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• W2046373003 abstract "In the cortex, synaptic latencies display small variations (∼1–2 ms) that are generally considered to be negligible. We show here that the synaptic latency at monosynaptically connected pairs of L5 and CA3 pyramidal neurons is determined by the presynaptic release probability (Pr): synaptic latency being inversely correlated with the amplitude of the postsynaptic current and sensitive to manipulations of Pr. Changes in synaptic latency were also observed when Pr was physiologically regulated in short- and long-term synaptic plasticity. Paired-pulse depression and facilitation were respectively associated with increased and decreased synaptic latencies. Similarly, latencies were prolonged following induction of presynaptic LTD and reduced after LTP induction. We show using the dynamic-clamp technique that the observed covariation in latency and synaptic strength is a synergistic combination that significantly affects postsynaptic spiking. In conclusion, amplitude-related variation in latency represents a putative code for short- and long-term synaptic dynamics in cortical networks. In the cortex, synaptic latencies display small variations (∼1–2 ms) that are generally considered to be negligible. We show here that the synaptic latency at monosynaptically connected pairs of L5 and CA3 pyramidal neurons is determined by the presynaptic release probability (Pr): synaptic latency being inversely correlated with the amplitude of the postsynaptic current and sensitive to manipulations of Pr. Changes in synaptic latency were also observed when Pr was physiologically regulated in short- and long-term synaptic plasticity. Paired-pulse depression and facilitation were respectively associated with increased and decreased synaptic latencies. Similarly, latencies were prolonged following induction of presynaptic LTD and reduced after LTP induction. We show using the dynamic-clamp technique that the observed covariation in latency and synaptic strength is a synergistic combination that significantly affects postsynaptic spiking. In conclusion, amplitude-related variation in latency represents a putative code for short- and long-term synaptic dynamics in cortical networks. Nerve cells transmit information not only by their firing rate but also by the temporal organization of their discharge (Rieke et al., 1997Rieke F. Warland D. de Ruyter van Steveninck R. Bialek W. Spikes: Exploring the Neural Code. MIT Press, Cambridge, MA1997Google Scholar). Temporally organized spiking in cortical networks is crucial for coding sensory information (Singer, 1999Singer W. Neuronal synchrony: a versatile code for the definition of relations?.Neuron. 1999; 24: 49-65Abstract Full Text Full Text PDF PubMed Scopus (1774) Google Scholar), induction of synaptic plasticity (Debanne et al., 1998Debanne D. Gähwiler B.H. Thompson S.M. Long-term synaptic plasticity between pairs of individual CA3 pyramidal neurons.J. Physiol. 1998; 507: 237-247Crossref PubMed Scopus (434) Google Scholar, Bi and Poo, 1998Bi G.Q. Poo M.M. Synaptic modifications in cultured hippocampal neurons: dependence on spike-timing, synaptic strength, and postsynaptic cell type.J. Neurosci. 1998; 18: 10464-10472Crossref PubMed Google Scholar) and synchronization of network activity (König et al., 1996König P. Engel A.K. Singer W. Integrator or coincidence detector? The role of the cortical neuron revisied.Trends Neurosci. 1996; 19: 130-137Abstract Full Text PDF PubMed Scopus (507) Google Scholar). In simple neuronal circuits, the timing of neuronal activity is determined by the interplay between geometrical factors and synaptic and voltage-gated currents. At the postsynaptic side, timing of spike generation is controlled by intrinsic and synaptic mechanisms (Fricker and Miles, 2000Fricker D. Miles R. EPSP amplification and the precision of spike timing in hippocampal neurons.Neuron. 2000; 28: 559-569Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar, Pouille and Scanziani, 2001Pouille F. Scanziani M. Enforcement of temporal fidelity in pyramidal cells by somatic feed-forward inhibition.Science. 2001; 293: 1159-1163Crossref PubMed Scopus (776) Google Scholar, Sourdet et al., 2003Sourdet V. Russier M. Daoudal G. Ankri N. Debanne D. Long-term enhancement of neuronal excitability and temporal fidelity mediated by metabotropic glutamate receptor subtype 5.J. Neurosci. 2003; 23: 10238-10248PubMed Google Scholar). The timing between connected neurons is usually described by the synaptic latency, which is the sum of the axonal conduction time, determined by the axonal length and the conduction velocity, and the synaptic delay (Sabatini and Regher, 1999Sabatini B.L. Regher W.G. Timing of synaptic transmission.Annu. Rev. Physiol. 1999; 61: 521-542Crossref PubMed Scopus (183) Google Scholar). Synaptic latencies in the cortex range between 0.2 and 6 ms (Markram et al., 1997Markram H. Lübke J. Frotscher M. Roth A. Sakmann B. Physiology and anatomy of synaptic connections between thick tufted pyramidal neurones in the developing rat neocortex.J. Physiol. 1997; 500: 409-440PubMed Google Scholar, Feldmeyer et al., 1999Feldmeyer D. Egger V. Lübke J. Sakmann B. Synaptic connections between spiny layer 4 neurones in the “barrel field” of rat somatosensory cortex.J. Physiol. 1999; 521: 169-190Crossref PubMed Scopus (311) Google Scholar), and this large variability is thought to enrich the storage capacity of neural networks (Izhikevitch, 2006Izhikevitch E.M. Polychronization: computation with spikes.Neural Comput. 2006; 18: 245-282Crossref PubMed Scopus (681) Google Scholar). Axonal conduction is temporally very precise but can be affected by the presence of branch points and swellings on the axon and by local voltage-gated currents (review in Debanne, 2004Debanne D. Information processing in the axon.Nat. Rev. Neurosci. 2004; 5: 304-316Crossref PubMed Scopus (268) Google Scholar). The synaptic delay is the consequence of a cascade of molecular events linking the depolarization of the presynaptic terminal by the sodium spike to the release of neurotransmitter (review in Meinrenken et al., 2003Meinrenken C.J. Borst J.G.G. Sakmann B. Local routes revisited: the space and time dependence of the Ca2+ signal for transmitter release at the rat calyx of Held.J. Physiol. 2003; 547: 665-689PubMed Google Scholar). In giant synapses, synaptic delay is largely determined by presynaptic Ca2+ influx (Bollmann et al., 2000Bollmann J.H. Sakmann B. Borst J.G.G. Calcium sensitivity of glutamate release in a Calyx-type terminal.Science. 2000; 289: 953-957Crossref PubMed Scopus (380) Google Scholar, Schneggenburger and Neher, 2000Schneggenburger R. Neher E. Intracellular calcium dependence of transmitter release rates at a fast central synapse.Nature. 2000; 406: 889-893Crossref PubMed Scopus (543) Google Scholar, Feldchyshyn and Wang, 2007Feldchyshyn M.J. Wang L.Y. Activity-dependent changes in temporal components of neurotransmission at the juvenile mouse calyx of Held synapse.J. Physiol. 2007; 581: 581-602Crossref PubMed Scopus (38) Google Scholar) and the waveform of the presynaptic AP (Katz and Miledi, 1967Katz B. Miledi R. A study of synaptic transmission in the absence of nerve impulses.J. Physiol. 1967; 192: 407-436PubMed Google Scholar, Augustine et al., 1985Augustine G.J. Charlton M.P. Smith S.J. Calcium entry and transmitter release at voltage-clamped nerve terminals of squid.J. Physiol. 1985; 369: 163-181Crossref Scopus (230) Google Scholar), but how synaptic timing is controlled at cortical synapses has yet to be determined. In cortical circuits, the synaptic latency at monosynaptic connections varies within ∼1–2 ms (Miles and Wong, 1986Miles R. Wong R.K.S. Excitatory synaptic interactions between CA3 neurones in the guinea-pig hippocampus.J. Physiol. 1986; 373: 397-418PubMed Google Scholar, Debanne et al., 1995Debanne D. Guérineau N.C. Gähwiler B.H. Thompson S.M. Physiology and pharmacology of unitary synaptic connections between pairs of cells in areas CA3 and CA1 of rat hippocampal slice cultures.J. Neurophysiol. 1995; 73: 1282-1294PubMed Google Scholar, Markram et al., 1997Markram H. Lübke J. Frotscher M. Roth A. Sakmann B. Physiology and anatomy of synaptic connections between thick tufted pyramidal neurones in the developing rat neocortex.J. Physiol. 1997; 500: 409-440PubMed Google Scholar). These small variations are generally considered to be functionally negligible, and therefore synaptic latency is often considered to be a constant parameter. We show here that latency at connected pairs of L5 cortical pyramidal neurons is not fixed but rather is determined by the presynaptic release probability (Pr). Our data provide evidence for a direct relationship between synaptic strength and synaptic timing in physiological conditions. This release-dependent process constitutes a putative temporal code for the efficacy of cortical synaptic strength. Monosynaptic connections were observed in 151 of 426 pairs of adjacent L5 pyramidal neurons (probability of 35%). The analysis was restricted to 50 connections with a mean amplitude larger than 10 pA. The latency of individual EPSCs was measured from the peak of the presynaptic AP measured in the cell body to 5% of the EPSC amplitude (Figure S1 available online). The mean EPSC latency was near 1 ms (1.21 ± 0.07 ms; n = 50; range: 0.2/4 ms), but this value is underestimated when the reference is the presynaptic AP measured in the cell body. Simultaneous somatic and axonal recordings showed that the conduction time from the site of initiation in the axon (5–60 μm) to the soma was ∼0.4 ms (Figure S2). In individual L5-L5 pairs (Figure 1A), EPSC latency was found to fluctuate from trial to trial in a stationary way, whereas synaptic latency was inversely related to EPSC amplitude. Large EPSCs had a short latency, whereas small EPSCs had a longer latency (Figure 1B). The variation in latency was in the millisecond range. To eliminate the potential impact of recording noise, individual EPSCs were averaged according to their amplitudes into three main groups. In the same connection, the latency of small averaged EPSCs was clearly longer than that of large averaged EPSCs (Figure 1C). A similar inverse correlation was observed across the whole set of connections (Figure 1D). In these experiments, the presynaptic spike jitter was not considered. However, presynaptic spike latency may fluctuate from trial to trial, thus eventually blurring the latency versus amplitude relation. To test this hypothesis, L5 pyramidal neurons were recorded in cell-attached configuration, and postsynaptic APs were triggered by EPSPs evoked by stimulating layer II/III. The stimulus intensity was adjusted to produce a spike in 50% of cases (Figure 2A). The standard deviation of the spike latency evoked in these conditions was 0.58 ± 0.05 ms (Figure 2B), confirming previous observations in the hippocampus (Pouille and Scanziani, 2001Pouille F. Scanziani M. Enforcement of temporal fidelity in pyramidal cells by somatic feed-forward inhibition.Science. 2001; 293: 1159-1163Crossref PubMed Scopus (776) Google Scholar). Next, the relation between this presynaptic jitter and the latency versus amplitude correlation was evaluated in six pairs. Although the introduction of a jitter of 0.58 ms by convolution of a random Gaussian distribution with the latency population decreased the coefficient of correlation (Figure 2C), among 105 random draws (see Experimental Procedures), the probability of observing a significant inverse correlation between latency and amplitude (p < 0.05 or p < 0.005) remained very high (96% ± 2%, n = 6 for p < 0.05 and 84% ± 7%, n = 6 for p < 0.005, Figure 2D). The differential timing of small and large EPSCs could be due to the fact that these synaptic responses result from activation of synapses located at different dendritic regions. The most distal synapses would produce responses attenuated by postsynaptic dendritic filtering. In this case, small EPSCs should have slower kinetics, hence longer latencies. However, no significant difference in the time-to-peak could be detected between maximal (100%) and small EPSCs (10%–90% of the maximal EPSC amplitude; 91% ± 2%, n = 50, Mann-Whitney p > 0.1, Figure 3A). Thus, the observed difference in latency between large and small EPSCs cannot be explained by differential dendritic filtering on the postsynaptic side. Alternatively, the long latencies measured for small EPSCs could correspond to an error in latency measurement because the signal-to-noise ratio is lower for small signals. To test this hypothesis, the amplitude of EPSCs was reduced to half of the control (48% ± 14%, n = 3) by partial blockade of postsynaptic AMPA receptors with 0.4 μM NBQX. Synaptic latency was, however, not significantly affected (from 1.10 ± 0.16 to 1.12 ± 0.17 ms, n = 3; paired t test p > 0.1; Figure 3B), indicating that the measurement of long latencies for small EPSCs is not due to poor signal detection. Furthermore, when the impact of noise on the synaptic latency was estimated with EPSCs simulated with Igor Pro (WaveMetrics), the latencies in our experiments were not significantly affected when the signal-to-noise ratio was greater than 3 (a condition always respected in our experiments). In fact, even large Gaussian noise of 10 pA had virtually no effect on the latency of EPSCs greater than 20/30 pA (Figure S3). We also tested the effect on latency of changing the driving force for AMPA receptor-mediated currents. Moving the holding potential from −70 mV to −50 mV reduced the EPSC amplitude (67% ± 5% of the control amplitude, n = 6) but did not change the latency (1.31 ± 0.22 ms versus 1.31 ± 0.22 ms, n = 6, paired t test, p > 0.5; data not shown). If postsynaptic filtering and detection of small synaptic responses are not responsible for the dependence we observed, presynaptic glutamate release may underlie the variation in latency. Pr was manipulated via modification of the extracellular [Ca2+] to [Mg2+] ratio or by application of the GABAB receptor agonist baclofen. Increasing the extracellular [Ca2+] to [Mg2+] ratio (from 3 mM Ca2+ and 2 mM Mg2+ to 5 mM Ca2+ and 0.5 mM Mg2+) enhanced synaptic transmission (173% ± 14% of the control EPSC amplitude, n = 18) and decreased synaptic latency (83% ± 2% of the control latency, n = 18, Figure 3C; from 1.32 ± 0.10 to 1.09 ± 0.09 ms, n = 18, paired t test p < 0.05). Conversely, when this ratio was decreased (from 3 mM Ca2+ and 2 mM Mg2+ to 1 mM Ca2+ and 3 mM Mg2+) synaptic transmission was reduced (35% ± 8% of the control EPSC amplitude, n = 6), and synaptic latency was increased by about 0.5 ms (from 0.99 ± 0.08 to 1.45 ± 0.09 ms, n = 6, paired t test p < 0.01; 145% ± 14% of the control, Figure 3D). Similar effects were also observed on multiunitary postsynaptic potentials (EPSPs) elicited by extracellular stimulation (mean latency 2.56 ± 0.16 ms in 1 mM Ca2+ and 3 mM Mg2+ versus 1.67 ± 0.19 ms in 5 mM Ca2+ and 0.5 mM Mg2+, n = 8; paired t test, p < 0.05; Figure S4A). In the presence of baclofen (20–60 μM), EPSC amplitude was reduced (to 54% ± 9% of the control amplitude, n = 4), and synaptic latency increased to 124% ± 4% of the control (n = 4; Mann-Whitney, p < 0.01; Figure 3D). Thus, our results show that synaptic latency depends on Pr at connections between L5 pyramidal cells. EPSPs between L5 neurons are mediated by the release of transmitter from several sites (Markram et al., 1997Markram H. Lübke J. Frotscher M. Roth A. Sakmann B. Physiology and anatomy of synaptic connections between thick tufted pyramidal neurones in the developing rat neocortex.J. Physiol. 1997; 500: 409-440PubMed Google Scholar). One cannot exclude the possibility that release sites have distinct latencies, and the actual latency could be determined by the release site with the shortest latency. Thus, short latencies would be measured when Pr is high, because all sites are recruited, whereas longer latencies would be measured with a low Pr. This hypothesis predicts that short latencies could occur when Pr is high or low. To test this possibility, the distributions of latency were compared in the same pairs when the [Ca2+] to [Mg2+] ratio varied from 1/3 to 5/0.5. Speaking against this hypothesis, events with short latencies were encountered only in high Ca, not in high Mg (Figure S4B). In fact, the first latency bin was shifted by 0.37 ± 0.09 ms (n = 4). Thus, selective sampling of short latencies within a distribution does not represent a consequential mechanism for Pr-dependent variation in latency. Paired-pulse plasticity at unitary cortical synapses is largely determined by presynaptic mechanisms (Zucker and Regher, 2002Zucker R.S. Regher W.G. Short-term synaptic plasticity.Annu. Rev. Physiol. 2002; 64: 355-405Crossref PubMed Scopus (2881) Google Scholar). To test whether synaptic latency is affected by induction of short-term plasticity, pairs of APs were elicited every 10 s in presynaptic L5 pyramidal cells at intervals of 50 ms. Although paired-pulse depression (PPD) dominates at this synaptic connection in young rats (Thomson et al., 1993Thomson A.M. Deuchars J. West D.C. Large, deep layer pyramid-pyramid single axon EPSPs in slices of rat motor cortex display paired pulse and frequency-dependent depression, mediated presynaptically and self-facilitation, mediated postsynaptically.J. Neurophysiol. 1993; 70: 2354-2369PubMed Google Scholar, Reyes and Sakmann, 1999Reyes A. Sakmann B. Developmental switch in the short-term modification of unitary EPSPs evoked in layer 2/3 and layer 5 pyramidal neurons of rat neocortex.J. Neurosci. 1999; 19: 3827-3835PubMed Google Scholar), the paired-pulse ratio (PPR) varied considerably from trial to trial, and both paired-pulse facilitation (PPF) and PPD were observed at the same connection. The amplitude of the second EPSC (EPSC2) was inversely correlated with the amplitude of the first EPSC (EPSC1) (Figure S5), suggesting that quantal fluctuation determines subsequent release (Debanne et al., 1996Debanne D. Guérineau N.C. Gähwiler B.H. Thompson S.M. Paired-pulse facilitation and depression at unitary synapses in rat hippocampus: quantal fluctuation affects subsequent release.J. Physiol. 1996; 491: 163-176PubMed Google Scholar). We analyzed the variation in latency (ΔLat = latencyEPSC1 − latencyEPSC2) as a function of PPR. PPD was associated with a relative increase in synaptic latency of EPSC2 (positive ΔLat), whereas PPF was associated with a relative decrease in latency (negative ΔLat). In fact, the variation in latency was cumulative during short-term plasticity (range of ± 1 ms) and was negatively correlated with the PPR (Figure 4A). To eliminate the potential impact of recording noise, individual traces were averaged according to their PPR into two main groups (one group with PPD and the other with PPF). Consistent with the previous observation, the variation in latency measured on averaged traces clearly depended upon PPR. This dependency was observed in all studied connections (n = 50, Figure 4B) when the postsynaptic cell was recorded in current-clamp (Figure S6), thus confirming that latency varies as a function of PPR. To provide further evidence that latency is influenced byshort-term synaptic plasticity, we changed PPR by modifying the extracellular [Ca2+] to [Mg2+] ratio. In saline containing a high [Ca2+]/[Mg2+] ratio, PPR decreased (from 62% ± 4% to 38% ± 4%, n = 8, paired t test p < 0.01), and the proportion of positive ΔLat increased (from 69% ± 4% to 77% ± 4% n = 8, paired t test p < 0.01; Figures S7A and S7B). Conversely, in saline containing a low [Ca2+]/[Mg2+] ratio, PPR increased (from 56% ± 3% to 122% ± 10%, n = 6, paired t test p < 0.01), and the proportion of positive ΔLat decreased (from 63% ± 5% to 35% ± 6%, n = 6, paired t test p < 0.01; Figures S7C and S7D). Therefore, variations in latency are observed during short-term plasticity and depend upon the PPR. During paired-pulse stimulation, the second presynaptic spike was generally broader than the first one, which may affect synaptic latency (reviewed in Lin and Faber, 2002Lin J.W. Faber D.S. Modulation of synaptic delay during synaptic plasticity.Trends Neurosci. 2002; 25: 449-455Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar). We therefore investigated whether spike broadening was also present in the axon or only in the soma. Simultaneous whole-cell recordings from the cell body and “loose-patch” recordings from the proximal part of the axon (10–170 μm) were obtained from L5 pyramidal neurons. Pairs of APs were evoked with an interval of 50 ms. Half-width of the second AP increased in the cell body (1.49 ± 0.06 ms versus 1.67 ± 0.07 ms for the second AP, n = 10), but the AP waveform recorded in the axon remained unchanged during the second stimulation (Figure S8). Thus, the changes in latency observed during paired-pulse plasticity are not a consequence of a modification of the presynaptic spike width but may rather correspond to a mechanism involving the presynaptic release machinery. Release-dependent variation in latency is present at L5-L5 connections, but it is not clear whether it is a general feature of central synapses. To address this question, we examined whether facilitating synapses also display release-dependent variations in latency. Pairs of CA3 pyramidal neurons were recorded in hippocampal slice cultures (Gähwiler, 1981Gähwiler B.H. Organotypic monolayer cultures of nervous tissue.J. Neurosci. Methods. 1981; 4: 329-342Crossref PubMed Scopus (732) Google Scholar, Debanne et al., 1995Debanne D. Guérineau N.C. Gähwiler B.H. Thompson S.M. Physiology and pharmacology of unitary synaptic connections between pairs of cells in areas CA3 and CA1 of rat hippocampal slice cultures.J. Neurophysiol. 1995; 73: 1282-1294PubMed Google Scholar). Twelve out of thirty pairs were connected, and in six connections, the amplitude of the mean evoked EPSC was larger than 15 pA. Release- and PPR-dependent variations in latency were observed at CA3-CA3 synaptic connections (Figure S9), suggesting that amplitude dependence of latency is a general principle at central synapses. Long-term synaptic plasticity at L5 pyramidal cell connections is associated with a change in the PPR (Markram and Tsodyks, 1996Markram H. Tsodyks M. Redistribution of synaptic efficacy between neocortical pyramidal neurons.Nature. 1996; 382: 807-810Crossref PubMed Scopus (592) Google Scholar, Sjöström et al., 2003Sjöström P.J. Turrigiano G.G. Nelson S.B. Neocortical LTD via coincident activation of presynaptic NMDA and cannabinoid receptors.Neuron. 2003; 39: 641-654Abstract Full Text Full Text PDF PubMed Scopus (457) Google Scholar) and/or in the coefficient of variation of EPSC amplitudes (Sjöström et al., 2003Sjöström P.J. Turrigiano G.G. Nelson S.B. Neocortical LTD via coincident activation of presynaptic NMDA and cannabinoid receptors.Neuron. 2003; 39: 641-654Abstract Full Text Full Text PDF PubMed Scopus (457) Google Scholar), indicating that it may result from a presynaptic change in glutamate release (but see Poncer and Malinow, 2001Poncer J.C. Malinow R. Postsynaptic conversion of silent synapses during LTP affects synaptic gain and transmission dynamics.Nat. Neurosci. 2001; 4: 989-996Crossref PubMed Scopus (51) Google Scholar). We tested whether changes in synaptic latency were observed following induction of a presynaptic form of long-term synaptic plasticity. At L5 pyramidal cell synapses, Pr is high in control conditions (low PPR and little effect of elevation of the [Ca2+]/[Mg2+] ratio). Thus, long-term downregulation of presynaptic efficacy is expected to be easily induced at this synapse. In fact, LTD was reliably induced by stimulating the presynaptic cell at 3 Hz for 3–5 min while the postsynaptic cell was held at −40/−30 mV. After induction, synaptic efficacy was reduced to 63% ± 7% of the control EPSC amplitude (n = 6, Figure 5A), the coefficient of variation was significantly reduced (normalized 1/CV2 = 57% ± 11%, n = 6, Figure 5B), and the PPR was increased (from 53% ± 10% to 89% ± 10%, n = 6, paired t test p < 0.01, Figure 5B), suggesting that presynaptic release was decreased following induction of LTD. Most interestingly, induction of LTD resulted in a long-lasting enhancement of mean latency (141% ± 8%; Figure 5C). In fact, after LTD induction, the latency was found to be increased (from 1.09 ± 0.16 to 1.52 ± 0.24 ms, n = 6; paired t test, p < 0.01). We then induced long-term potentiation (LTP) by stimulating the presynaptic cell at 1 Hz for 2–3 min while the postsynaptic cell was held at −10 mV. After induction, synaptic efficacy (142% ± 7%, n = 4, Figure 6A) and the coefficient of variation (1/CV2 = 256% ± 12%, n = 4) were enhanced, and PPR was decreased (from 73% ± 10% to 42% ± 4%; paired t test, p < 0.01), suggesting a presynaptic facilitation of glutamate release underlying LTP (Figure 6B). Here again, the latency was found to decrease (from 1.63 ± 0.32 ms to 1.38 ± 0.31 ms, n = 4, paired t test, p < 0.03, Figure 6C). Thus, synaptic latency is also subject to long-term regulation when presynaptic long-term synaptic plasticity is induced.Figure 6Change in Latency Associated with Presynaptic LTP at L5-L5 SynapseShow full caption(A) Presynaptic LTP was induced at L5-L5 connections by repetitively stimulating the presynaptic neuron at 1 Hz while the postsynaptic neuron was held at −10 mV. (Top) Synaptic currents before (control) and after 1 Hz stimulation (LTP). (Middle) Time course of the normalized EPSC amplitude. (Bottom) Normalized 1/CV2 versus normalized EPSC amplitude in four experiments (•, individual connections; ○, pooled data).(B) Decreased PPR after LTP induction. (Upper traces) Synaptic currents evoked by a pair of presynaptic APs before (control) and 10 min after the high-frequency stimulation (LTP). Note the enhancement of PPD. (Middle graph) Time course of the normalized PPR. (Bottom) Summary of four experiments.(C) Reduction of synaptic latency associated with LTP. (Top) EPSC latency versus EPSC amplitude data in control (○) and after LTP induction (•). (Left) Representative traces (averages over six trials). (Middle graph) Time course of the normalized EPSC latency. (Bottom) Summary of four experiments.Error bars show SEM.View Large Image Figure ViewerDownload Hi-res image Download (PPT) (A) Presynaptic LTP was induced at L5-L5 connections by repetitively stimulating the presynaptic neuron at 1 Hz while the postsynaptic neuron was held at −10 mV. (Top) Synaptic currents before (control) and after 1 Hz stimulation (LTP). (Middle) Time course of the normalized EPSC amplitude. (Bottom) Normalized 1/CV2 versus normalized EPSC amplitude in four experiments (•, individual connections; ○, pooled data). (B) Decreased PPR after LTP induction. (Upper traces) Synaptic currents evoked by a pair of presynaptic APs before (control) and 10 min after the high-frequency stimulation (LTP). Note the enhancement of PPD. (Middle graph) Time course of the normalized PPR. (Bottom) Summary of four experiments. (C) Reduction of synaptic latency associated with LTP. (Top) EPSC latency versus EPSC amplitude data in control (○) and after LTP induction (•). (Left) Representative traces (averages over six trials). (Middle graph) Time course of the normalized EPSC latency. (Bottom) Summary of four experiments. Error bars show SEM. Next, we determined whether amplitude-dependent variation in latency observed following LTD may affect the input-output function of L5 pyramidal neurons. To test this hypothesis, in vivo-like background synaptic conductance was injected using the dynamic-clamp technique (Galaretta and Hestrin, 2001Galaretta M. Hestrin S. Spike transmission and synchrony detection in networks of GABAergic interneurons.Science. 2001; 292: 2295-2299Crossref PubMed Scopus (288) Google Scholar, Zsiros and Hestrin, 2005Zsiros V. Hestrin S. Background synaptic conductance and precision of EPSP-spike coupling at pyramidal cells.J. Neurophysiol. 2005; 93: 3248-3256Crossref PubMed Scopus (29) Google Scholar), and the effect of amplitude-dependent latency variation on EPSP-spike coupling was investigated (Figure 7A). Unitary synaptic events were triggered in the middle of the background train (at a latency of ∼500 ms). Two conductance amplitudes were used (3.4 nS [250 pA at −70 mV] and 2.2 nS [170 pA at −70 mV]), with two different latencies (respectively, 0 ms and 0.5 ms, see Figure 1C). Importantly, the raster plot and cumulative probability curve were shifted toward long latencies when synaptic conductance was reduced from 3.4 to 2.2 nS with a latency shift of 0.5 ms (n = 16 neurons, Figure 7B). The cumulative probability curve was shifted by 1.1 ms (Mann-Whitney U test, p < 0.005), showing that the amplitude-dependent variation in latency has a significant effect on the activity of the postsynaptic neuron. When a latency shift of 0.5 ms was introduced without changing synaptic conductance, the output message was also shifted by 0.5 ms (n = 16; Figure 7C). Interestingly, reduction of synaptic conductance without any change in the latency, delayed the output firing by 0.7 ms (n = 16; Figure 7D). Finally, the opposite configuration was tested where the reduction in amplitude was associated with a shortening of the latency by 0.5 ms (Figure 7E). In these conditions, the two effects compensate each other, and the net effect on postsynaptic spiking was nearly zero. Thus, our findings show that the inverse amplitude-latency variation represents an optimal configuration to affect the timing of the output message. We show here that synaptic latency between pairs of L5 neurons varies within 1–2 ms in an amplitude-dependent" @default.
• W2046373003 created "2016-06-24" @default.
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• W2046373003 creator A5025832347 @default.
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• W2046373003 date "2007-12-01" @default.
• W2046373003 modified "2023-09-29" @default.
• W2046373003 title "Release-Dependent Variations in Synaptic Latency: A Putative Code for Short- and Long-Term Synaptic Dynamics" @default.
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