Department of Physiology, Royal Free and University College Medical School, Rowland Hill Street, London NW3 2PF, UK
Address correspondence to Professor Alex M. Thomson, Department of Pharmacology, The School of Pharmacy, 29/39 Brunswick Square, London WC1N 1AX, UK. Email: alext{at}ucl.ac.uk.
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Abstract |
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Introduction |
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Previous studies have demonstrated three presynaptic mechanisms that reduce the probability of transmitter release, or the number of available release sites (del Castillo and Katz, 1954; Elmqvist and Quastel, 1965
; Mallart and Martin, 1968
; Auerbach and Bennett, 1969
; Betz, 1970
; Thomson and Bannister, 1999
; Thomson, 2000
) and three that increase release probability following one or more presynaptic APs (action potentials) (Liley, 1956
; Hubbard, 1963
; Mallart and Martin, 1967
; Magleby and Zengel, 1975
, 1976
; Stanley, 1986
; Swandulla et al., 1991
; Thomson, 2000
). The relative functional expression of each of these several mechanisms depends on the class of pre- and post-synaptic neuron involved (Thomson, 1997
; Markram et al., 1998b
, Reyes et al., 1998
). A simple summary of several previous studies would be that at some connections (e.g. pyramidal inputs to some classes of inhibitory interneuron) transmitter release probability is extremely low (<0.01), and since the release-dependent mechanisms that depress subsequent release are not activated when no release occurs, the mechanisms that enhance release in response to subsequent APs dominate the picture (Thomson et al., 1993a
; Thomson, 1997
; Markram et al., 1998b
, Reyes et al., 1998
). At other connections (e.g. pyramid to pyramid), probability is relatively high and release-dependent mechanisms that depress subsequent release are dominant (Thomson et al., 1993b
; Markram et al., 1997
, 1998b
). One modeling study (Tsodyks et al., 1998
) has investigated the possible outcomes of the co-expression of several such presynaptic mechanisms, particularly where both facilitating and depressing mechanisms are co-expressed. Such co-expression results in more complex, interspike interval-dependent patterns of transmitter release than are typically considered.
Most previous studies documenting the relative expression of these presynaptic mechanisms have not, however, studied the presynaptic mechanisms active at very short interspike intervals in detail, but have concentrated on one or a very few interspike intervals and often on responses to relatively low frequencies, e.g. <50 Hz (Markram et al., 1998b; Reyes et al., 1998
; Reyes and Sakmann, 1999
). In the absence of more detailed analysis, response amplitudes at one frequency are assumed to predict those at other frequencies and synapses are described as either facilitating or depressing based on the relative amplitudes of second excitatory postsynaptic potentials (EPSPs) at one or a few interspike intervals. The purpose of the present study was therefore to investigate, in more detail, the efficacy of synaptic transmission over a range of shorter interspike intervals corresponding to the gamma frequency band (30>80Hz) at a range of neocortical synapses.
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Materials and Methods |
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Data Analysis
Presynaptic neurons were depolarized with combinations of square-wave and ramped currents delivered once every 3 s to elicit trains of APs with different patterns and at different frequencies; postsynaptic responses were recorded. Data were digitized (510 kHz, voltage resolution 0.0050.01 mV) and analysed off-line (Spike 2 data collection and in-house analysis software).
During off-line analysis, paired recordings in which the first EPSP shape and amplitude and the postsynaptic membrane potential were stable over time and which spanned a suitable range of brief interspike intervals (<10 to >30 ms) were selected. Each single sweep was checked by hand to ensure that every presynaptic AP was recognized by the software and that the trigger points used for subsequent analysis were accurately aligned with the rising phase of each AP in each sweep. Sweeps including artefacts or large spontaneous events were excluded from averaged records.
To obtain measurements of averaged second EPSP amplitudes, subsets of sweeps were then selected on the basis of the interspike interval that preceded the second AP. Each subset included sweeps in which the second EPSP followed a given interspike interval. The width of the selection window was typically narrower for short interspike intervals (0.10.5 ms) than for broader intervals (up to 25 ms for the longest interspike intervals studied). The number of sweeps included in the average was partially determined by the coefficient of variation (CV) of the EPSP. Where this was high (>0.3), a larger number (2050 sweeps) was required to provide an adequate estimate of average EPSP amplitude at that interval than when CV was low (510 sweeps). The second EPSPs occurring at each interspike interval were then averaged, using the rising phase of each second AP as the trigger. The averaged first EPSP for each of these data subsets (triggered from the rising phase of the first AP) was also computed to determine whether an adequate number of sweeps had been included in that subset. Only where the average of the first EPSP in this subset matched the average of a much larger sample of first, or single-spike, EPSPs in both shape and amplitude was that data subset used for measurements of averaged EPSP amplitude.
The averaged second EPSP was then superimposed on an average of all EPSPs elicited by single APs in that data set. The amplitude of the averaged second EPSP was measured from its peak to the appropriate point on the falling phase of the averaged single-spike EPSP (see Fig. 1). These averaged EPSP amplitudes were then plotted against the interval between the first and second spike. Single exponential curves were fit using PSI-Plot. Averaged EPSPs elicited by later APs in trains were analysed similarly.
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Morphological Identification of Recorded Neurons
All recorded cells were filled with biocytin and processed histologically. All reported neurons were identified as pyramidal cells, spiny stellate cells or as aspiny (or sparsely spiny) inhibitory interneurons. Details of the processing procedures and the morphology of these neurons can be found elsewhere (Thomson et al., 2002).
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Results |
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The Early Phase of Recovery from Paired-pulse Depression
In 27 pairs of synaptically connected spiny excitatory cells (pyramidal and spiny stellate cells) in rat and 15 in cat, responses to pairs of presynaptic spikes at several different interspike intervals were studied. Paired-pulse depression was apparent at the shortest interspike intervals studied under our control conditions (Fig. 1A), even at those connections in which modest facilitation was apparent at longer intervals (e.g. Fig. 3
). The second EPSP amplitude at an interspike interval of 56 ms was equivalent to 69.2 ± 16.1% (mean ± SD, n = 11) of the average first EPSP amplitude in rat and 60.4 ± 13.2% (n = 7) in cat.
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A Simple Time Course for Recovery from Paired-pulse Depression at Some Connections
In 9 of the 28 depressing connections studied in more detail, the early phase of recovery from paired-pulse depression appeared adequately described by a single exponential. In six of these nine pairs the postsynaptic neuron was an inhibitory interneuron (three in rat, three in cat, all parvalbumin-immunonegative, or not successfully tested with immuno-fluorescence, Fig. 1B). The remaining three pairs included two pyramid-to-pyramid (one in rat, Fig. 1A
) and one spiny stellate-to-pyramid connection (in cat). Time constants for recovery from short interval paired pulse depression ranged from 3.1 to 27.7 ms for these data sets (12.4 ± 8.1 ms, mean ± SD) and did not differ significantly between spiny excitatory and inhibitory neurons, or between rat and cat with this sample.
A contribution to the recovery from an additional, more slowly decaying component, which accounted for some 1020% depression (relative to average first EPSP amplitude) at intervals >50 ms, was indicated by extrapolation of this simple curve (Fig. 1) in all nine connections. Facilitation was only rarely apparent at any interspike interval studied in these nine connections under our control conditions, and the third, fourth, . . ., seventh EPSPs in trains were generally more strongly depressed than second EPSPs at similar interspike intervals (Fig. 2
). These later EPSPs exhibited a slower recovery at short interspike intervals and/or a larger contribution from the more slowly decaying component. With this increasingly more powerful and more slowly recovering depression as the spike train proceeds, EPSP amplitude continues to be powerfully depressed at lower frequencies than were required to produce the same degree of depression at the start of the train.
A More Complex Time Course for Recovery from Paired-pulse Depression
In 19 of the 28 depressing connections studied in detail a simple exponential decay could not adequately describe the recovery from short interval depression (Figs 35). These connections included the majority (83%) of connections between spiny excitatory cells (12:14 pyramid to pyramid, 2:3 spiny stellate to pyramid and 1:1 spiny stellate to spiny stellate) (Figs 3 and 4
) and all four pyramid-to-parvalbumin-immunopositive interneuron connections studied (one in cat, Fig. 5
). At these 19 connections, the recovery from paired-pulse depression at short interspike intervals was interrupted by a notch during which the second EPSP again decreased in average amplitude before recovering again. The maximum EPSP depression within this notch was most commonly seen between 13 and 25 ms (n = 16) after the first EPSP (mean 20.3 ± 7.6 ms, range 1140 ms, n = 19).
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To determine whether non-linear summation of postsynaptic events might have contributed to the expression of the notch, the following properties were compared for connections that displayed a notch and those that did not. No significant difference was found in the postsynaptic membrane potential (71.7 ± 4.9 versus 67.5 ± 9.7 mV), the first EPSP average amplitude (2.1 ± 1.9 versus 2.7 ± 1.2 mV), 1090% rise time (2.3 ± 1.1 versus 1.44 ± 0.7 ms), or the width at half amplitude (17.1 ± 11.3 versus 11.6 ± 6.2 ms) for those with and those without a notch. Nor was a correlation found between any of these parameters and the amplitude of the notch or its width at half amplitude. In addition, the expression of the notch was not altered by changing postsynaptic membrane potential (n = 2), which at pyramid-to-pyramid connections dramatically alters EPSP time course and non-linear summation at short interspike intervals. These data suggest that non-linear summation did not contribute significantly to the expression of the notch.
Effect of First EPSP Amplitude on the Notch
The effect of first EPSP amplitude on the notch was examined in six pairs by comparing data subsets selected on the amplitude of the first EPSP in the train (Fig. 4). In one pair the effect of second and third EPSP amplitude on the notch expressed during third and fourth EPSP recovery was also studied (Fig. 5B
, insert). The notch was equally apparent in all these data subsets, suggesting that its expression is not dependent on the amplitude of the preceding EPSP. Its precise timing could vary between these data subsets, suggesting that the amplitude of the first EPSP, or the factors that determine first EPSP amplitude may influence its rate of onset.
It was not possible to determine with certainty whether the notch was absolutely dependent upon a release of transmitter occurring in response to the first AP. In none of the pairs in which single-sweep EPSP amplitudes could be measured accurately were there enough total failures of transmission following the first AP at all the necessary interspike intervals to allow a full time course for recovery from depression to be plotted. It is only possible to state that data subsets that included both first spike failures and very small first EPSPs (<0.3 mV) exhibited a notch when the second EPSP amplitude for these sweeps was plotted against interspike interval. In two pairs, trains of EPSPs that followed brief and/or low-frequency spike trains were compared with those that followed longer, higher-frequency trains, i.e. those that exhibited post-tetanic potentiation. The appearance of the notch was not affected by this potentiation.
All 19 connections displaying the notch exhibited paired-pulse depression at the shortest intervals studied (<10 ms) under control conditions. In eight (including three of the pyramid-inhibitory interneuron connections), the second EPSP remained depressed relative to the first EPSP at all intervals studied (Fig. 3C) and for all EPSPs in trains (Fig. 5A
). In four connections the second EPSP remained depressed until after the notch when it became modestly facilitated (by 520% versus average first EPSP amplitude). Later EPSPs in trains were generally depressed at all intervals studied, however. While in the remaining seven connections (one pyramid-to-inhibitory interneuron connection), the earliest depression gave way to modest facilitation (520%) before the notch. The EPSP was then depressed during the notch, but facilitated again after. In two of these seven connections all EPSPs in brief trains exhibited a similar profile, alternating between depression and facilitation during the recovery period studied (Fig. 3A,B
).
A Presynaptic Locus for the Notch Filter
To determine whether the mechanism underlying the notch was of pre- or of post-synaptic origin two tests were performed. Where sweep-to-sweep fluctuations in the second (third or fourth) EPSP amplitude included total apparent failures of transmission, a higher proportion of failures was found to occur during the notch as well at the briefest intervals (corresponding to the earliest phase of depression), than at intermediate, or longer interspike intervals (n = 3 pairs, Fig. 6). This indicates a presynaptic locus for the expression both of the notch and of the earliest phase of paired pulse depression. In addition, when normalized CV-2 (coefficient of variation-2 = [np/(1 p)] for a binomial distribution) (Clements, 1990
; Faber and Korn, 1991
) was plotted against normalized M (mean EPSP amplitude = npq), the slope was equal to, or, more typically exceeded 1. This was the case when second EPSPs elicited at notch frequencies were compared with second EPSPs elicited at shorter and at longer intervals (six pairs, 12 tests, Fig. 6
). This indicates that a decrease in release probability (p) underlies the expression of the notch.
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Discussion |
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Averaging of Data
Most of the data presented here are averages obtained either by averaging single-sweep responses digitally, or calculated from measurements of single-sweep EPSP amplitudes. In many pairs it was possible to see the patterns described here by observing sequential original sweeps, but the large spontaneous sweep-to-sweep fluctuations in amplitude, particularly with EPSPs in inhibitory interneurons, often obscured the trends when only a few sweeps were observed. Visualization of the notch and of some of the other components of depression and facilitation often required data to be averaged. This does not, however, indicate an insignificant role for these mechanisms. In vivo, several presynaptic neurons will be activated near simultaneously by afferent input and/or in association with, for example, gamma oscillations. The postsynaptic neuron will average these several inputs and be most effectively excited by coincident inputs that follow appropriate interspike intervals.
Brief Time Constants for Recovery from Short Interval Depression
When a range of short interspike intervals were used to activate EPSPs, time constants for recovery from short interval paired-pulse depression were found to be onetwo orders of magnitude lower than previous reports (Markram et al., 1998b). One explanation for this difference might be that the underlying mechanisms are slower to decay in immature brain. The other possibility is that many previous studies utilized a smaller range of rather longer interspike intervals and investigated therefore the more slowly decaying components of depression (equivalent to the residual depression apparent at 50100 ms in the present study).
Caution should be exercised in attempting to put specific values on single mechanisms within a complex system, unless they can be isolated experimentally. This is almost impossible to achieve with synaptic transmission since many presynaptic mechanisms are affected by the same conditions, such as [Ca2+]i. To put an absolute value on the recovery from paired-pulse depression is problematic. All connections studied appropriately to date have exhibited facilitation to some degree. This is often masked by the relatively high probability of release at depressing connections, but can be revealed when only those second EPSPs that follow failures of transmission in response to the first AP are measured (Thomson and Bannister, 1999). This facilitation is sufficient to confound assessment of the precise time course of recovery from paired-pulse depression (Markram et al. 1998a
,b
, Tsodyks et al., 1998
). In addition, there are several mechanisms that can contribute to depression (Thomson, 2000
). The range of time constants reported here (3.127.7 ms) for recovery from short interval depression may therefore reflect differential expression of these various mechanisms.
Complexity in the Time Course for Recovery from Paired-pulse Depression
Some of the complexity described here has been predicted by modelling studies (Markram et al. 1998a; Tsodyks et al., 1998
). The present observation that very short interval paired-pulse depression can give way to modest facilitation at slightly longer interspike intervals (at some pyramid-to-pyramid and a few pyramid-to-inhibitory interneuron connections) is predicted by phenomenonological models that include both facilitating and depressing components, provided that appropriate time constants for decay/recovery are utilized. The main difference between the previous model and the present experiment is the faster time course of events in the current work. What such models do not predict, however, is the notch as described here. Attempts were made to fit the present data with curves that combined one or two exponentially decaying facilitating and two or three depressing components, but they gave poor correlations when all points were included and failed to fit the notch in the data. Careful selection of variables in these models could generate a notch that interrupted the recovery from short interval depression, or one that interrupted a phase of facilitation following brief interval depression, but this notch either occurred at a much shorter interspike interval than in the data (e.g. 5 ms), or was more broadly tuned (half width >20 ms) (also A. Destexhe, personal communication). This suggests that a combination of previously described mechanisms cannot entirely account for the complex recoveries observed here, unless a previously unreported delay to the onset of one or more of the components is introduced into the model.
To explain the notch, therefore, a presynaptic mechanism is required that has a delayed onset some 1215 ms after a presynaptic action potential and decays rapidly thereafter, with little desensitization or inactivation, since all EPSPs in brief high-frequency trains exhibited a similar notch. None of the manipulations tested removed the notch, so at this stage we can only exclude some possible mechanisms, such as non-linearities in postsynaptic responsiveness, or mechanisms that are strongly dependent upon the release that occurred in response to the preceding AP, such as release site refractoriness or presynaptic autoreceptor activation.
High-frequency Tuning in the Neocortical Circuit
The complexity of the time course of recovery from presynaptic depression described here complements the inherent firing characteristics of the presynaptic pyramidal cells. At the high instantaneous firing frequencies (>100 Hz), achieved during pyramidal spike-pair, or burst firing, paired-pulse depression can be powerful, but summation of successive EPSPs can maintain or increase the depolarization achieved by the first EPSP. This is particularly effective in pyramidal cells and some regular-spiking inhibitory interneurons in which EPSPs are broader than in fast-spiking inhibitory interneurons. At slightly lower frequencies (70100 Hz) summation is reduced, but recovery from early depression and the modest facilitation seen here at some connections can compensate. Even modest facilitation may be significant since at these intervals the spike accommodation and the prolonged spike afterhyperpolarization (AHP) in regular spiking cells increase postsynaptic spike threshold. A further small decrease in frequency brings the majority of local circuit excitatory inputs onto pyramidal cells into the notch filter range (4070 Hz). Temporal summation is further reduced at these intervals, while in regular- and burst-firing postsynaptic cells, spike accommodation and the AHP persist, so that even a relatively weak notch could reduce recruitment at these frequencies. At longer intervals, recovery from all forms of depression is more advanced and, with the concomitant decline in spike accommodation and in the spike AHP, pyramidal cells are again more excitable. The gradual increase in the onset and duration of the notch with later EPSPs in the train matches the adapting firing patterns typical of pyramidal cells.
Fast-spiking inhibitory interneurons generate much briefer EPSPs than pyramidal cells and temporal summation is only significant at extremely brief interspike intervals. Since at these intervals paired-pulse depression is profound, these inter-neurons rarely fire in response to a second, very short interval EPSP. If they fire at all in response to the beginning of a presynaptic spike train, therefore, the timing of that AP is extremely accurate, in striking contrast to the responses of pyramidal cells and regular-spiking interneurons. If the inter-neuron fires in response to the first EPSP, the deep-spike AHP typical of these neurons will preclude activation by a second very short interval AP. The depth and rapid onset of these AHPs prevents significant spike accommodation, however, and their brief duration allows the interneuron to be readily excitable again within 715 ms. At intervals >715 ms therefore, whether the interneuron can be repetitively activated by a pyramidal spike train at a given frequency will depend on the degree of EPSP depression and the rate of recovery. This depression is typically greater and its recovery slower for later EPSPs in trains, matching the frequency adaptation typical of pyramidal cell discharge and a relatively stable (depressed) EPSP amplitude is often achieved early in an adapting train before the pyramidal cell achieves a stable firing rate. The notch adds additional detail to these responses and during a single adapting spike train the profound depression seen at the shortest intervals and during the notch can sometimes be seen to alternate with less profound depression, or with modest facilitation at intermediate and longer intervals.
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Concluding Remarks |
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Footnotes |
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Our thanks to Mr A.P. Bannister for the histological processing referred to herein. This work was supported by the Medical Research Council, Novartis Pharma and the Wellcome Trust.
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References |
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