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Interplay Between Facilitation, Depression, and Residual Calcium at Three Presynaptic Terminals

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Interplay Between Facilitation, Depression, and Residual Calcium at Three Presynaptic Terminals The Journal of Neuroscience, February 15, 2000, 20(4):1374–1385 Interplay between Facilitation, Depression, and Residual Calcium at Three Presynaptic Terminals Jeremy S. Dittman, Anatol C. Kreitzer, and Wade G. Regehr Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115 Synapses display remarkable alterations in strength during re- refractory depression. Facilitation is caused by a calcium- petitive use. Different types of synapses exhibit distinctive syn- dependent increase in the probability of release. Refractory aptic plasticity, but the factors giving rise to such diversity are depression is a consequence of release sites becoming tran- not fully understood. To provide the experimental basis for a siently ineffective after release. These sites recover with a time general model of short-term plasticity, we studied three syn- course that is accelerated by elevations of Cares. Facilitation apses in rat brain slices at 34°C: the climbing fiber to Purkinje and refractory depression are coupled by their common depen- cell synapse, the parallel fiber to Purkinje cell synapse, and the dence on Cares and because increased transmitter release Schaffer collateral to CA1 pyramidal cell synapse. These syn- leads to greater synaptic depression. This model captures the apses exhibited a broad range of responses to regular and behavior of three different synapses for various stimulus con- Poisson stimulus trains. Depression dominated at the climbing ditions. The interplay of facilitation and depression dictates fiber synapse, facilitation was prominent at the parallel fiber synaptic strength and variability during repetitive activation. synapse, and both depression and facilitation were apparent in The resulting synaptic plasticity transforms the timing of pre- the Schaffer collateral synapse. These synapses were modeled synaptic spikes into varying postsynaptic response amplitudes. by incorporating mechanisms of short-term plasticity that are Key words: short-term plasticity; residual calcium; cerebellar known to be driven by residual presynaptic calcium (Cares ). In granule cell; cerebellar Purkinje cell; climbing fiber; Schaffer our model, release is the product of two factors: facilitation and collateral; hippocampal CA1 pyramidal cell; synaptic model Fast, chemical synaptic transmission provides the dominant presynaptic properties but identical postsynaptic properties (Fig. means of information transfer between neurons, but presynaptic 1B,C). The temporal pattern of postsynaptic depolarization in action potentials do not all give rise to identical postsynaptic each example reflected the amount of facilitation and depression responses. It has long been known that the history of recent present during periods of high- and low-frequency activity. At activity dynamically regulates the strength of most synapses one synapse, bursts of activity transiently boosted synaptic (Eccles et al., 1941; Feng, 1941; Magleby, 1987; Zucker, 1989). By strength (Fig. 1B). In contrast, the other synapse conveyed the converting trains of action potentials into varying amplitudes of average rate of activity through EPSPs of relatively constant postsynaptic responses, synapses perform a type of temporal amplitude (Fig. 1C). These simulations highlight the importance filtering (Lisman, 1997; Zador and Dobrunz, 1997). This synaptic of understanding presynaptic properties that determine the influ- plasticity results from presynaptic changes in neurotransmitter ence of a neuron on the firing of its targets. release (Varela et al., 1997) and alterations in the responses of To understand the mechanisms underlying presynaptic plastic- postsynaptic neurons to a given amount of transmitter (Trussell ity, it is necessary to consider presynaptic residual calcium and Fischbach, 1989; Magee et al., 1998). In this study, we focus (Cares ) (Zucker, 1999). In contrast to the high calcium levels that on how the temporal pattern of activity influences neurotransmit- trigger transmitter release after presynaptic depolarization (Ͼ10 ter release on the time scale of milliseconds to seconds. ␮ ϳ M for 1 msec), Cares is the modest elevation in calcium levels Synapses show a wide range of responses to high-frequency (hundreds of nanomolar) lasting for hundreds of milliseconds. stimulation such as enhancement, depression, and more complex During periods of high-frequency presynaptic activity, Cares ac- behaviors (Feng, 1941; Eccles et al., 1964; von Gersdorff et al., cumulates and is involved in various short-term plasticities such as 1997; Selig et al., 1999; Kreitzer and Regehr, 2000). This diversity facilitation (Katz and Miledi, 1968; Zucker and Stockbridge, has important implications for the transmission of information in 1983; Kamiya and Zucker, 1994; Atluri and Regehr, 1996), aug- the CNS. To demonstrate the effects of use-dependent plasticity mentation (Zengel et al., 1980; Swandulla et al., 1991; Delaney on synaptic transmission, we considered some possible responses and Tank, 1994), post-tetanic potentiation (Delaney et al., 1989), to a typical spike train recorded in vivo (Fig. 1A). We simulated and recovery from presynaptic depression (Dittman and Regehr, responses to this spike train for two synapses with different 1998; Stevens and Wesseling, 1998; Wang and Kaczmarek, 1998). It is likely that differences in the contribution of various calcium- Received Oct. 8, 1999; revised Nov. 16, 1999; accepted Dec. 6, 1999. dependent mechanisms to synaptic strength will add to the diver- This work was supported by National Institutes of Health Grant R01-NS32405-01. We thank John Assad, Adam Carter, Chinfei Chen, and Matthew Xu-Friedman for sity of synaptic behavior during repetitive activation. comments on this manuscript. Here, we present a simple framework for understanding syn- Correspondence should be addressed to Dr. Wade Regehr, Department of Neu- aptic dynamics in terms of underlying plasticities and Ca .We robiology, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115. res E-mail: [email protected]. build on different aspects of models that were developed previ- Copyright © 2000 Society for Neuroscience 0270-6474/00/201374-12$15.00/0 ously (Magleby, 1987; Abbott et al., 1997; Markram et al., 1998) Dittman et al. • A General Scheme for Synaptic Plasticity J. Neurosci., February 15, 2000, 20(4):1374–1385 1375 solution. The access resistance and leak current (Ϫ20 to Ϫ200 pA holding at Ϫ40 mV) were monitored continuously. Experiments were rejected if either access resistance or leak current increased significantly during recording. Presynaptic fibers were stimulated with two glass electrodes (tip diameter, 10–12 ␮m) filled with external saline solution placed in the molecular layer. Brief pulses (200 ␮sec) of current (5–15 ␮A) were passed between the two stimulating electrodes. This configu- ration greatly reduced the size of the stimulus artifact. The inter-stimulus interval was 2 min for trains of Յ10 stimuli and 3 min for trains of Ͼ10 stimuli. Low stimulus intensities were used to keep initial synaptic currents small (Ϫ50 to Ϫ150 pA) thereby minimizing series resistance errors during the train. Detecting presynaptic calcium transients. Parallel fibers, made up of granule cell axons and presynaptic terminals, were labeled with a high- pressure stream of the low-affinity calcium indicator magnesium green-AM (Molecular Probes, Eugene, OR) (Zhao et al., 1996) using techniques developed previously (Regehr and Atluri, 1995). Parallel fiber tracts were stimulated extracellularly, and epifluorescence was measured with a photodiode from a spot several hundred micrometers from the Figure 1. Effects of presynaptic plasticity on synaptic transmission. A, loading site, where the vast majority of the fluorescence signal arises from parallel fiber presynaptic boutons that synapse onto Purkinje cells. Representative spike train recorded from the basal ganglia of an awake, ⌬ behaving macaque. B, C, Simulated EPSPs resulting from the stimulus in The peak F/F change produced by a single stimulus was used as a linear A (see Materials and Methods). The mean peak EPSPs were the same in measure of presynaptic calcium influx, as established previously (Regehr both examples (i.e., synaptic currents were normalized to give the same and Atluri, 1995). average depolarization). The only difference between the presynaptic Data acquisition and analysis. Outputs of the Axopatch 200A were terminals in B and C is the amount of facilitation and initial release filtered at 1 kHz and digitized at 20 kHz with a 16-bit D/A converter (Instrutech, Great Neck, NY) using Pulse Control software (Herrington probability (F1 ). Comparison of the traces reveals the different temporal patterns of depolarization associated with each type of presynaptic plas- and Bookman, 1995). Random train stimuli were generated off-line and ticity. The postsynaptic cell was simulated using a passive single compart- sent through the DAC to the stimulus isolation unit. Both on- and off-line ␶ ϭ ϭϪ ϭ analysis as well as computer simulations were performed using Igor Pro ment model with parameters m 20 msec, Vrest 70 mV, RN 100 ⍀ ␳ ϭ ϭ ␶ ϭ software (Wavemetrics, Lake Oswego, OR). M . The FD model parameters for B were 3.1, F1 0.05, F 100 ␶ ϭ ϭ Ϫ1 ϭ Ϫ1 ϭ Model of use-dependent plasticity driven by presynaptic calcium. We msec, D 50 msec, kmax 30 sec , ko 2 sec , KD 2. Model parameters for C were ␳ ϭ 2.2, F ϭ 0.24, ␶ ϭ 100 msec, ␶ ϭ 50 msec, modeled the experimentally determined EPSC size as the product of the
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