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NEUROSCIENCE |
1 INSERM U641
2 Université de la Méditerranée, Faculté de médecine secteur nord, IFR 11, Marseille, F-13916, France
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Abstract |
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(Received 19 October 2007;
accepted after revision 26 November 2007;
first published online 29 November 2007)
Corresponding author D. Debanne: Université de la Méditerranée, Faculté de médecine secteur nord, IFR 11, Marseille, F-13916, France. Email: dominique.debanne{at}univmed.fr
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Introduction |
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In the hippocampus, homosynaptic long-term synaptic potentiation (LTP) induced by high-frequency presynaptic stimulation is associated with enhanced firing probability of the postsynaptic neurons in response to a given excitatory synaptic input (Bliss & Lømo, 1973; Bliss et al. 1973; Andersen et al. 1980; Abraham et al. 1987). This component has been called EPSP-to-spike potentiation (E–S potentiation) which is complementary to synaptic potentiation and functionally important. E–S potentiation is partly independent of GABAA and GABAB receptor-mediated synaptic inhibition (Daoudal et al. 2002; Staff & Spruston, 2003; Marder & Buonomano, 2003), indicating that E–S potentiation may involve long-lasting modulation of intrinsic voltage-gated conductances. GABA receptor-independent E–S potentiation is input specific (Hess & Gustafsson, 1990; Daoudal et al. 2002), suggesting that the underlying changes in excitability might be restricted to a small region of the dendrites. In accordance with the Bienenstock et al. (1982) theory of synaptic modification (or BCM rule), low-frequency presynaptic stimulation (1–5 Hz) produced long-term synaptic depression (LTD) (Artola et al. 1990; Dudek & Bear, 1992; Mulkey & Malenka, 1992). Most importantly, this form of LTD is associated with a GABA receptor-independent and input-specific depression in E–S coupling in CA1 pyramidal neurons (Daoudal et al. 2002). Thus, the BCM learning rule is valid for both synaptic changes and plasticity of dendritic integration in the hippocampus.
Synaptic plasticity is also induced associatively in hippocampal and cortical neurons. Based on Hebbian learning rules, positively correlated pre- and postsynaptic spiking activity (pre before post) leads to the induction of LTP (Gustafsson et al. 1987) whereas negative correlation (post before pre) induces LTD (Debanne et al. 1994, 1996, 1998; Markram et al. 1997; Bi & Poo, 1998; Feldman, 2000; review in Dan & Poo, 2006). Changes in intrinsic excitability have been reported following LTP induced by STDP-like protocols (Jester et al. 1995; Wang et al. 2003; Frick et al. 2004; Xu et al. 2005; Fan et al. 2005). However, it is not yet clear whether plasticity of dendritic integration follows the temporal specificity of the STDP learning rule and respects the input specificity conveyed by synaptic plasticity. We show here that positive correlation between pre- and postsynaptic activity induced LTP and facilitated dendritic integration (E–S potentiation) in CA1 pyramidal neurons whereas negative correlation induced LTD and depressed dendritic integration (E–S depression). These changes in dendritic integration required NMDA receptor activation and are input specific. Our data demonstrate that STDP is a common learning rule for both synaptic plasticity and plasticity of dendritic integration. Thus, the synergistic modifications in dendritic integration observed after LTP or LTD induction might represent a mechanism of functional redundancy that insures significant changes in the neuronal output when synaptic plasticity is induced.
Some of these results have been published previously in abstract form (Campanac & Debanne, 2006).
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Methods |
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The methods have been detailed previously (Daoudal et al. 2002). Hippocampal slices (350–400 µm) were prepared from postnatal day 15–20 Wistar rats. All experiments were carried out according to the European and institutional guidelines for the care and use of laboratory animals (Council Directive 86/609/EEC and French National Research Council). Rats were deeply anaesthetized with chloral hydrate (intraperitoneal, 200 mg kg–1) and killed by decapitation. Slices were cut in a sodium-free solution (mM: sucrose, 280; NaHCO3, 26; D-glucose, 10; KCl, 1.3; CaCl2, 1; MgCl2, 10). The slices were maintained for 1 h at room temperature in oxygenated (95% O2–5% CO2) artificial cerebrospinal fluid (ACSF; (mM): NaCl, 125; KCl, 2.5; NaH2PO4, 0.8; NaHCO3, 26; CaCl2, 3; MgCl2, 2; D-glucose, 10). Each slice was transferred to a temperature-controlled (29°C) recording chamber with oxygenated ACSF. Neurons were visualized in DIC infrared (IR)-videomicroscopy for patch-clamp experiments. In all experiments, the GABAA receptor channel blocker picrotoxin (PiTX, 100 µM) was applied. The area CA1 was surgically isolated to prevent epileptiform bursting. Whole-cell patch-clamp recordings were obtained from CA1 pyramidal cells. The electrodes were filled with an internal solution containing (mM): potassium gluconate, 120; KCl, 20; Hepes, 10; EGTA, 0.5; MgCl26H2O, 2; Na2ATP, 2. Glass stimulating electrodes filled with extracellular saline were placed in the stratum radiatum. In control and test conditions, EPSPs were evoked at 0.1 Hz. The stimulus intensity (80–180 µs, 40–100 µA) was adjusted to evoke EPSPs that elicited postsynaptic spikes in 
30% of cases. LTP and LTD were induced by the repetitive association of an EPSP and a postsynaptic spike (at 0.33 Hz). The EPSP was generated by extracellular stimulation of the Schaffer collaterals and the spike by the injection of a positive step of current (300–800 pA, 3–5 ms). The temporal relation between the EPSP and the spike (
t, measured between the onset of the EPSP and the peak of the spike) determined the sign of the synaptic plasticity. Positive pairing (t: +5/+50 ms, 100 repetitions) induced LTP, whereas negative pairing (t: –5/–50 ms, 150 repetitions) induced LTD. The number of repetitions was not equal because LTD usually requires a large number of stimulations to produce a sustained and moderate elevation in postsynaptic calcium concentration whereas LTP can be induced with a limited number of stimulations that cause a brief and nearly maximal postsynaptic calcium elevation. The test of E–S coupling during pre- and postconditioning periods corresponds to the positive correlation protocol (t = 13 ± 1 ms, n = 13). However, the number of supra-threshold EPSPs during the control period (20 ± 3 for positive correlation experiments and 24 ± 4 for negative correlation experiments) was not sufficient to produce a significant change in synaptic transmission. We show that 25 positive pairings with a delay of 13 ms between the EPSP and the postsynaptic spike did not significantly affect the EPSP slope (see online Supplemental Fig. 1).
Drugs were bath applied. PiTX, 4-AP (4-amino-pyridine), riluzole, CsCl and D-AP5 (D-(–)-2-amino-5-phosphonopentanoic acid) were purchased from Sigma and ZD-7288 was obtained from Tocris. Riluzole (6 µM) reduced postsynaptic firing, confirming its action on sodium channels (Urbani & Belluzzi, 2000). ZD-7288 has been shown to have presynaptic effects at concentrations greater than 10 µM (Chevaleyre & Castillo, 2002). The low concentration used here (1 µM) did not affect the synaptic strength but efficiently blocked postsynaptic Ih indicating that ZD-7288 had no major presynaptic effect in our experiments. In addition to its major effect on Ih, Cs+ also blocks inward rectifier K+ (Kir) currents (Thompson et al. 2000). However, the effects of Cs+ or ZD were comparable and could be perfectly mimicked by local reduction in the h-conductance (E. Campanac, N. Ankri & D. Debanne, unpublished observations). Furthermore, Kir2.1 channels are only weakly expressed in CA1 neurons (Prüss et al. 2005). 4-AP is not specific to the A-type K+ current (Storm, 1988) but it effectively blocks the transient A-current in CA1 pyramidal neurons and enhances EPSP amplitude (Hoffman et al. 1997).
Data acquisition and analysis
Electrophysiological recordings were obtained using an Axoclamp 2B amplifier, Acquis1 software (Bio-Logic, Orsay, France) or pCLAMP version 8 and 9. Data were analysed with IGOR version 5.03 (WaveMetrics, Lake Oswego, OR, USA). Pooled data are presented as either mean ± S.E.M. or box plots and statistical analysis was performed using the Mann–Whitney U test or the paired t test of Student.
E–S coupling was represented by the firing probability as a function of the EPSP slope. EPSP slopes measured during the first 2 ms were sorted in 0.2–0.5 mV ms–1 bins. The firing probability was determined for each bin. Changes in E–S coupling were quantified by expressing the mean firing probability after pairing as a percentage of the mean firing probability in the control period. In two neurons, the mean firing probability was 0 before pairing, thus E–S coupling in these cells was arbitrarily set to the mean E–S potentiation (194%) calculated from the other data points. To confirm this analysis, the E–S shift for a firing probability of 50% has also been analysed (Staff & Spruston, 2003). Since the intensity was kept constant during the experiment, the E–S curves were not always complete. Therefore the number of cells where the E–S shift could be measured was slightly reduced.
The amplitude/slope (A/Slp) relation of the EPSP was studied to assess the change in EPSP amplification. To quantify the change in A/Slp, EPSP slopes were sorted in 0.2–0.5 mV ms–1 bins and the mean EPSP amplitude was calculated for each bin. The change value of each cell was obtained by averaging the normalized EPSP amplitude corresponding to each class of EPSP slope. A linear fit was performed for each group of data to facilitate the estimation of the A/Slp change in the figures. The spike threshold was determined as the voltage corresponding to the time where the derivative exceeded 10 mV ms–1.
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Results |
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All the experiments were performed in the presence of 100 µM PiTX to block GABAA receptor-mediated inhibition. To avoid epileptiform activity, the CA1 region was surgically isolated. Stable whole-cell patch-clamp recordings were obtained from CA1 pyramidal neurons. Positive pairing with short delays (+5 < t < +50 ms) induced a stable potentiation of the EPSP slope (Fig. 1A
; 129 ± 6% of the control, n = 29). Dendritic integration was evaluated before and after pairing by plotting the probability of spiking versus EPSP slope. After positive pairing, the EPSP–spike (E–S) curve was shifted towards the left and the firing probability was increased for a given EPSP slope, attesting to E–S potentiation (Fig. 1B). On average, the E–S potentiation was 194 ± 21% of the control; n = 11) and the mean E–S shift was –0.23 ± 0.06 mV ms–1 (n = 10). No change in the input resistance tested with a brief hyperpolarizing pulse (50 ms; –20 pA) was observed after the induction of LTP and E–S potentiation (Fig. 1A; 101 ± 1%, n = 29).
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Temporal dependence of long-term plasticity of E–S coupling
Synaptic plasticity precisely depends on the timing between pre- and postsynaptic activities and synaptic efficacy is not affected for long positive or negative intervals (Debanne et al. 1998; Bi & Poo, 1998; Feldman, 2000). We have therefore examined whether E–S coupling was affected by pairing protocols with long positive or negative delays (> ±50 ms). We observed that positive correlation with long delay (t > +50 ms) failed to induce LTP (106 ± 4%, n = 4; Fig. 2A)
and did not affect E–S coupling (105 ± 6% of the control; n = 3; Fig. 2B). Neither LTD (101 ± 3%, n = 8; Fig. 2C) nor E–S depression (111 ± 9% of the control E–S coupling, n = 4; Fig. 2D) were observed with a delay greater than –50 ms. In contrast with short delays, there was no differential changes for long positive or long negative intervals (Mann–Whitney U test: EPSP slope, P > 0.5 and E–S coupling, P > 0.5). Most importantly, the time-windows for synaptic and E–S plasticity were virtually identical (Fig. 3A and B).
Moreover, E–S potentiation was found to occur when the EPSP was potentiated whereas E–S depression was concomitant with synaptic depression (Fig. 3C), indicating that both types of plasticity are functionally synergistic. We conclude that E–S plasticity in CA1 pyramidal neurons follows the STDP rule initially established for synaptic transmission.
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In the CA1 region of the hippocampus, E–S potentiation and depression require NMDA receptor activation (Daoudal et al. 2002). We therefore tested whether long-term plasticity of E–S coupling induced by STDP protocols also depended upon activation of these receptors. In the presence of D-AP5 (50 µM), positive correlation of pre- and postsynaptic activity failed to induce LTP (94 ± 2%, n = 5) and E–S potentiation (77 ± 14% of the control coupling, Fig. 4A). Similarly, NMDA receptor activation was necessary for inducting long-term E–S depression with negative pairings. In the presence of 50 µM D-AP5, neither LTD (98 ± 3%, n = 11), nor E–S depression were observed (117 ± 14% of the control E–S coupling, Fig. 4B). These results are significantly different from those obtained in the absence of D-AP5 (Mann–Whitney U test, P < 0.05). Therefore, we conclude that long-term E–S potentiation and depression induced by STDP protocols require activation of NMDA receptors.
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In cerebellar granule cells, facilitation of EPSP–spike coupling associated with LTP results from a reduction in the spike threshold (Armano et al. 2000). Similarly, the increased excitability observed after STDP-induced LTP in CA1 pyramidal neurons is associated with a hyperpolarization of the spike threshold (Xu et al. 2005). We therefore analysed whether the threshold of the action potential (AP), defined as the voltage where dV/dt exceeded 10 mV ms–1, was altered after positive or negative correlation. No differential modification in the threshold was observed when LTP or LTD was induced with short positive or negative correlation, respectively (variation in the threshold: –0.48 ± 0.23 mV n = 7 for +5/+50 ms versus –0.61 ± 0.32 n = 11 for –5/–50 ms, Mann–Whitney U test P > 0.05). Thus, changes in EPSP–spike coupling cannot be accounted for by a modification in the AP threshold measured at the cell body and other mechanisms should be envisaged.
Changes in the amplitude/slope relation of the EPSP
Alternatively, E–S changes may result from a change in EPSP amplification under the control of voltage-gated conductances located in the dendrites. In CA1 hippocampal neurons, hyperpolarizing-activated cationic current (Ih) and A-type K+ current (IA) attenuate EPSPs (Hoffman et al. 1997; Magee, 1998) whereas persistent sodium current (INaP) amplified EPSPs (Lipowsky et al. 1996). It is not yet clear how these currents determine the EPSP–spike coupling. A simple way to test their role on EPSP waveform consists in determining their action on the amplitude/slope (A/Slp) relation of subthreshold EPSPs (see Methods). Blockade of attenuating voltage-gated currents (with 2.5 mM external Cs+ or 1 µM ZD-7288 for Ih or with 1 mM 4-AP for IA) increased the A/Slp ratio of the EPSP (Fig. 5A and B). On average, A/Slp was, respectively, 107 ± 3% of the control (P < 0.05 paired t test; n = 9) when Ih was blocked with h-channel blockers and 128 ± 9% (P < 0.05 paired t test; n = 6; Fig. 5D) when IA was blocked with 4-AP. Conversely, the blockade of INaP with 6 µM riluzole (Urbani & Belluzzi, 2000) reduced the A/Slp ratio of the EPSP (Fig. 5C). On average, A/Slp was 91 ± 2% of the control (P < 0.05 paired t test; n = 5; Fig. 5D). These results indicate that voltage-gated currents (such as Ih, IA or INaP) regulate the A/Slp relation of the EPSP and may thus be the expression mechanism of the bi-directional plasticity of EPSP–spike coupling induced by STDP protocols.
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The spatial restriction of activity-dependent synaptic plasticity is thought to preserve a high potential for information storage. This level of functional and spatial resolution would be dramatically reduced if the plasticity of dendritic integration was generalized to other synaptic inputs. Input specificity has been demonstrated for long-term facilitation in dendritic integration associated with LTP and LTD induced by patterned presynaptic stimulation (Daoudal et al. 2002). However, it is not yet clear whether long-term changes in dendritic integration induced with STDP protocol are also restricted to the conditioned pathway. To address this question, the A/Slp relation of the EPSP was monitored at two independent synaptic pathways before and after positive or negative correlation. One pathway located at 100 µm from the pyramidal cell layer was paired with a postsynaptic spike procedure whereas the second pathway located at 40 µm from the cell body layer was stimulated as in control conditions (0.1 Hz). After positive correlation, the paired pathway was potentiated (normalized EPSP slope: 145 ± 5%, n = 4) but the control pathway remained unchanged (97 ± 4% of the control, n = 4; paired t test P < 0.05; Fig. 7).
Most importantly, the A/Slp ratio was differentially increased at the paired pathway (109 ± 4% of the control, n = 4) but not at the control pathway (99 ± 4%, n = 4; paired t test, P < 0.05), suggesting that the facilitation in dendritic integration is specific to the positively paired pathway. Thus, these results indicate that there are local input-dependent changes in EPSP amplification, presumably in the dendrites.
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Discussion |
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t < +50 ms) but decreased after LTD induction with short negative correlation (t < –50 ms). Thus, the observed plasticity of dendritic integration represents a mechanism of functional redundancy that ensures significant changes in the neuron output when synaptic plasticity is induced. The temporal selectivity of the effect was demonstrated by the lack of changes in both synaptic transmission and dendritic integration for long positive or negative correlation (> ± 50 ms). Plasticity of dendritic integration required activation of NMDA receptors, indicating that the plasticity of dendritic integration and synaptic plasticity share common induction pathways. Synaptic and E–S changes were found to be correlated, suggesting that both the synaptic strength and the input–output function of the neuron changed synergistically at the postsynaptic side. All these changes were observed in the presence of a blocker of GABAA receptors indicating that these modifications do not result from changes in the balance between synaptic excitation and inhibition but rather from a modification in the activity of voltage-gated channels that shape EPSPs. This conclusion is supported by the fact that the EPSP amplification evaluated by the A/Slp relation was differentially affected following induction of spike timing-dependent synaptic plasticity. For a given slope the EPSP amplitude was, respectively, increased or decreased when LTP or LTD was induced. These modifications are likely to facilitate spike generation after LTP or conversely decrease spike generation after LTD. Importantly, these modifications were found to be specific to the conditioning input. Similar modifications in the A/Slp ratio of the EPSP could be mimicked by bath application of blockers of EPSP amplification or EPSP attenuation, suggesting that changes in dendritic integration might be mediated by the regulation of intrinsic voltage-gated conductances. Synaptic plasticity induced by STDP with single spikes
Our results show that LTP or LTD could be consistently induced in the presence of the GABAA receptor antagonist PiTX when the test EPSP was positively or negatively paired with single postsynaptic spikes, respectively. Although induction of LTD with single postsynaptic spikes is a robust phenomenon, induction of LTP is a matter of controversy. Induction of LTP using single postsynaptic spikes was initially reported in organotypic (Debanne et al. 1998) and dissociated hippocampal cultures (Bi & Poo, 1998). These findings were questioned by subsequent studies in acute slices showing that LTP was consistently induced in CA1 neurons when EPSPs were paired with bursts of two to three action potentials but not with single spikes (Pike et al. 1999; Wittenberg & Wang, 2006). Development of GABAergic synaptic inhibition represents a major gating mechanism for induction of LTP and may account for this discrepancy. In fact, LTP is consistently induced with single postsynaptic spikes in young rats (< P15) but not in old rats (> P20) (Meredith et al. 2003). In mature animals, robust LTP is induced with single postsynaptic spikes when GABAA receptors are blocked with PiTX. Our data therefore confirm these results. The control of LTP by synaptic inhibition may result from the interference of inhibitory synaptic potentials with NMDA receptor activation and/or with back-propagated action potentials (reviewed in Sourdet & Debanne, 1999).
STDP is a learning rule for synaptic and non-synaptic plasticity
Our study supports the conclusion that the learning rules established for synaptic transmission may also be valid for intrinsic plasticity. We previously showed that the BCM rule not only describes synaptic changes but also E–S plasticity in CA1 pyramidal neurons (Daoudal et al. 2002; Daoudal & Debanne, 2003a). The present study generalizes this statement to the second major learning rule, the STDP rule, and strengthens the evidence for the essential similarity of the two rules (Karmakar & Buonomano, 2002; Shouval et al. 2002).
Postsynaptic changes in EPSP summation have been reported in CA1 pyramidal neurons following a STDP protocol (Wang et al. 2003). These changes were synergistic with synaptic plasticity but the temporal specificity was not tested. Our results demonstrate that STDP represents a common learning rule for synaptic plasticity and plasticity of dendritic integration at the postsynaptic side of CA1 pyramidal neurons. More specifically, our study shows that the STDP rule is not only valid for E–S coupling (Fig. 3) but also for EPSP amplification (Fig. 6). EPSP amplification was facilitated following induction of LTP by positive correlation but depressed when LTD was induced with negative correlation. Thus, plasticity induced by the precise temporal relationship between pre- and postsynaptic activity not only affects the excitatory postsynaptic current but also determined voltage-gated mechanisms controlling EPSP amplification in a functionally synergistic way.
A functional synergy between synaptic changes and plasticity of presynaptic intrinsic excitability has been also reported in central neurons. In synaptically connected hippocampal and neocortical neurons, positive or negative correlation not only affects synaptic efficacy but also increases or decreases the global excitability of the presynaptic neuron, respectively (Ganguly et al. 2000; Li et al. 2004). Thus, long-term pre- and postsynaptic changes in neuronal excitability are induced in parallel and in synergy with long-term synaptic plasticity (Campanac & Debanne, 2007). In conclusion, plasticity of intrinsic excitability should be incorporated into a general framework in which synaptic and non-synaptic plasticity interact coherently and harmoniously (Daoudal & Debanne, 2003a; Campanac & Debanne, 2007).
In vivo, CA3 and CA1 neurons fire not only single spikes but also bursts of spikes. The protocols used here could be closer to physiological patterns of activity; however, the parameters are controlled and these protocols provide very simple and reproducible results. It will be important to define in the future the rules governing E–S plasticity with more realistic patterns of activity including multiple temporal spike interaction (Paulsen & Sejnowski, 2000; Sjöström et al. 2001; Froemke & Dan, 2002; Wang et al. 2005).
Long-term regulation of EPSP amplification, a mechanism for E–S plasticity
E–S potentiation and E–S depression are partly mediated by an imbalance between synaptic excitation and GABAergic inhibition (Hess & Gustafsson, 1990; Jester et al. 1995; Daoudal et al. 2002; Staff & Spruston, 2003; review in Daoudal & Debanne, 2003a). All the experiments reported here were performed in the presence of the GABAA receptor blocker PiTX. Although our study addressed the mechanisms underlying GABAA receptor-independent E–S plasticity, it does not preclude the existence of a GABAergic component in E–S plasticity induced by STDP protocols (see Marder & Buonomano, 2004).
The bidirectional changes in EPSP–spike coupling were not associated with a modification in the spike threshold. This finding is apparently in discrepancy with the study by Xu et al. (2005) where a hyperpolarization of 10 mV was reported after LTP induction. However, the hyperpolarization of the spike threshold may result from the elevated postsynaptic spiking during the induction protocol (400 spikes at 20 Hz in their study versus 100 spikes at 0.3 Hz in ours). In fact, postsynaptic firing at 30–40 Hz is sufficient to increase intrinsic excitability in L5 cortical neurons by a reduction in the spike threshold (Cudmore & Turrigiano, 2004). Thus, the lack of hyperpolarization of the spike threshold may well result from the fact that postsynaptic spiking was moderate in our experiments. Rather, EPSP amplification was bi-directionally regulated following LTP or LTD induced with spike timing-dependent protocols. Changes in field EPSP waveform have been reported following induction of LTP (Hess & Gustafsson, 1990) but our study constitutes the first report to our knowledge of a bidirectional long-term plasticity of EPSP amplification. These modifications could well account for the change in EPSP–spike coupling induced by STDP since the EPSP amplitude for a given slope was, respectively, enhanced after positive correlation or depressed after negative correlation.
These changes are unlikely to be mediated by a synaptic component. In principle, a change in EPSP waveform after LTP could result from a modification in synaptic inhibition, in the recruitment of polysynaptic circuits, in the kinetics of AMPA receptor-mediated EPSC or in the NMDA receptor-mediated component that controls EPSP amplitude. GABAA receptors were blocked with PiTX, thus eliminating the first possibility. Furthermore, the change in EPSP waveform is unlikely to be the result of the recruitment of polysynaptic pathways since the CA1 region was surgically isolated from the CA3 area and the subiculum, and the onset of EPSPs was always monotonic. In addition, the waveform of the AMPA receptor-mediated synaptic current remains unchanged following induction of LTP (Benke et al. 1998; Rammes et al. 1999) or LTD (Lüthi et al. 2004) in CA1 pyramidal neurons. Thus, the last possibility for a synaptic origin in the change in A/Slp involves the NMDA receptor-mediated component (Wang et al. 2003). However, this possibility is again unlikely since it is now well established that the AMPA/NMDA ratio at the Schaffer collateral–CA1 cell synapse is increased after induction of LTP (Isaac et al. 1995; Liao et al. 1995) and decreased after LTD (Beattie et al. 2000; review in Carroll et al. 2001). Therefore, EPSPs with similar initial slopes (i.e. similar AMPA components) would have a relatively reduced NMDA component after LTP and a relatively increased NMDA component after LTD. Supporting this view, synaptically triggered APs begin as a depolarizing ramp that is highly sensitive to QX314 but not to D-AP5 (Hu et al. 1992). In conclusion, the changes in EPSP amplification are unlikely to be mediated by a change in the NMDA receptor-mediated component but rather by a modification in the voltage-dependent conductances. This last hypothesis is strongly supported by the fact that the pharmacological blockade of Ih with Cs+ or ZD-7288 and IA with 4-AP increased the A/Slp relation of the EPSP whereas the blockade of INaP with riluzole had the opposite effect. EPSP amplification after LTP might result either from a decrease in IA (Frick et al. 2004; Kim et al. 2007), in Ih (Daoudal & Debanne, 2003b; E. Campanac, G. Daoudal, N. Ankri & D. Debanne, unpublished observation) or an increase in sodium channel activity (Xu et al. 2005). Conversely, EPSP attenuation observed after LTD might result from regulation of one or more of these currents in the opposite direction. The identification of the expression mechanisms underlying E–S depression will be the purpose of another study.
Local changes in dendritic integration
Our results indicate that postsynaptic changes in dendritic integration are not global in CA1 pyramidal neurons. Both STDP-induced facilitation and depression of dendritic integration were found to be input specific, indicating that these changes are spatially restricted. The functional consequence of the input specificity of long-term plasticity of dendritic integration is that the storage capacity conveyed by synapses will be preserved (Zhang & Linden, 2003). In contrast to a previous study (Xu et al. 2005), the spike threshold measured at the cell body was not affected. Rather, the change in dendritic integration may result from a local modification in EPSP amplification. In fact, the A/Slp relation was differentially affected on the paired and unpaired pathways following induction of LTP or LTD. These results confirm previous findings indicating that E–S plasticity (Daoudal et al. 2002), EPSP summation (Wang et al. 2003; Xu et al. 2006) and dendritic excitability (Frick et al. 2004) induced in parallel with synaptic plasticity are spatially restricted in CA1 pyramidal neurons. However, a local change in intrinsic excitability is not a general rule since synaptic activity may also produce global changes in postsynaptic excitability in central neurons (Armano et al. 2000; Aizenman & Linden, 2000; Sourdet et al. 2003; Zhang et al. 2004).
How could a local change in dendritic excitability produce an input-specific modification in dendritic integration? Our experimental results are compatible with mathematical models of synaptic integration in active dendrites. Theoretical work shows that E–S potentiation simulated by adding local hot spots of depolarizing conductances in dendrites tends to be specific to the tetanized input if the untetanized contacts were electrically closer to the soma than the tetanized contacts (Wathey et al. 1992). In this study, specificity was also high if the tetanized and untetanized contacts were segregated to different primary dendrites. Thus, input-specific changes in dendritic integration are possible if voltage-gated activity is locally regulated in the dendrites. Further experimental studies will be required to identify the underlying conductances. All the experiments were performed with a control pathway more proximal (40 µm) than the paired input (100 µm). The spatial configuration of the two inputs relative to the cell body is unlikely to be the only source of input specificity since the facilitation of EPSP summation observed after LTP induction is equally observed when distal or proximal inputs are co-activated (Wang et al. 2003).
What is the precise degree of input specificity? This question has not yet been fully addressed for dendritic integration and would require detailed analysis with a systematic exploration of the spatial spread of potentiation and depression of dendritic integration. However, shared long-term facilitation in EPSP summation may occur between a potentiated and a control input separated by 50 µm, but not when the inputs are more distant (Wang et al. 2003). It will be important to test whether the basic computational unit estimated for synaptic transmission to 70 µm of dendritic length (Engert & Bonhoeffer, 1997) is maintained for plasticity of dendritic integration. Further studies will be required to address this question.
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Footnotes |
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) the changes were not significant. Scale bars 20 ms, 5 mV.
