed in silent neurons. Furthermore, plasticity that is induced by dSpikes that remain localized to individual dendritic branches has been proposed to enhance the memory-storing capacity of individual neurons (Poirazi and Mel, 2001; Mehta, 2004; Wu and Mel, 2009). Collectively, these considerations underscore the importance of understanding the dendritic events leading to the postsynaptic calcium entry necessary for the induction of LTP.

At synapses from the perforant path (PP; which carries predominantly spatial information from the entorhinal cortex) to the distal apical tuft of hippocampal CA1 pyramidal neurons, LTP requires strong synaptic activation, and LTP induction can have a significant impact on the output of CA1 neurons (Colbert and Levy, 1993; Remondes and Schuman, 2002; Ahmed and Siegelbaum, 2009; Takahashi and Magee, 2009). In previous work, we showed that LTP at these synapses does not require bAPs; rather, LTP is correlated with the initiation of dSpikes, which often do not trigger action potential firing and bAPs (Golding and Spruston, 1998; Golding et al., 2002). This pathway therefore offers an ideal opportunity to study the potential role of dSpikes in the induction of LTP.

The hypothesis that dSpikes are a causal step in the induction of LTP has not been directly tested, owing to the difficulty of blocking them selectively. Three types of dSpikes have been described, which have been named according to the primary channel type supporting the regenerative event: dendritic sodium spikes (Na-dSpikes) and dendritic calcium spikes (Ca-dSpikes) are mediated primarily by voltage-gated sodium (Na_v) channels and Ca_v channels, respectively, while dendritic NMDA spikes (NMDA-dSpikes) are mediated primarily by NMDAR channels (Schwartzkroin and Slawsky, 1977; Andreasen and Lambert, 1995; Schiller et al., 1997; Golding et al., 1999; Larkum et al., 1999; Spruston, 2008; Larkum et al., 2009; Major et al., 2013). NMDAR and Ca_v channels are known to contribute to the induction of LTP at PP-CA1 synapses (Golding et al., 2002; Takahashi and Magee, 2009), but it is difficult to disentangle the importance of the calcium permeability of these channels from their roles in mediating regenerative dendritic voltage changes. Furthermore, the importance of dendritic Na_v channels and Na-dSpikes has not been addressed, mostly because these channels are essential for action potential firing in presynaptic axons and terminals, thus making it difficult to block them without inhibiting synaptic transmission.

One strategy to block postsynaptic Na_v channels without affecting presynaptic Na_v channels is to use the intracellular blocker QX-314; however, this drug also blocks Ca_v channels, voltage-gated potassium (K_v) channels and has effects on other channels and receptors, making the overall consequences difficult to interpret (Nathan et al., 1990; Andrade, 1991; Oda et al., 1992; Lambert and Wilson, 1993; Martin et al., 1993; Otis et al., 1993; Perkins and Wong, 1995; Talbot and Sayer, 1996). As an alternative strategy, we used a relatively low concentration of bath-applied tetrodotoxin (TTX; 20 nM) to achieve partial block of the Na_v channels (Kaneda et al., 1989; Madeja, 2000), which we demonstrate is able to inhibit postsynaptic dSpikes mediated by Na_v channels without blocking presynaptic action potential firing or synaptic transmission. This strategy works because the density of Na_v channels is much lower in dendrites than in axons. As a result, the safety factor for spike initiation is lower in dendrites, so partial block of Na_v channels affects postsynaptic (dendritic) dSpikes much more than presynaptic (axonal) action potentials (Mackenzie and Murphy, 1998). Using this strategy, we demonstrate that Na-dSpikes are necessary for the induction of LTP in response to theta-burst stimulation (TBS) of the PP synapses in the apical tuft dendrites of CA1 pyramidal neurons, and we offer an explanation for why these spikes are an essential mechanism.

To determine whether a low concentration of TTX (20 nM) could be used without interfering with synaptic transmission over a range of stimulus intensities, we performed whole-cell recordings from CA1 pyramidal neurons in rat hippocampal slices while stimulating the PP (‘Materials and methods’) to activate synapses in the distal apical tuft dendrites (henceforth ‘PP → CA1_tuft’ synapses). We adjusted stimulus intensity to yield single PP → CA1_tuft excitatory postsynaptic potentials (EPSPs) of 3–10 mV at the soma, which likely corresponds to activation of several tens of synapses onto the apical tuft dendrites of the recorded neuron (Golding et al., 2005; Nicholson et al., 2006). We chose 20 nM TTX (henceforth ‘low TTX’) because it was the highest concentration we could use without obviously reducing the size of EPSPs. The IC₅₀ of TTX on Na_v channels has been estimated as 6–10 nM in dissociated hippocampal neurons (Kaneda et al., 1989; Madeja, 2000), but it may be higher for slice experiments due to limited drug penetration in brain slices. Single EPSPs in response to low-frequency (single shock) stimulation were not affected by bath application of low TTX (control: 4.57 ± 0.36 mV, low TTX: 5.02 ± 0.49 mV, n = 7; p > 0.05 by Student's t-test; data not shown). We also tested the effects of low TTX on the responses to low-frequency or high-frequency (5 stimuli at 100 Hz) activation of the PP, while using localized application of a higher concentration of TTX (10 µM in the application pipette) to the vicinity of the soma and proximal axons (‘Materials and methods’; Figure 1A) in order to prevent somatic or axonal action potential initiation. Bath application of low TTX had no significant effect on PP → CA1_tuft EPSPs in response to either type of stimulation, across a wide range of stimulus intensities resulting in EPSPs from ∼3 mV (single shock) up to ∼27 mV (high-frequency burst; Figure 1B–G; Figure 1—source data 1). These results suggest that excitatory synaptic transmission is not affected by bath application of low TTX within the range of stimulus intensities and frequencies tested here.

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Consistent with this result and with the notion of a high safety factor for action potential initiation in the axon (Coombs et al., 1957; Mainen et al., 1995; Raastad and Shepherd, 2003; Clark et al., 2005; Khaliq and Raman, 2006; Kole and Stuart, 2008; Hu and Jonas, 2014), low TTX did not block action potential firing in response to somatic current injection, though it did raise the voltage threshold and reduce action potential amplitude slightly, as expected from a reduction of Na_v channel availability (Figure 1—figure supplement 1A–C; Figure 1—source data 2; see also Mackenzie and Murphy, 1998; Magee and Carruth, 1999; Fan et al., 2005). In addition, we tested the effects of low TTX on action potentials evoked by repeated bursts of antidromic stimulation of CA1 axons and found that low TTX only affected antidromic action potential firing at low stimulus intensities. At high stimulus intensities, antidromic spikes were not blocked by low TTX (Figure 1—figure supplement 1D,E; Figure 1—source data 2). Together with the lack of effect of low TTX on synaptic responses, these data suggest that the effects of low TTX on presynaptic action potential firing and glutamate release are minimal.

To analyze the effects of low TTX on dSpike initiation, we performed recordings from the primary apical dendrite (n = 9; 200–320 µm from the soma, mean distance = 250 µm; about 50–80% of the distance from the soma to the end of the apical tuft). Dendritic recording is necessary to increase the probability of detecting dSpikes originating in the apical tuft, because their steep attenuation makes them impossible to detect hundreds of microns away in somatic recordings. We used a stimulus pattern known to cause dSpikes (Golding et al., 2002), which consisted of PP stimulation in high-frequency bursts (5 stimuli at 100 Hz), repeated five times at theta frequency (5 Hz; a ‘theta-burst stimulation’, TBS, consisting of 25 stimuli in total). Stimulus intensity was set to evoke single PP → CA1_tuft EPSPs of 4–10 mV recorded in the dendrites, approximately the same as that required to produce single PP → CA1_tuft EPSPs of 2–5 mV recorded at the soma (Golding et al., 2005). This stimulus pattern is intended to mimic the theta rhythm observed both in the hippocampus and in the entorhinal cortical neurons forming the PP (Buzsáki and Moser, 2013), and is known to be an effective stimulus for induction of LTP in the hippocampus (Larson et al., 1986; Phillips et al., 2008). A TBS is normally repeated multiple times to induce LTP, but in this first series of experiments, we used a single TBS in the presence of low TTX followed by another single TBS after washout of TTX. We used this order of drug application and avoided repeating TBS in each condition in order to prevent the induction of LTP, which would confound the comparison of responses in the presence and absence of TTX.

Consistent with previous results (Golding and Spruston, 1998; Golding et al., 2002; Losonczy and Magee, 2006), we observed three types of regenerative dendritic responses: (1) bAPs, (2) large dSpikes, and (3) small dSpikes (also known as ‘spikelets’). These three kinds of events were distinguishable in most cases by their voltage amplitude, first temporal derivative of voltage (dV/dt) and onset kinetics (Figure 2A,B; Figure 2—source data 1; ‘Materials and methods’). Large dSpikes reflect dSpikes that have propagated actively from their initiation site to the recording site. However, dSpikes can fall below threshold for active propagation (often because of large impedance drops at branch points) and then propagate passively to the recording electrode, where they appear as small dSpikes (spikelets) (Golding and Spruston, 1998; Golding et al., 2002; Jarsky et al., 2005; Losonczy and Magee, 2006; Katz et al., 2009). dSpikes that are generated far from the recording site may not be visible at all. Observations of events with amplitudes in between those of large dSpikes and small dSpikes (spikelets) are rare, because the transition from a large dSpike to a small dSpike occurs over very short distances due to the large attenuation at branch points (Katz et al., 2009). Accordingly, we observed a large gap in the distribution of event amplitudes, with no events having amplitudes in the 30–40 mV range (Figure 2—figure supplement 1A; Figure 2—source data 2). Small dSpikes (spikelets) were distinguishable from the cases without any regenerative events (i.e., EPSPs only) because they had larger dV/dt values (Figure 2B and Figure 2—figure supplement 1B; Figure 2—source data 2; see below and ‘Materials and methods’).

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In the presence of low TTX, both the number and the amplitude of large-amplitude dendritic events (i.e., bAPs and large dSpikes, all with amplitudes >40 mV; see ‘Materials and methods’) were reduced (control: amplitude = 56.2 ± 1.8 mV, n = 39 events; low TTX: amplitude = 44.8 ± 1.7 mV, n = 17 events; p < 10⁻⁴ by Student's t-test). Although distinguishing between bAPs and large dSpikes was only possible in some cases (Figure 2—figure supplement 2; Figure 2—source data 2; see ‘Materials and methods’), the two events that were the most clearly large dSpikes were reduced to spikelets in response to the same stimulus in the presence of low TTX (Figure 2A).

Of the smaller events (i.e., <30 mV), some small dSpikes were relatively easy to identify in dendritic recordings (e.g., Figure 2B), because they were the most extreme outliers in the distribution of event dV/dt values. Other small dSpikes were more difficult to resolve because their attenuation from the site of origin makes them barely distinguishable from the cases without regenerative events (i.e., EPSPs only). Thus, rather than using a single definition for small dSpikes, we employed a range of definitions; then for each definition we compared the control and low TTX conditions. In this way, we could determine whether conclusions about the effects of low TTX on dSpikes were dependent on the definition used.

We varied the dV/dt criterion for small dSpikes from a relatively inclusive one (outside the 85% prediction band of a fit to the distribution of all events normalized dV/dt in control and low TTX; Figure 2C; see ‘Materials and methods’) to a more restrictive one (outside the 99% prediction band). We found that application of low TTX dramatically reduced the number of small dSpikes defined by all confidence levels in this range (Figure 2C,D; Figure 2—source data 1; see Figure 2—figure supplement 3 for all small dSpikes identified by the 99% confidence level; Figure 2—source data 2). Similar results were obtained using other methods for identifying small dSpikes (Figure 2—figure supplement 4; Figure 2—source data 2; see ‘Materials and methods’). As both large dSpikes and small dSpikes (spikelets) reflect the presence of dSpikes initiated in the tuft dendrites, and both were inhibited by low TTX, we conclude that low TTX is an effective inhibitor of dSpikes generated in response to TBS of the PP.

Given the ability of low TTX to inhibit dendritically initiated spikes, we tested its effects on the induction of LTP using TBS at PP → CA1_tuft synapses (using stimulus intensities yielding single EPSPs of 2–5 mV in somatic recordings). TBS was repeated three times (TBSx3) and was either paired with brief somatic current injections (TBSx3+Current) to evoke action potential firing during each burst of presynaptic stimuli (Figure 3A; Figure 3—source data 1) or delivered with somatic voltage clamp (TBSx3+SomaticVC) to prevent somatic action potential firing (holding potential −68 to −70 mV; see ‘Materials and methods’). The magnitude of PP → CA1_tuft LTP was similar in these two conditions (Figure 3B–E; TBSx3+Current, potentiation ratio = 1.63 ± 0.16, n = 9; TBSx3+SomaticVC, potentiation ratio = 1.53 ± 0.07, n = 9; p = 1.00 by one-way ANOVA; Figure 3—source data 1), suggesting that action potential firing did not contribute to LTP induction at these synapses (see also Golding et al., 2002). Under both conditions, PP → CA1_tuft LTP was blocked completely in the presence of low TTX (Figure 3C–E; Figure 3—source data 1).

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Because low TTX blocks both dSpikes and bAPs, it is conceivable that TTX inhibits LTP by blocking either or both of these sources of postsynaptic depolarization. However, consistent with our previous study (Golding et al., 2002), we showed here again that PP → CA1_tuft LTP is not affected by blocking bAPs. Thus, we attribute the effect of low TTX on this particular form of LTP to its effect on Na-dSpikes. This is a surprising result, because of the brief duration of Na-dSpikes, compared to Ca- or NMDA-dSpikes.

One possible explanation for the requirement of Na-dSpikes during PP → CA1_tuft LTP induction is that they are required to activate channels mediating synaptic calcium influx. We therefore sought to determine which calcium-permeable channels are responsible for the underlying sources of calcium influx. We previously showed that PP → CA1_tuft LTP was reduced ∼50% by blocking NMDARs, ∼50% by blocking L-, T-, and R-type Ca_v channels, and almost completely by blocking NMDARs and Ca_v channels together (Golding et al., 2002). We confirmed these results here and showed further that the effects of Ca_v channel blockers were attributable to blocking L-type Ca_v channels (with 10 µM nimodipine), but not blocking T-, R-, or other types of Ca_v channels (with 50 µM Ni²⁺; Figure 4; Figure 4—source data 1; see also Remy and Spruston, 2007). Furthermore, 10 µM nimodipine had no effect on synaptic responses, either before or after the induction of PP → CA1_tuft LTP (Figure 4—figure supplement 1; Figure 4—source data 2), suggesting that L-type Ca_v channels are involved in the induction rather than the expression of LTP.

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These results suggest that NMDAR and L-type Ca_v (L-Ca_v) channels are the two main sources of calcium entry during LTP induction by TBS of PP → CA1_tuft synapses. The observation that partial block of Na_v channels by low TTX blocked PP → CA1_tuft LTP almost completely (Figure 3B–E) indicates that Na_v channel-mediated events are required to activate these two types of calcium-permeable channels, and these events are unlikely to be bAPs, as we showed here and in our previous study (see above). We therefore performed additional analyses on the dendritic recordings (described above) to determine how low TTX affects membrane potential changes that can activate these channels.

As described above, low TTX blocked large and small dSpikes (Figure 2 and Figure 2—figure supplement 4). In one of the two dendritic recordings where we observed inhibition of a clear large dSpike by low TTX, we subsequently washed out TTX and applied 50 µM AP5, which did not block the large dSpike (Figure 5A; Figure 5—source data 1). By contrast, low TTX had almost no effect on the slow depolarization produced by each burst of PP → CA1_tuft EPSPs in response to TBS, whereas 50 µM AP5 had a much greater effect on the slow depolarization associated with each burst. This differential effect of low TTX and 50 µM AP5 on the slow depolarization was confirmed in additional dendritic recordings (n = 9; for four cases, data in TTX and AP5 were obtained from the same cell; Figure 5B; Figure 5—source data 1). Because low TTX was a more potent inhibitor of PP → CA1_tuft LTP than 50 µM AP5 (Figure 4F), these results suggest that the fast depolarization associated with Na-dSpikes is more important for the induction of PP → CA1_tuft LTP than the slow synaptic depolarization mediated solely by EPSPs.

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To test this conclusion further, we designed a stimulation protocol expected to have differential effects on Na-dSpikes and slow synaptic depolarization. A modified TBS pattern consisting of only 2 stimuli in each burst (2-stim TBSx3, Figure 6A; Figure 6—source data 1) is expected to greatly reduce the slow synaptic depolarization while preserving about 50% of Na-dSpikes (based on Figure 2C). This 2-stim protocol induced LTP at PP → CA1_tuft synapses of approximately the same magnitude as various TBSx3 protocols consisting of 5 stimuli (5-stim) in each burst (Figure 6B,C; Figure 6—source data 1). The 2-stim TBSx3 protocol yielded PP → CA1_tuft LTP of 82% of the average LTP induced by all variants of the 5-stim TBSx3 protocol, despite a greatly reduced integral of the slow depolarization (27% of that with 5-stim TBSx3; Figure 6D,E; Figure 6—source data 1).

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Collectively, the results above indicate that low TTX blocks PP → CA1_tuft LTP by inhibiting fast Na-dSpikes, with minimal effect on the slow synaptic depolarization induced by each high-frequency burst during TBS. We next turned our attention to investigating the calcium entry that links Na-dSpikes with the induction of PP → CA1_tuft LTP. Given that NMDAR and L-Ca_v channels are both voltage-dependent sources of calcium entry, and they both contribute to PP → CA1_tuft LTP (approximately equally, see Figure 4F), the most parsimonious hypothesis is that Na-dSpikes are effective activators of calcium entry via these pathways. Although LTP induction at these synapses may depend on the complex spatiotemporal properties of calcium entry, the simplest scenario is that Na-dSpikes produce particularly large calcium entry in synaptically activated portions of the tuft dendrites, which triggers LTP.

To test this idea, CA1 pyramidal neurons were filled with 100 µM Oregon Green 488 BAPTA-1 (OGB-1) and 50 µM Alexa Fluor 594 Hydrazide (AF-594) and imaged on a two-photon laser-scanning microscope during stimulation of the PP with single burst of 5 stimuli at 100 Hz (‘Materials and methods’). In these experiments, the soma was voltage-clamped at ∼ −70 mV in order to prevent action potential firing, thus limiting detected calcium influx to that induced by synaptic events and dendritically initiated spikes. For quantification of calcium signals, the calcium-induced change in OGB-1 fluorescence was measured as a fraction of the baseline fluorescence of the calcium-insensitive reference, AF-594 (ΔG/R; see ‘Materials and methods’). Although we could easily resolve dendritic spines, we could not determine which spines received direct synaptic input, so we restricted our analysis to the calcium signals in dendritic shafts (Figure 7A), using the response integral as the best measure of dendritic calcium entry (see ‘Materials and methods’; Figure 7—figure supplement 1; Figure 7—source data 2).

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Burst stimulation of the PP resulted in clear ΔG/R responses (79 ± 14%, n = 17 cells), which were significantly reduced by 50 µM AP5 (Figure 7B; Figure 7—source data 1), indicating that we were able to detect calcium entry dependent on synaptic activation—likely mediated by multiple channel types—when imaging from dendritic shafts. Importantly, however, low TTX was far less potent at inhibiting intracellular calcium elevations than 50 µM AP5 (Figure 7B,C; Figure 7—source data 1). This result was surprising, given that it is opposite to what one would expect from the result that low TTX was a far more potent inhibitor of PP → CA1_tuft LTP than 50 µM AP5. This suggests that the effectiveness of low TTX as a blocker of LTP cannot be explained by its effect on the measured dendritic calcium signals.

To assist with the interpretation of our results, we used a compartmental model of a CA1 pyramidal neuron. The model was adapted from a previous model that contained Na_v and K_v channels in the dendrites to reproduce experimental data on bAPs and dSpikes (Golding et al., 2001; Jarsky et al., 2005; Katz et al., 2009); it was extended to include NMDARs at all synapses and L-Ca_v channels (high-voltage-activated Ca_v channels) in the dendrites, as well as simple models of calcium buffers (including endogenous buffer and OGB-1), calcium diffusion, and calcium extrusion (‘Materials and methods’).

The model was able to reproduce the effects of low TTX (simulated by 50% reduction of Na_v channel conductance) and 50 µM AP5 (simulated by complete block of NMDARs) on dSpikes and EPSPs recorded from the distal apical trunk (Figure 8A–C; Figure 8—source data 1). The simulations were also able to reproduce the effects of TTX and AP5 on dendritic calcium transients (Figure 7), as measured by the modeled increase in the concentration of simulated calcium-bound OGB-1 ([Ca²⁺]_OGB) in response to burst activation of simulated synapses (Figure 8B,C; Figure 8—source data 1). The ability of the model to reproduce these experimental observations allowed us to use it to explore the possible mechanism by which Na-dSpikes mediate calcium influx that may be critical for the induction of PP → CA1_tuft LTP.

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In response to burst activation of simulated synapses a single large dSpike was observed in the apical trunk. However, in small apical tuft branches, where direct patch-clamp recording cannot be performed, simulations revealed that a dSpike was initiated on several branches in response to burst activation of spatially distributed synaptic inputs, appearing as multiple dSpikes on the apical tuft branch (Figure 8D; Figure 8—source data 1). This is consistent with the observations in the experiments that multiple spikelets occurred in response to burst stimulation (see Figure 2—figure supplement 3).

The simulations also offered insight into how Na-dSpikes could provide the calcium influx necessary for PP → CA1_tuft LTP induction. By comparing the dendritic calcium signals (reported by simulated OGB-1) and the calcium influx through the synaptic channels in the model, we could clearly distinguish the difference between dendritic ‘bulk’ calcium signals and the calcium signals near the mouth of channels. Simulations at the synapses revealed that the largest instantaneous calcium currents (I_Ca) through NMDAR and L-Ca_v channels were mediated by locally generated Na-dSpikes, owing to efficient relief of magnesium block of NMDAR channels and strong activation of L-Ca_v channels, respectively (Figure 8D; Figure 8—source data 1). These simulations, combined with the experimental results, suggest that a large, rapid, Na-dSpike-mediated component of calcium entry may produce transient, localized increases in intracellular calcium concentration that are essential for the induction of TBS-induced PP → CA1_tuft LTP. To further test this model, we experimentally tested two predictions.

First, we posited that blocking L-Ca_v channels, which inhibits LTP by ∼50%, would have minimal effect on measurements of bulk calcium entry in the distal apical dendrites, as indicated in our model (Figure 8—figure supplement 1D–F; Figure 8—source data 2; see also Tsay et al., 2007). Indeed, we found that 10 µM nimodipine did not have a significant effect on dendritic calcium responses during burst stimulation of the PP (Figure 8—figure supplement 1A–C; Figure 8—source data 2). This result is consistent with our hypothesis that L-Ca_v channels contribute to the induction of PP → CA1_tuft LTP by mediating increases in localized calcium near the channel pores rather than in dendritic bulk calcium.

Second, we posited that LTP would be inhibited by chelating intracellular calcium, but only when the buffering kinetics were fast enough to disrupt localized calcium signaling close to the channel pores (see ‘Discussion’). 1,2-Bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA) has a much faster calcium binding kinetics than ethylene glycol-bis(2-aminoethylether)-N,N,N',N'-tetraacetic acid (EGTA) (Tsien, 1980), and we therefore tested this hypothesis by buffering cytoplasmic calcium elevations with either a relatively low or high concentration of EGTA or BAPTA (Maravall et al., 2000; Henneberger et al., 2010), while maintaining the basal calcium concentration at 50 nM by adding an appropriate amount of CaCl₂ (‘Materials and methods’). We predicted that only a high concentration of BAPTA should buffer intracellular calcium increases rapidly and effectively enough to block PP → CA1_tuft LTP, and this was indeed found to be the case (Figure 9; Figure 9—source data 1). These results suggest that NMDAR and L-Ca_v channels contribute to the induction of TBS-induced PP → CA1_tuft LTP by mediating calcium influx, and are consistent with the hypothesis that it is the large, transient, localized increases in intracellular calcium concentration mediated by Na-dSpikes that are critical for this form of LTP.

Figure 9

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Figure 9—source data 1

Source data of Figure 9.

https://doi.org/10.7554/eLife.06414.033

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Our strategy of partially blocking Na_v channels with a low concentration of TTX was designed to test the hypothesis that Na-dSpikes are important contributors to the postsynaptic depolarization required for TBS-induced LTP of PP synapses in the distal tuft of CA1 pyramidal neurons. The results support this hypothesis, as this manipulation resulted in block of PP → CA1_tuft LTP. The completeness of the block further suggests that Na-dSpikes are a critical component of the LTP induction process at these synapses.

Mechanisms for coupling Na-dSpikes to the induction of PP → CA1_tuft LTP

The finding that Na-dSpikes play such a critical role in the induction of PP → CA1_tuft LTP is somewhat surprising, given the brief duration of these Na-dSpikes compared to slow depolarization mediated by EPSPs, Ca-dSpikes, or NMDA-dSpikes. The fact that simultaneously blocking NMDAR and L-Ca_v channels eliminated PP → CA1_tuft LTP (Golding et al., 2002; Remondes and Schuman, 2003; Ahmed and Siegelbaum, 2009) suggests that Na-dSpikes contribute to the induction of PP → CA1_tuft LTP by increasing calcium influx through these channels. But how does this work, given that Na-dSpikes have a brief duration and thus a limited contribution to the increase in ‘bulk’ calcium concentration (i.e., the calcium measurable with the spatiotemporal resolution provided by imaging with calcium-sensitive dyes) compared to slow synaptic depolarization?

A simple explanation, supported by our modeling (Figure 8) and the subsequent experiments (Figure 9), is that the calcium influx during Na-dSpikes (via NMDAR and L-Ca_v channels) is vigorous and brief, whereas the calcium influx during slow synaptic depolarization (via NMDAR channels) is smaller, but longer lasting. Although the latter ultimately contributes more to the total amount of calcium entry during a burst and comprises the vast majority of the bulk calcium measured with dendritic calcium imaging, the vigorous and brief calcium entry during Na-dSpikes is more critical for the induction of PP → CA1_tuft LTP.

During TBS, Na-dSpikes produce the largest voltage excursions and maximize I_Ca through both NMDAR and L-Ca_v channels (Figure 10). Activation of NMDAR channels is strongly voltage dependent (through voltage-dependent magnesium block) as is activation of L-Ca_v channels (through high-voltage-activated conformational changes). Thus, these calcium-permeable channels that we implicate in PP → CA1_tuft LTP are activated more by the Na-dSpike than by the slow synaptic depolarization. The large I_Ca caused by the Na-dSpike produces a brief, high calcium concentration near the mouth of the channels, which will quickly diffuse away and contribute modestly to the bulk calcium concentration in the rest of the dendritic spine and shaft. On the other hand, most of the bulk calcium is generated by the smaller, but longer-lasting flux of calcium through the NMDAR channels activated during the slow synaptic depolarization. The calcium concentration near the mouth of the channels is proportional to the instantaneous amplitude of I_Ca, while the bulk calcium concentration is proportional to the time integral of I_Ca through the calcium-permeable channels (Augustine et al., 2003; Eggermann et al., 2012; Tadross et al., 2013).

Figure 10

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The efficacy of low TTX as a blocker of LTP by inhibiting Na-dSpikes could be explained by the existence of a calcium sensor near the channels that triggers a series of LTP-inducing biochemical events (Figure 10). The affinity and co-operativity of the calcium sensor would have to be matched to the spatiotemporal features of the calcium concentration profiles near the mouths of NMDAR and L-Ca_v channels in response to TBS. The affinity of the sensor would need to be relatively low, in order to respond only to the high calcium concentration near the calcium-conducting pores during a large Na-dSpike. As our model predicts a modest increase in peak I_Ca (proportional to local calcium concentration) during a dSpike, relative to the slow synaptic depolarization, it is likely that the sensor would also need high cooperativity in order to respond selectively during the dSpike. Importantly, experimentally observed Hill coefficients are indeed high enough for this operation; for example, assuming a Hill coefficient of 4, a modest dSpike-driven difference in peak I_Ca (∼twofold; Figure 8) would increase calcium sensor activation from 20% to 80%. The identities of the calcium sensors and the downstream biochemistry leading to LTP induction are the subjects of ongoing research (Amici et al., 2009), but calmodulin may have the properties necessary to serve this function, namely low affinity, rapid binding kinetics, and high cooperativity for calcium binding (Faas et al., 2011). Calmodulin has been postulated to be the initial calcium sensor coupled to other key LTP-inducing molecules such as calcium/calmodulin-dependent protein kinase II (Bradshaw et al., 2003; Lisman et al., 2012).

Alternatively, Na-dSpikes might couple activation of NMDAR or L-Ca_v channels to LTP via mechanisms that operate independently of postsynaptic calcium influx or in concert with it. For example, it is well known that the gating of L-Ca_v channels is coupled to muscle contraction independently of calcium flux through the channels and that similar mechanisms may exist in neurons (Kaczmarek, 2006). Indeed, activation of NMDARs in the absence of calcium influx through the channels has been suggested to be sufficient for induction of long-term depression (LTD; Nabavi et al., 2013; but see Babiec et al., 2014). In keeping with this possibility, we observed LTD in neurons buffered with 10 mM BAPTA. However, the block of LTP by intracellular calcium buffering (Figure 9) suggests that NMDAR and L-Ca_v channels contribute to the induction of PP → CA1_tuft LTP by their ionotropic rather than metabotropic functions. Moreover, high-frequency stimulation of PP → CA1_tuft synapses has been shown to result in LTP expression mediated by functional upregulation of presynaptic Ca_v channels (Ahmed and Siegelbaum, 2009), but the lack of effect of nimodipine on synaptic responses after LTP induction (Figure 4—figure supplement 1) indicates that the effect of nimodipine on TBS-induced PP → CA1_tuft LTP cannot be explained by the block of a presynaptic expression mechanism mediated by L-Ca_v channels. Nevertheless, we cannot rule out a possible role of presynaptic NMDARs in LTP induction (Kunz et al., 2013).

The requirement for Na-dSpikes has interesting functional implications for PP → CA1_tuft LTP. The activation of multiple synapses on a single dendritic branch leads to initiation of a dSpike (Losonczy and Magee, 2006), but dSpikes tend to fail at branch points (Spruston, 2008; Katz et al., 2009). Thus, the spatial extent of a Na-dSpike-dependent LTP event may be restricted to a particular dendritic branch, or even a segment of a branch containing the synapses that contribute to initiation of a Na-dSpike. If true, such compartmentalization of plasticity (Losonczy et al., 2008; Makara et al., 2009; Makino and Malinow, 2011) would have substantial implications for the granularity of associations learned at the dendritic level, and consequently, the information-carrying capacity of a pyramidal neuron, as information may be stored discretely in individual dendritic branches or segments, rather than in an entire neuron (Poirazi and Mel, 2001; Mehta, 2004; Wu and Mel, 2009).

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Author details

1. Yujin Kim

   1. Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States
   2. Department of Neurobiology, Northwestern University, Evanston, United States

   Contribution

   YK, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Contributed equally with

   Ching-Lung Hsu

   Competing interests

   The authors declare that no competing interests exist.

2. Ching-Lung Hsu

   1. Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States
   2. Department of Neurobiology, Northwestern University, Evanston, United States

   Contribution

   C-LH, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Contributed equally with

   Yujin Kim

   Competing interests

   The authors declare that no competing interests exist.

3. Mark S Cembrowski

   Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States

   Contribution

   MSC, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

4. Brett D Mensh

   Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States

   Contribution

   BDM, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

5. Nelson Spruston

   1. Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States
   2. Department of Neurobiology, Northwestern University, Evanston, United States

   Contribution

   NS, Conception and design, Analysis and interpretation of data, Drafting or revising the article

   For correspondence

   sprustonn@janelia.hhmi.org

   Competing interests

   The authors declare that no competing interests exist.

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