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Department of Biomedicine and Surgery, Faculty of Health Sciences, Linköping University, SE-581 85 Linköping, Sweden
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(Received 4 August 2003;
accepted after revision 9 January 2004;
first published online 14 January 2004)
Correspondence address B. Granseth: MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, UK. Email: bjogr{at}mrc-lmb.cam.ac.uk
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Introduction |
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One shared feature of the feedback originating in layer 6 in all cortical areas is a pronounced frequency-dependent enhancement of synaptic strength (Ferster & Lindström, 1985a,b; Lindström & Wróbel, 1990; McCormick & von Krosigk, 1992; Mishima & Ohta, 1992; Turner & Salt, 1998; Bartlett & Smith, 2002). Depending on the firing frequency, this synaptic enhancement can be ascribed to the actions of different phases of short-term synaptic plasticity, a characteristic of synapses in both the central and peripheral nervous system (Magleby, 1987; Zucker & Regehr, 2002). A fast and a slow component of facilitation as well as augmentation have so far been identified at the corticogeniculate synapse in the dLGN (Granseth et al. 2002; Granseth & Lindström, 2003, 2004).
The facilitation at the corticogeniculate synapse has previously been quantified using paired pulse stimulation protocols (Lindström & Wróbel, 1990; Turner & Salt, 1998; Granseth et al. 2002; Granseth & Lindström, 2003). However, such results are hard to extrapolate to the normal behaviour of the synapse since visual stimuli more often induce continuing firing in corticogeniculate neurones (Livingstone & Hubel, 1981). Their activity is maintained until the stimulus is moved out of their receptive field or, in the case of stationary stimuli, until the eyes move (Martinez-Conde et al. 2002). Train stimulation of the corticogeniculate pathway has been carried out before (Lindström & Wróbel, 1990; McCormick & von Krosigk, 1992; Turner & Salt, 1998) but without detailed quantification of the facilitation process. Such data are required to define the effective gain of the suggested neuronal amplifier.
Hence, the effects of repetitive stimulation of corticogeniculate axons were systematically investigated using patch-clamp recordings of dLGN principal cells in vitro. The present paper focuses on facilitation while augmentation is described in an accompanying paper (Granseth & Lindström, 2004). The results show that facilitation induces and maintains a manifold increase in EPSC amplitude that is Ca2+ dependent. The EPSC enhancement is linearly related to the firing frequency in the physiological range, a property that makes the corticogeniculate synapse particularly well suited for the suggested amplifier function.
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Methods |
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Brain slices were prepared from pigmented DA-HAN rats (BK Universal, Sollentuna, Sweden) of either sex, 23–37 days old, as previously described (Granseth et al. 2002). The animals were anaesthetized with halothane (ISC Chemicals, Avonmouth, UK) and decapitated. All procedures were approved by the Committee for Ethics in Animal Research of Linköping, in accordance with Swedish animal-welfare legislation. Slices containing the dLGN, 250–300µm thick, were cut in a plane that preserves the distal ramifications of retinogeniculate and corticogeniculate fibre tracts (Turner & Salt, 1998). After at least 1h of incubation at 37°C the slices were transferred to the recording chamber. Individual principal cells in the dLGN were identified using an Axioskop FS microscope (Zeiss, Jena, Germany) with water immersion objectives and infrared differential phase contrast optics and an infrared digital camera (C7500, Hamamatsu, Hamamatsu City, Japan). Whole-cell patch-clamp recordings were made with the EPC9 amplifier (HEKA Elektronik, Lambrecht, Germany) with slices submerged in Krebs solution (mM: NaCl, 124; NaH2PO4, 1.25; NaHCO3, 26; KCl, 3.0; MgCl2 2.0; CaCl2, 2.0; and glucose, 10; at 34°C equibrilated with 95% O2 in 5% CO2) as previously described (Granseth et al. 2002). Picrotoxin (100 µM) and DL-2-amono-5-phosphonovaleric acid (DL-APV, 100 µM) obtained from Sigma, St Louis, MO, USA, were routinely included to block GABAA and NMDA receptor currents. Cyclothiazide (Sigma) was added to the medium to final concentrations of 50–100µM from a 100 mM stock solution in DMSO to hinder AMPA receptor desensitization in some experiments. When (S)-
-methyl-4-carboxyphenylglycine [(S)-MCPG] or (RS)--cyclopropyl-4-phosphonophenylglycine [(RS)-CPPG], both obtained from Tocris Cookson (Bristol, UK), were used to antagonize metabotropic glutamate receptors, they were added to final concentrations of 100 and 200µM from 10 and 100 mM stock solutions in Krebs solution and NaOH, respectively. To minimize changes in nerve fibre excitability and maintain a high-quality gigaseal, [Mg2+]o was adjusted on an equimolar basis to changes in [Ca2+]o as previously described (Granseth et al. 2002). Borosilicate glass microelectrodes (Clark Electromedical, Reading, UK) were filled with a caesium gluconate-based buffer (mM: caesium gluconate, 100; NaCl, 10; Hepes, 10; TEA-Cl, 20; QX-314, 5.0; EGTA, 0.10; and MgATP 1.0; pH adjusted to 7.3 and osmolality adjusted with H2O from hyperosmolar to 300 mmol kg–1). Tip resistance was 3–6M
. Seals were initially 1.0–2.5G and after rupturing the cell membrane access resistance was less than 25M. Neurones were voltage clamped at –70 mV, adjusted for a liquid junction potential of 8 mV. Corticogeniculate axons were stimulated by amplitude graded voltage pulses of 0.2 ms duration (Granseth et al. 2002). For the present study, trains of 5–40 pulses at frequencies from 1 to 50Hz were used with the trains separated by resting periods of at least 60s. Unless specified, trains at 25Hz with 10 impulses at intensities recruiting multiple corticogeniculate fibres were used (Granseth & Lindström, 2003).
Data analysis
Records were filtered at 4.0kHz and sampled at 20kHz using the Pulse software (HEKA Elektronik) and stored to the hard disk of a computer. After additional digital Bessel filtering at 1.5kHz, EPSC amplitudes were measured from baseline to peak. When EPSCs overlapped temporally, amplitudes were measured from the EPSC peak to the extrapolated decay level of the preceding EPSC. Averaging of EPSCs was made using the PulseFit or IgorPro software (Wavemetrics, Lake Oswego, OR, USA). A measurement of facilitation was obtained by EPSCn/EPSC1. Functions were fitted to the data using a least-sum-of-squares method with Origin (MicroCal, Northampton, MA, USA) or IgorPro software. Fits with exponential functions of the type
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Results |
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Unitary corticogeniculate EPSCs are small in amplitude with low resting transmitter release probability (psyn) (
5 pA at –70 mV holding potential; psyn < 0.1; Granseth & Lindström, 2003). For the present analysis compound EPSCs, typically exceeding 50 pA in amplitude were obtained by stimulation of a large group of convergent corticogeniculate axons (Fig. 1A). In this way, the response variability was minimized by averaging the activity over many synapses, a procedure justified by the rather uniform properties of corticogeniculate synapses (Granseth et al. 2002). Recordings were obtained from a total of 45 dLGN cells in slices from 36 animals.
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To further investigate for EPSC depression during repetitive synaptic activity, trains were prolonged to contain 40 impulses (Fig. 2). In all five cells the EPSC amplitudes were maintained without obvious signs of depression. Thus, at physiological firing frequency, facilitated transmitter release can be upheld well beyond normal train durations (Livingstone & Hubel, 1981; Martinez-Conde et al. 2002).
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1) –K2x exp(–t/2), where Fss is the theoretical steady-state EPSC ratio approached with time constants 1 and 2. A least-sum-of-squares fit to the pooled data of 30 cells gave Fss= 7.0 with the time constants 1= 39 ms and 2= 450 ms for trains at 25Hz (Fig. 1B, continuous line). The moderate increase in amplitude of late EPSCs could also be approximated by a linear function (Fig. 1B, dotted line). The likely reason for this is that the fast component already reaches 95% of steady state within 120 ms, with growth thereafter defined primarily by the slow component. A linear regression would satisfactorily describe the latter when train duration is short relative to the slow time constant. The sample traces in Fig. 1A and C are from one cell where EPSC3 was 4.6 times the size of EPSC1. In spite of this multifold increase in size there was no change in EPSC waveform between the first and third stimuli (Fig. 1C). For the last stimulus in the train, when the amplitude ratio had increased to 5.0, the EPSC duration was slightly longer (Fig. 1C, dotted line). However, such a change was not consistently encountered in all 30 cells investigated. The average EPSC3 and EPSC10 ratios were 5.1 ± 1.9 and 6.3 ± 2.7, while the EPSC duration at half-peak amplitude was not significantly different (EPSC1= 8.5 ± 2.9 ms; EPSC3= 9.0 ± 2.8 ms; EPSC10= 9.3 ± 2.4 ms; P= 0.49, single-factor ANOVA). Thus, the facilitation was not paralleled by a corresponding change in EPSC duration.
The magnitude and time course of facilitation was the same for compound EPSCs of different amplitudes obtained by varying the stimulation intensity (4 cells; Fig. 2). This uniformity with different degrees of axon recruitment is in agreement with earlier findings for paired pulse facilitation and confirms that corticogeniculate synapses constitute a quite homogeneous population of synapses with regard to short-term synaptic plasticity (Granseth et al. 2002).
Metabotropic glutamate receptors
In addition to ionotropic glutamate receptors that mediate the fast EPSC, metabotropic glutamate receptors have been identified at the corticogeniculate synapse. The Group I metabotropic glutamate receptor mGlu1 causes a slow depolarizing response associated with an increase in membrane resistance of dLGN principal cells (McCormick & von Krosigk, 1992; Turner & Salt, 1998, 2000). However, GTP wash-out with whole cell recordings and the fact that EPSC peak currents were measured from the extrapolated decay of the preceding EPSC (see Methods) assure that metabotropic currents would not have much bearing on the above estimates of facilitation. As expected, EPSC growth was unaffected with 200µM (S)-MCPG to antagonize Group I metabotropic receptors (P= 0.43, two-factor ANOVA with replication, 3 cells).
Activation of Group III glutamate receptors has been shown to reduce the strength of corticogeniculate synapses, possibly acting directly on the presynaptic terminal (Turner & Salt, 1999). To explore if this receptor influences EPSC growth during trains, the Group III antagonist (RS)-CPPG was added to a final concentration of 100µM (4 cells). The facilitation remained unchanged (P= 0.59, two factor ANOVA with replication), arguing against any major role for metabotropic glutamate receptor activation in the present experiments.
EPSC growth with different train frequencies
The EPSC facilitation varied with stimulation frequency. Double exponential functions with the same time constants as earlier (1= 39 ms and 2= 450 ms) could well describe the EPSC build-up in the frequency range 5–25Hz (pooled data from 10 cells; Fig. 3A). The steady-state facilitation (Fss) inferred by the fitted functions increased linearly with train frequency (Fig. 3B, dotted line). The steady-state level would essentially be attained after 1–2s but corticogeniculate neurones in vivo are unlikely to maintain elevated firing this long. Animals make eye and head movements several times per second in order to prevent fading of stationary stimuli (Ditchburn & Ginsborg, 1952; Fuller, 1985; Chelazzi et al. 1989; Martinez-Conde et al. 2002). Hence, the EPSC amplitude attained at train durations as short as 0.2 and 0.4 s would be physiologically relevant. When the EPSC size ratios were plotted for EPSCs at or immediately preceding t= 0.2 s and 0.4 s they also varied linearly with train frequency. Slopes were similar (
yt = 0.2s= 0.23; yt = 0.4s= 0.25; yt =
= 0.26) but amplitudes were generally lower than for Fss (y0t = 0.2s= 0.86; y0t = 0.4s= 0.99; y0t == 1.7) (Fig. 3B). This simple relationship between facilitation, firing frequency and train duration might be useful in the construction of neuronal network models aimed at probing the function of the corticogeniculate feedback system.
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3= 4.8s) had to be included in the curve fits (Fig. 4A). This component, presumably being augmentation, could solely account for the data at 1Hz. When this time constant was included in triple exponential curve fits f(t) =Fss–K1x exp(–t/1) –K2x exp(–t/2) –K3x exp(–t/3), it did not contribute to the response at train frequencies >10Hz.
The values of K for the different exponentials in the above curve fits are plotted against frequency in Fig. 4C. K1 (fast facilitation) increased linearly with frequencies >2Hz (yK1= 0.20), while the increase of K2 (slow facilitation) was roughly linear at frequencies > 5Hz (yK2= 0.07). K3 (augmentation) contributed at the lowest frequencies but given short gaze holding times, it may be of little relevance in the present context. This component is further investigated and discussed in an accompanying paper (Granseth & Lindström, 2004).
The rate of EPSC growth was most pronounced for the first two or three stimuli at all train frequencies. This was particularly obvious when EPSC ratios were plotted against sequential stimulus number (Fig. 4A). The EPSC3/EPSC1 ratio varied from 78 to 83% (mean 80%) of that for EPSC10/EPSC1 when going from 1 to 25Hz. Most of the EPSC enhancement at the higher frequency came from the fast component of facilitation that did not contribute at all at the lowest frequency. It follows that the pronounced frequency modulation of corticogeniculate EPSCs is primarily due to fast facilitation. Its relative contribution compared to the sum of the two slower components was 3.3:1, as estimated from the yK1: yK2+K3 ratio (0.2/0.06; 77%; Fig. 4C).
EPSC growth at different extracellular calcium ion concentrations
Fast transmitter release is Ca2+-dependent and the same appears to be valid for the mechanism of facilitation (Katz & Miledi, 1968; Zucker & Regehr, 2002; Felmy et al. 2003; Blatow et al. 2003; Trommershäuser et al. 2003). When the Ca2+ inflow into the corticogeniculate terminal was altered by changing [Ca2+]o, there was a dramatic effect on the EPSCs evoked by a 25Hz train. Sample records, at 1.0 and 4.0mM, well below and above the standard [Ca2+]o of 2.0mM, are shown for a representative cell in Fig. 5A. Note that there was no indication of EPSC depression during the trains, not even at the highest Ca2+ level.
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N+[Ca2+]oN). In the functions, amplitudes increased from 0 to EPSCmax, with [Ca2+]o defined by the cooperativity constant (N) and binding constant (K). EPSC1 was less affected by changes in [Ca2+]o than subsequent EPSCs which resulted in a lower value for N (1.6) in the best fit Hill function (EPSCmax was constrained to the same value as for EPSC7). The [Ca2+]o relationship was steeper for EPSC2 and EPSC7, both with similar values for N (2.6 and 2.7, respectively). Furthermore, the apparent K decreased with sequential stimulus number, shifting the curves leftwards in the diagram. Qualitatively similar results were seen in two more cells. These changes in the Hill functions are compatible with a mechanism where substantially more Ca2+ becomes available at the presynaptic Ca2+ sensor with repetitive activity. The physiological [Ca2+]o is at the lower part of the Hill functions, where EPSC amplitudes increase just about exponentially with [Ca2+]o. Facilitation was as a result more prominent in this range of [Ca2+]o (Fig. 5C). This effect was more expressed for EPSC7 than for EPSC2. It was also visible when facilitation for sequential EPSCs in 25Hz trains was compared at three different [Ca2+]o (1.0, 2.0 and 3.0mM; pooled data from 6 cells; Fig. 6). These plots clearly demonstrate that the temporal pattern of EPSC growth changed with [Ca2+]o, in parallel to the absolute amplitudes of evoked EPSCs (Fig. 6A). EPSCs grew more gradually at low [Ca2+]o compatible with a lengthened time constant for the fast facilitation (Fig. 6A, inset). The opposite was true for high [Ca2+]o. This change in the fast time constant corresponds to the increase in N between Hill functions for EPSC1 and EPSC2 (Fig. 5B). Moreover, in the double exponential functions in Fig. 6B, the relative contribution by each component of facilitation (K1 and K2) changes in favour of the fast facilitation with increasing [Ca2+]o.
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Discussion |
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40 and 450ms. The growth of compound EPSCs in the present study was similar to the facilitation previously seen for unitary EPSCs of corticogeniculate fibres (Granseth & Lindström, 2003). At lower frequencies, a third component with time constant of 4.8 s was apparent, presumably representing augmentation (Granseth & Lindström, 2004). Short-term plasticity during trains
It is appealing to ascribe the two time constants that describe EPSC growth during trains to the two components that can be seen in the decay of paired pulse facilitation (Magleby, 1987; Zucker & Regehr, 2002; Granseth et al. 2002). For the simplest model containing two elements of facilitation with immediate onset and separate monoexponential decays, a linear superposition during trains would yield the same time constants for the build-up as for the decay (Helmchen et al. 1996). Such an assumption would be appropriate for facilitation that has been shown to enhance transmitter release independently of the history of preceding release (Katz & Miledi, 1968; Granseth & Lindström, 2003). It would not hold for EPSC depression, since it is a release-dependent process, whether it arises from depletion of transmitter vesicles, receptor desensitization or both (Dittman et al. 2000; Wong et al. 2003).
The build-up time constants for EPSC facilitation during trains were indeed similar, although consistently 3 times slower than the decay time constants for paired pulses previously identified at the corticogeniculate synapse (Granseth et al. 2002). It is unlikely that this disparity originates from a release-dependent activation of metabotropic glutamate receptors since facilitation of corticogeniculate EPSCs was the same in the presence of receptor antagonists. A more likely explanation would be that one or both components of facilitation do not scale linearly during trains. Since facilitation is a Ca2+-dependent process, intracellular Ca2+ buffer binding and diffusion rates could produce such non-linearity. It is, however, noteworthy that the relation between fast and slow time constants was consistent, 2 was 15 times longer than 1 in both growth and decay. Considering the limitations of exponential curve fitting, the moderate disparity between build-up and decay should not be over-emphasized and the two time constants most likely reflect fast and slow components of facilitation. The third time constant (3), identified at trains with low frequency, is likely to result from augmentation since it develops and decays in the range of seconds (Magleby, 1987; Zucker & Regehr, 2002; Granseth & Lindström, 2004).
Facilitation increases the synaptic release probability (Katz & Miledi, 1968; Hanse & Gustafsson, 2001; Granseth & Lindström, 2003; Felmy et al. 2003). At the corticogeniculate synapse, transmitter release is raised >6 times during trains but the store of synaptic vesicles seems not to be depleted with ensuing EPSC depression. Corticogeniculate terminals are small (cross-sectional area 0.5µm2) but they contain large numbers of synaptic vesicles (Erisir et al. 1997). If vesicles located at some distance from the active zone belong to a reserve pool, the competence for maintaining transmitter release during prolonged periods in time should be substantial. However, the rate of mobilization of such reserve vesicles also has to be quite rapid to compensate for the increased transmitter release at high frequencies. The resistance to depletion combined with a low basal synaptic release probability (psyn < 0.1; Granseth & Lindström, 2003) implies that transmitter release at the corticogeniculate synapse is primarily mediated by synaptic vesicles with properties similar to the slowly releasable pool of vesicles identified at the calyx of Held giant synapse (Sakaba & Neher, 2001a,b).
In a recent model it has been suggested that slowly (or reluctantly) releasable vesicles are positioned at some distance from the release-triggering Ca2+ channels at the active zone (Trommershäuser et al. 2003). The unfavourable position with respect to the Ca2+ influx leads to a low vesicular release probability that is susceptible to modulation by intraterminal Ca2+ buffers (Meinrenken et al. 2003). The low cooperativity constant (N) in the Hill function for EPSC1 at the corticogeniculate synapse supports this notion. The trigger for transmitter release is usually considered to bind four or five Ca2+ with positive cooperativity producing an N with the same value (Bollmann et al. 2000; Schneggenburger & Neher, 2000). If the conditions for high cooperativity cannot be fulfilled, such as when [Ca2+] is minute at the calcium sensor and the binding of Ca2+ significantly reduces the concentration of free Ca2+, the constant will be lower (Weiss, 1997). Hence, the particularly low N for EPSC1 could be due to a very small amount of Ca2+ reaching the sensor at the first impulse, consistent with the modest basal release probability.
The fast component of facilitation accounts for most of the modulation of EPSC amplitude in trains of physiological duration. Steady state is essentially reached within 0.2 s of neuronal firing and the contribution by fast facilitation increases linearly with firing frequency (Fig. 4C). This component resembles the ‘pseudofacilitation’ that can be observed after loading synapses with a low amount of a high affinity calcium buffer (Rozov et al. 2001; Blatow et al. 2003). The efficient binding of free Ca2+ by the buffer inhibits transmitter release for the first presynaptic spike but as the free buffer is consumed the buffer capacity starts to saturate. The Ca2+ influx for the next spike would then encounter a partially saturated buffer with more Ca2+ reaching the release trigger. Recent evidence suggests that this kind of facilitation is actually present under normal conditions in neocortical and hippocampal terminals containing the fast Ca2+ buffer calbindin-D28k (Blatow et al. 2003). Since the time constant of fast facilitation at the corticogeniculate synapse was Ca2+ dependent, such an endogenous buffer mechanism might also operate at the present synapse (although the molecular nature of the buffer remains unidentified). A larger amount of Ca2+ entering the presynaptic terminal with an increased [Ca2+]o would saturate an intra-terminal buffer with fewer spikes, resulting in a more rapid time constant describing the build-up of facilitation. At sufficiently low [Ca2+]o the endogenous buffer would not saturate, and the fast time constant would merge with the slow component of facilitation. The reduced paired pulse facilitation at 0.5mM[Ca2+]o encountered in a previous study at the corticogeniculate synapse is in line with this prediction (Granseth et al. 2002; see also Fig. 5C). Further support for an increase in the Ca2+ reaching the release trigger comes from the increase in the cooperativity constant (N) in Hill functions for EPSCs subsequent to EPSC1. However, a facilitation mechanism where Ca2+ remains bound to a high affinity binding site at the secretory trigger could also be surmised (Bertram et al. 1996).
The slow component of facilitation dominates the growth in amplitude after the fast component has reached steady state. Given the short duration of fixation of the retinal image, the slow facilitation has little time to develop and would therefore add only marginally to the attained EPSC amplitude during viewing. It is well established that residual Ca2+ accumulating in the presynaptic terminal with repetitive spikes contributes to synaptic facilitation (Katz & Miledi, 1968; Atluri & Regehr, 1996; Zucker & Regehr, 2002; Felmy et al. 2003). At the corticogeniculate synapse the slow component of facilitation becomes less prominent with higher [Ca2+]o (Fig. 6), in agreement with a direct summation of residual [Ca2+]i at the secretory trigger. If the Ca2+ that remains in the presynaptic terminal adds to the Ca2+ influx of subsequent spikes, the effect on transmitter release will be greatest at the exponentially growing part of the Hill functions, that is at low [Ca2+]o (Rozov et al. 2001; Felmy et al. 2003). The subsistence of [Ca2+]i at the corticogeniculate synapse has, however, not been confirmed with fluorescent Ca2+ dyes or probed with intracellular Ca2+ chelators, as is the case at other synapses (Atluri & Regehr, 1996; Rozov et al. 2001; Felmy et al. 2003; Jackson & Redman, 2003). Such experiments, although elaborate because of the small size of this synapse, are desirable for elucidating the mechanism of corticogeniculate facilitation, not only since it seems unrivalled in magnitude in the central nervous system, but also because it could define the function of the corticothalamic feedback pathway.
Facilitation defines the gain of the neuronal amplifier
The observed EPSC facilitation at different firing frequencies was comparable to findings in the cat in vivo (Lindström & Wróbel, 1990). Since EPSPs evoked in the latter study superimposed on a steady depolarizing shift, the steady-state enhancement was underestimated for high stimulation frequencies. Therefore, trains > 20Hz were excluded when comparing the steady-state facilitation. The linear firing frequency relationship y= 0.23in vivo is then in good agreement with the value obtained in the present study (0.25). This confirms that the marked short-term plasticity is also present under physiological conditions and almost certainly affects the function of the visual system in living animals.
Corticogeniculate feedback has been suggested to function as a neuronal amplifier for the thalamic relay of visual input to the cortex (Ahlsén et al. 1985; Ferster & Lindström, 1985b; Lindström & Wróbel, 1990; Granseth et al. 2002; Granseth & Lindström, 2003). The visually driven feedback excitation would add to the visual input from the retina at the dLGN principal cells and increase the transfer to the primary visual cortex (Fig.7A). As illustrated by the black line in Fig.7B, such mechanism would increase the slope of the theoretical firing rate–input current relationship, in other words, increase the dynamic range of neuronal firing. The increase mediated by the neuronal amplifier is different from a general thalamic depolarization resulting from modulatory input from the brainstem (Ahlsén et al. 1984;McCormick & Bal, 1997; Fjeld et al. 2002), as the latter would have no effect on the dynamic range. A general increase in excitability of the principal cells would rather shift the cell firing to higher frequencies, as illustrated by the grey line in Fig. 7B.
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Acknowledgements |
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Author's present address
B. Granseth: MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, UK.
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) and 3.5 V (
); means ±S.E.M. Note the lack of depression and that the facilitation is similar despite a fourfold increase in EPSC amplitudes.
) and 5Hz (
). Lines are least-sum-of-squares fits of a double exponential function as in 
). Lines are exponential functions with time constants (
; K2, 
; K3,
). Continuous lines are curve fits; for K1 a linear regression between 2 and 25Hz (
, EPSC1; •, EPSC2; 
, EPSC7. Lines are least-sum-of-squares fits of Hill functions, f([Ca2+]o) = EPSCmaxx[Ca2+]oN/(K
