 |
||||
|
||||
|
||||
|
||||
Previous Article | Next Article
The Journal of Neuroscience, November 1, 1998, 18(21):8770-8779
Presynaptic Induction and Expression of Homosynaptic Depression at Aplysia Sensorimotor Neuron Synapses
Beth A. Armitage and Steven A. Siegelbaum Center for Neurobiology and Behavior, Department of Pharmacology, Columbia University, Howard Hughes Medical Institute, New York, New York 10032
ABSTRACT
Top
Abstract
Introduction
The cellular mechanisms underlying the induction and expression of homosynaptic depression at the glutamatergic synapse between Aplysia sensory and motor neurons were studied in dissociated cell culture. Intracellular microelectrodes were used to stimulate action potentials in the presynaptic sensory neuron and record the depolarizing EPSP from the motor neuron. Homosynaptic depression (HSD) was induced by repeatedly stimulating the sensory neuron at rates as low as one action potential per minute. Activation of postsynaptic Glu receptors was neither sufficient nor necessary to induce HSD. Thus, repeated applications of exogenous Glu did not depress the synaptically evoked EPSP. Moreover, normal HSD was observed when the sensory neuron was stimulated during a period when the Glu receptors were blocked with the antagonist DNQX. The induction of HSD is thus likely to occur within the presynaptic terminal. We explored the role of presynaptic calcium in the induction of HSD by injecting the sensory neuron with EGTA, a relatively slow calcium chelator that does not alter rapid release but effectively buffers the slow residual calcium transient thought to be important for plasticity. EGTA had little effect on HSD, indicating that residual Cai is not involved. HSD does not appear to involve a decrease in presynaptic calcium influx, because there was no change in the presynaptic calcium transient, measured by calcium indicator dyes, during HSD. We conclude that HSD is induced and expressed in the presynaptic terminal, possibly by a mechanism directly coupled to the release process.
Key words: synaptic transmission; synaptic plasticity; Glu receptors; presynaptic calcium; transmitter release; learning and memory
INTRODUCTION
Synaptic plasticity is an important aspect of neuronal function that underlies certain forms of memory and learning in both invertebrates and vertebrates (Hawkins et al., 1993
). It occurs by both heterosynaptic mechanisms in which one synaptic input modifies the efficacy of a second and by homosynaptic mechanisms that are intrinsic to a single synapse. Homosynaptic depression (HSD), a progressive decrease in the amplitude of the postsynaptic potential in response to successive presynaptic stimuli, is one of the simplest examples of synaptic plasticity. Compared with other forms of plasticity that require trains of presynaptic action potentials, such as long-term potentiation (Bliss and Lomo, 1973
Although HSD has been characterized in a number of systems, its mechanism of induction and expression are not completely understood. Here, we investigate the properties of HSD at the well characterized synapse between Aplysia mechanoreceptor sensory neurons and their target motor neurons, in which this form of plasticity is thought to underlie behavioral habituation (Castellucci et al., 1970
Studies using quantal analysis at the sensorimotor neuron synapse in the abdominal ganglion have shown that HSD is caused by a decrease in transmitter release, with no postsynaptic change in the quantal amplitude (Castellucci and Kandel, 1974
Finally, it is not known whether HSD is induced postsynaptically, similar to long-term potentiation and long-term depression (Bear and Malenka, 1994
To address the mechanism of expression and induction of HSD, we studied the monosynaptic connection between a single Aplysia pleural sensory neuron and postsynaptic L7 motor neuron in dissociated cell culture. The transmitter at this synapse is most likely Glu (Dale and Kandel, 1993
MATERIALS AND METHODS
Identified Aplysia pleural sensory neurons and L7 motor neurons were grown together in cell culture to form synapses as described previously (Rayport and Schacher, 1986
A gravity-fed multichamber microperfusion system was used to apply most solutions to the cells, and the reservoirs were enclosed in tin foil to protect the solutions from light. DNQX (Sigma) was used as a 10 µM solution in L-15-ASW and was applied by microperfusion. To ensure a rapid solution exchange necessary for fast and thorough washout of DNQX, the total volume around the cells was maintained at ~25 µl. The L-type calcium channel antagonist nitrendipine (a gift from Miles Pharmaceuticals) was applied at a concentration of 10 µM dissolved in 0.1% EtOH and L-15-ASW and was applied by microperfusion. Serotonin (Sigma) was prepared at a concentration of 10 µM in L-15-ASW and was applied by microperfusion. Glu (Sigma) was dissolved to a concentration of 10 mM in L-15-ASW and adjusted to pH 7.6. This solution was pressure-applied through a pipette with an opening 1-5 µm in diameter, located 10-15 µm from the site of synaptic contact, with a Picospritzer (General Valve, Fairfield, NJ) set to deliver a 100 msec pulse at 15 psi.
Electrical recording was performed using intracellular microelectrodes. When substances were to be injected intracellularly, the electrodes were pulled to have an initial resistance of 50-70 M
when filled with a 0.5 M NaCl solution and then beveled to 30-40 M
For calcium imaging experiments, the presynaptic sensory neuron was loaded with the free acid form of calcium Green-1 (Molecular Probes, Eugene, OR) by iontophoresis from an intracellular microelectrode. The microelectrode was filled with a solution containing 10 mM of the dissolved dye in 0.5 M KCl. Five hundred millisecond hyperpolarizing current pulses (0.1-0.5 nA) applied at 1 Hz for 10-20 min were used to eject the dye. Based on the intensity of staining, we estimate the final dye concentration to be 50-100 µM.
In some experiments, cells were injected with the calcium buffer EGTA from an electrode filled with 100 mM or 1 M K2EGTA. Rhodamine was included in the electrode to determine when the EGTA had diffused to the region of the presynaptic terminals and to estimate its concentration there. This process took 20-30 min and resulted in an EGTA concentration that was 1-10% of that included in the pipette.
Cells were viewed on a Zeiss (Oberkochen, Germany) IM-35 inverted microscope with an Olympus Optical (Tokyo, Japan) 40×/1.30 NA oil immersion objective. Illumination was provided by a Xenon arc lamp and was filtered through a standard FITC filter set. Images were collected by a Hamamatsu intensified CCD camera and stored in analog form on a Panasonic TQ-2026F optical memory disk recorder. The storage of video images to disk was triggered by an electronic signal synchronized with a current pulse that stimulated action potentials in the presynaptic sensory neuron. In this way, full frame images, temporally correlated with presynaptic action potentials, were collected at video rates.
Image analysis was accomplished using the VIDEOPROBE program (ETM Systems, Irvine, CA). We designated several "areas of interest" within a cell, and then the program calculated the average fluorescence intensity of each area in all frames. Regions were selected based on their location (e.g., presynaptic varicosities that contacted the primary motor neuron axon), their morphology (local swellings that were >50% of the neurite diameter), and/or their calcium responses (uniform increase in intensity that was >5 times the SD of the baseline). For each area of interest, the resting intensity values from the five frames before the onset of the train (F) were averaged, as were the intensity values from the five frames starting at the peak value of the calcium concentration transient (Fpeak). The relative amplitude of the calcium transient was then approximated by the ratio
F/F = (Fpeak - F)/F. We did not correct for background fluorescence before loading with indicator dye, because this was negligible compared with the dye signal (<10%).
For all statistical analyses of significance, a paired Student's t test was used. Error values and error bars reflect SE of the mean.
RESULTS
Effects of postsynaptic activation on HSD
An initial set of experiments was aimed at elucidating the site of induction of HSD. As shown in Figure 1A, repeated stimulation of the presynaptic sensory neuron at a rate of one action potential per minute induced a cumulative depression in the EPSP recorded from the motor neuron, which reached a steady-state level after five to seven presynaptic stimuli, which was ~30% of the initial EPSP amplitude. To test whether postsynaptic activity alone is sufficient to induce HSD, we gave repeated pulses (100 msec) of exogenous Glu to induce depolarizing postsynaptic responses of similar magnitude to the synaptically generated EPSPs (Fig. 1A). To maximize the likelihood that the same receptors activated in response to sensory neuron stimulation were also activated by the exogenous Glu, we applied the transmitter to the region of the motor neuron that was innervated by the sensory neuron, as determined by imaging of presynaptic terminals. In any given motor neuron, the amplitude of the depolarization in response to exogenous Glu ranged from 0.2 to 3 times the amplitude of the EPSP evoked by presynaptic stimulation. Unlike the evoked responses, the depolarizing responses to repetitive Glu applications at 1 min intervals showed no significant change in average amplitude (Fig. 1B). This suggests that either the induction and/or the expression of HSD must have a presynaptic component.
View larger version (14K):[in this window]
[in a new window]
Figure 1. Glu receptor activation is not sufficient to induce HSD. A, Effect of Glu at a representative sensory to motor neuron synapse. A1, HSD in response to low-frequency presynaptic stimulation. EPSPs were recorded from a postsynaptic motor neuron in response to intracellular stimulation of presynaptic action potentials in a sensory neuron. Responses were elicited at 1 min intervals. A2, The effect of exogenous Glu application on synaptically evoked EPSP. The first trace (bold) shows the first EPSP recorded from a motor neuron in response to firing an action potential in the presynaptic sensory neuron. Five brief Glu pulses (100 msec) were then applied from a puffer pipette to elicit postsynaptic depolarizations (thin traces) of approximately equal amplitude to the synaptically evoked EPSP. The final trace (bold) is a second synaptically evoked EPSP. All responses were elicited at 1 min intervals. Calibration: A1, 10 mV, 100 msec; A2, 10 mV, 250 msec. B, Summary of mean data for Glu applications. Protocol is identical to that shown in A. For each synapse analyzed using presynaptic stimulation, the amplitudes of the EPSPs evoked during successive presynaptic stimuli were normalized to that of the first EPSP (triangles, Control). The amplitudes of depolarizing responses to exogenous Glu were normalized to the first response to Glu (small squares, +Glu). In the same experiments, the EPSP evoked by presynaptic stimulation after the Glu pulses was normalized to the first evoked EPSP before the Glu pulses (large squares). The normalized responses were then averaged among the different cells. Triangles, n = 4; squares, n = 5. Error bars indicate SEM.
Although postsynaptic receptor activation does not depress the response to exogenous Glu application, it is possible that it may depress the EPSP evoked by presynaptic stimulation. To investigate this possibility, we measured the postsynaptic response to a presynaptic action potential before and after five repeated applications of exogenous Glu. The amplitude of the evoked response 1 min after the last of five Glu applications was not significantly different from the amplitude of the first evoked response (95 ± 6 vs 100%; n = 5; p > 0.25) (Fig. 1B). This is in sharp contrast to the result when five presynaptic action potentials were substituted for the five exogenous applications of Glu. In this case, a robust depression occurred in which the amplitude of the last EPSP was significantly different from that of the initial event (34 ± 8 vs 100%; n = 4; p < 0.01) (Fig. 1B).
Effects of presynaptic activation on HSD
The above results show that postsynaptic Glu receptor activation is not sufficient to induce HSD. The next question we addressed was whether activation of the postsynaptic receptors that underlie the fast EPSP is necessary for the induction of HSD or whether presynaptic activity alone is sufficient. We evoked presynaptic action potentials while the postsynaptic Glu receptors were blocked with DNQX (Fig. 2), an effective antagonist of the Glu receptors at this synapse (Dale and Kandel, 1993
View larger version (15K):[in this window]
[in a new window]
Figure 2. Effect of blockade of postsynaptic Glu receptors on induction of HSD. EPSPs were recorded from a postsynaptic motor neuron (top traces) in response to intracellular stimulation of action potentials in a presynaptic sensory neuron once per minute (bottom traces). After the first stimulus, 10 µM DNQX (filled bar) was applied by microperfusion. After the fifth stimulus, presynaptic stimulation was halted, and DNQX was washed out for a period of 10 min. Presynaptic stimulation was then resumed.
View larger version (14K):[in this window]
[in a new window]
Figure 3. Activation of ionotropic Glu receptors is not required for induction of HSD. Mean data shown for induction of HSD during three experimental protocols to test the effects of DNQX. The first protocol is similar to that shown in Figure 2 (triangles). The presynaptic cell was first stimulated to evoke an EPSP (left point, 0 min). Cells were then exposed to 10 µM DNQX for 10 min (bottom bar). In the continued presence of DNQX, eight additional presynaptic stimuli were applied at a rate of one per minute (middle points, 11-18 min). The DNQX was then washed from the bath for 10 min, and eight more presynaptic stimuli were applied (right points, 28-35 min). The second protocol was identical to the first, except that the cells were not exposed to DNQX (squares). In the third protocol, cells were exposed to DNQX as in the first protocol, except that the first group of eight presynaptic stimuli during DNQX were omitted (circles). For each cell, EPSP amplitudes were normalized to the first EPSP, and then the normalized values in each group were averaged. n = 5 for each protocol.
To compare the extent of depression when the presynaptic cell alone was activated to that observed when activity occurred in both cells, a group of control cells received an identical presynaptic stimulation protocol but without DNQX application (Fig. 3). The amplitudes of all EPSPs in a given cell were normalized to the initial response to allow comparisons among cells. There was virtually no difference in the extent of HSD between the DNQX-treated cells and the control cells, as determined by the average normalized amplitude of the EPSPs in response to the second series of presynaptic stimuli (n = 5).
A trivial explanation for the decreased EPSP amplitude after the presynaptic stimuli in the presence of DNQX is that the postsynaptic receptors had not fully recovered from blockade, so that the postsynaptic response remained partially inhibited, independent of any HSD. To rule out this possibility, a second control experiment was performed in which a group of cells was treated identically to the DNQX-treated cells (as above) but without the first series of presynaptic action potentials (n = 5). For these cells, the response to the first stimulus of the second series of action potentials showed no significant decrease as a result of the DNQX treatment when compared with the initial EPSP, demonstrating that 10 min was sufficient for complete washout of DNQX (Fig. 3). From these experiments, we conclude that presynaptic stimulation alone is sufficient to induce robust HSD independent of postsynaptic receptor activation.
Induction of HSD is not mediated by residual presynaptic Cai
Because HSD appears to be both induced and expressed presynaptically, we next investigated the potential role that presynaptic Ca influx plays in the induction of HSD, given the important role of Cai in other forms of synaptic plasticity. Because a rise in Cai triggers transmitter release, it was necessary to dissociate any slow modulatory effect of increased Cai that may underlie HSD from the rapid transient Cai increase that mediates transmitter release. To accomplish this, we injected the slow calcium buffer EGTA into the presynaptic cell. At the squid giant synapse, EGTA has been shown to be relatively ineffective in altering fast transmitter release, presumably because the kinetics of Ca binding to the buffer are too slow to affect the large rapid Cai transient near the membrane (Smith et al., 1984
We used two different concentrations of EGTA in the microelectrodes, 100 and 1 M, which should result in 1-10 or 10-100 mM concentrations of EGTA, respectively, at the axon terminals. This estimate was based on a comparison of rhodamine fluorescence in the electrodes and terminals. Rhodamine has a similar size (577 MW) to EGTA (380 MW), distributes uniformly throughout the cytoplasm, and has a fluorescence intensity sufficient to allow rapid measurement at low light levels, thereby minimizing photodamage.
Experimental support that EGTA actually reached the synaptic terminals at sufficient concentrations to buffer calcium effectively was provided by the observation that EGTA injection inhibited synaptic transmission. Thus, when the synapse was tested once before loading with EGTA and then stimulated 30 min later, the EPSP was decreased to 80 and 36% of its initial amplitude with electrodes containing 100 and 1 M EGTA, respectively. The 30 min interval between preloading and postloading stimuli is too long to produce any significant HSD. Thus, the decrease in synaptic strength most likely reflects altered Cai buffering by EGTA. Apparently, fast release at the Aplysia sensorimotor neuron synapse is more sensitive to EGTA than the squid giant synapse.
Despite the decrease in synaptic transmission, marked HSD persisted in response to a series of presynaptic action potentials in experiments using electrodes containing either 100 or 1 M EGTA. The magnitude and time course of the HSD was not substantially different from the HSD under control conditions. After eight presynaptic stimuli, the EPSP was decreased on average to 43% of its initial amplitude in control cells (n = 3), to 40% of its initial amplitude in cells injected with 100 mM EGTA (n = 2), and to 51% of its initial amplitude in a cell injected with 1 M EGTA (n = 1) (Fig. 4). Thus, HSD does not appear to depend on a residual increase in Cai (although we cannot rule out the possibility that there was some residual Cai transient that was not altered by the EGTA).
View larger version (12K):[in this window]
[in a new window]
Figure 4. Presynaptic injection of EGTA does not inhibit induction of HSD. Peak EPSP amplitudes from four motor neurons are plotted in response to successive stimulation of the sensory neurons. EPSP amplitudes are normalized to that of the first EPSP. In two cells, the presynaptic microelectrode contained 100 mM EGTA (diamonds), and in a third cell, the microelectrode contained 1 M EGTA (triangles). In a control cell, the presynaptic electrode did not contain EGTA (squares). The presynaptic cell was stimulated at 20 sec intervals. Before these measurements were obtained, solution was ejected from the presynaptic electrode using 500 msec pressure pulses.
HSD is not associated with altered calcium transients in presynaptic terminals
We next investigated the expression of HSD by testing the hypothesis that the decrease in transmitter release is a result of inhibition of voltage-dependent calcium influx (Klein et al., 1980
Two possible mechanisms for HSD that depend on changes in Ca influx were investigated. The first involves a progressive decrease in calcium influx into presynaptic terminals in response to successive stimuli. To address this possibility, we evaluated the Cai signals in presynaptic varicosities, local swellings of the thin axonal branches of the sensory neuron that have been shown to contain active zones (Glanzman et al., 1989
View larger version (16K):[in this window]
[in a new window]
Figure 5. Ca influx in a single presynaptic varicosity does not change during induction of HSD. Cai transients, plotted as
We obtained images of Cai using the
View larger version (K):[in this window]
[in a new window]
Figure 6. Spatial distribution of Cai influx does not change during HSD. Pseudocolor images of the peak calcium response (
The presynaptic Cai transient was measured in a total of 38 varicosities from nine sensory cells while the EPSP was simultaneously recorded from the postsynaptic motor neuron. Whereas the EPSP produced in the motor neuron elicited by successive action potentials during the train showed a progressive depression, there was virtually no change in the mean size of the Cai transient elicited by successive action potentials (Fig. 7). The average amplitude of the calcium transient in response to the sixth stimulus was 107 ± 6% (n = 38) of the Cai transient amplitude in response to the first stimulus (100%; p > 0.1). In contrast, the average EPSP in these same cells in response to the sixth stimulus decreased to 37 ± 4% (n = 9) of its size relative to the first stimulus (100%; p < 0.0005). Therefore, despite the substantial decrease in transmitter release during HSD, there is no change in calcium influx in the presynaptic boutons.
View larger version (9K):[in this window]
[in a new window]
Figure 7. Mean data for Cai transient amplitude during HSD. The mean peak amplitude of the presynaptic Cai transient (
Although we observed no change in the average Cai transient in these experiments, we considered a second possible mechanism for HSD that involves a decrease in Ca influx that could be obscured by this averaging. Thus, if HSD were caused by a failure of the action potential to invade a subset of presynaptic boutons, the Cai transient averaged among all boutons might not change dramatically (for example, if the Cai transient were to increase in boutons that remained excitable). To investigate this possibility, we followed the behavior of a large number of individual varicosities in response to the six action potentials triggered at 20 sec intervals (Fig. 8). Among varicosities that showed a Cai transient in response to the first action potential, there was never an instance in which a subsequent action potential failed to elicit a measurable change in calcium concentration. In only 3 of 38 varicosities did the transient fall below 50% of its initial value (Fig. 8). In addition, in sites in which there was a decrease in calcium transient amplitude, there were only two instances in which this decrease was maintained throughout the train of action potentials (subsequent responses being equal to or less than previous responses). In all the other cases, the amplitude of the Cai transient fluctuated up and down during the action potential train. Therefore, the number of presynaptic boutons responding to an action potential remained relatively constant and cannot explain the accompanying decrease in transmitter release caused by HSD.
View larger version (107K):[in this window]
[in a new window]
Figure 8. Multiple stimuli activate a constant number of varicosities. Calcium responses in individual varicosities from presynaptic sensory neurons were measured in response to successive action potentials used to induce HSD (n = 38). For each varicosity, the amplitude of the calcium transient in response to each successive action potential,
DISCUSSION
The induction of HSD is presynaptic
The above results suggest that the induction of HSD is presynaptic. Thus, when the postsynaptic cell was stimulated by exogenous Glu, no depression resulted. A trivial explanation for this failure to induce HSD is that Glu is not the endogenous transmitter. Although definitive proof is lacking, two lines of evidence support Glu as the sensory neuron transmitter (Dale and Kandel, 1993
As a second approach to investigate the site of induction of HSD, we stimulated the presynaptic cell in the presence of DNQX to block the postsynaptic response. Under these conditions, the synapse became depressed to the same extent to that which occurred with stimulation in the absence of DNQX. Although the simplest interpretation of the above two results is that the induction of HSD is presynaptic, there are two schemes consistent with a role for the postsynaptic cell. In the first scheme, induction of HSD would result from the co-release of a substance with Glu from presynaptic terminals. This would explain why Glu application did not induce HSD and why depression occurred in the presence of Glu receptor antagonists. One candidate cotransmitter is the sensory neuron peptide sensorin (Brunet et al., 1991
Residual calcium is not the induction event
There are three principal components of presynaptic activity that could induce HSD: (1) calcium influx, (2) transmitter release acting on presynaptic receptors, and (3) vesicle fusion.
The calcium influx during an action potential could trigger a second messenger pathway that modulates transmitter release. When calcium first enters the cell, it exists momentarily within domains of high concentration localized just under the membrane, which are required to trigger exocytosis of synaptic vesicles. The calcium then rapidly diffuses down its steep concentration gradient to the surrounding cytoplasm, producing a relatively small longer-lasting elevation in Cai concentration. This residual Cai has been implicated in other forms of synaptic plasticity, most notably PTP (Swandulla et al., 1991
A second possible mechanism for HSD depends on a presynaptic feedback mechanism in which one or more transmitters act on presynaptic receptors to induce HSD. Activation of presynaptic Glu receptors alone is not sufficient to induce HSD, because application of exogenous Glu to the synaptic region did not change the synaptic strength. However, induction may require simultaneous receptor binding and presynaptic activity and/or binding of a cotransmitter (e.g., sensorin) to its presynaptic receptor.
The third possibility is that induction of HSD could result from the fusion event itself and not directly depend on an effect of any substances that are released. It is now known that there are numerous proteins on the vesicle surface, on the plasma membrane, and in the cytoplasm, which interact to regulate vesicle fusion (Sudhof, 1995
The expression of HSD is not caused by decreased calcium influx
Quantal analysis demonstrated that the expression of HSD is presynaptic (Castellucci and Kandel, 1974
One potential mechanism for the depression of Ca-evoked transmitter release is via a decrease of Ca influx associated with a presynaptic action potential. It has been shown that the voltage-gated calcium current measured in the sensory cell body undergoes a use-dependent decrease caused by cumulative inactivation during trains of action potentials that induce HSD (Klein et al., 1980
Using fluorescence microscopy, we directly measured the calcium transient in response to single presynaptic action potentials in regions of the presynaptic cell that are likely to correspond to the presynaptic terminals (Glanzman et al., 1989
Our results thus indicate that both the induction and expression of HSD may be an integral part of the release process itself. With an expanding knowledge of the fusion process and of the molecular components of the release apparatus, it may soon be possible to test the role of specific presynaptic proteins. In particular, future studies of genetically modified animals offer the promise of identifying specific proteins involved in homosynaptic depression.
FOOTNOTES Received March 20, 1998; revised Aug. 10, 1998; accepted Aug. 10, 1998.
This work was partly supported by National Institute of Mental Health Grant P50-MH50733. We thank Huan Yao for expert technical assistance in preparing the Aplysia cultures and Eric Kandel and Bob Hawkins for critical reading of this manuscript.
Correspondence should be addressed to Steven A. Siegelbaum, Center for Neurobiology and Behavior, Columbia University, 722 W. 168 Street, New York, NY 10032.
REFERENCES
- Adler EM, Augustine GJ, Duffy SN, Charlton MP (1991) Alien intracellular calcium chelators attenuate neurotransmitter release at the squid giant synapse. J Neurosci 11:1496-1507[Abstract].
- Bailey CH, Chen M (1988) Morphological basis of short-term habituation in Aplysia. J Neurosci 8:2452-2459[Abstract].
- Bao JX, Kandel ER, Hawkins RD (1997) Involvement of pre- and postsynaptic mechanisms in posttetanic potentiation at Aplysia synapses. Science 275:969-973
[Abstract/Free Full Text] .- Bear MF, Malenka RC (1994) Synaptic plasticity: LTP and LTD. Curr Opin Neurobiol 3:389-399.
- Bliss TV, Lomo T (1973) Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path. J Physiol (Lond) 232:331-356
[Abstract/Free Full Text] .- Brunet JF, Shapiro E, Foster SA, Kandel ER, Iino Y (1991) Identification of a peptide specific for Aplysia sensory neurons by PCR-based differential screening. Science 252:856-859
[Abstract/Free Full Text] .- Byrne JH (1982) Analysis of synaptic depression contributing to habituation of gill-withdrawal reflex in Aplysia californica. J Neurophysiol 48:431-438
[Abstract/Free Full Text] .- Castellucci V, Pinsker H, Kupfermann I, Kandel ER (1970) Neuronal mechanisms of habituation and dishabituation of the gill-withdrawal reflex in Aplysia. Science 167:1745-1748
[Abstract/Free Full Text] .- Castellucci VF, Kandel ER (1974) A quantal analysis of the synaptic depression underlying habituation of the gill-withdrawal reflex in Aplysia. Proc Natl Acad Sci USA 71:5004-5008
[Abstract/Free Full Text] .- Dale N, Kandel ER (1993) L-Glutamate may be the fast excitatory transmitter of Aplysia sensory neurons. Proc Natl Acad Sci USA 90:7163-7167
[Abstract/Free Full Text] .- Dudek SM, Bear MF (1992) Homosynaptic long-term depression in area CA1 of hippocampus and effects of N-methyl-D-aspartate receptor blockade. Proc Natl Acad Sci USA 89:4363-4367
[Abstract/Free Full Text] .- Edmonds B, Klein M, Dale N, Kandel ER (1990) Contributions of two types of calcium channels to synaptic transmission and plasticity. Science 250:1142-1147
[Abstract/Free Full Text] .- Eliot LS (1991) Presynaptic modulation of Aplysia sensory-to-motor neuron synapses in culture. PhD thesis, Columbia University.
- Eliot LS, Kandel ER, Siegelbaum SA, Blumenfeld H (1993) Imaging terminals of Aplysia sensory neurons demonstrates role of enhanced Ca2+ influx in presynaptic facilitation. Nature 361:634-637[Medline].
- Eliot LS, Kandel ER, Hawkins RD (1994) Modulation of spontaneous transmitter release during depression and posttetanic potentiation of Aplysia sensory-motor neuron synapses isolated in culture. J Neurosci 14:3280-3292[Abstract].
- Fischer TM, Zucker RS, Carew TJ (1997) Activity-dependent potentiation of synaptic transmission from L30 inhibitory interneurons of Aplysia depends on residual presynaptic Ca2+ but not on postsynaptic Ca2+. J Neurophysiol 78:2061-2071
[Abstract/Free Full Text] .- Gingrich KJ, Byrne JH (1985) Simulation of synaptic depression, posttetanic potentiation, and presynaptic facilitation of synaptic potentials from sensory neurons mediating gill-withdrawal reflex in Aplysia. J Neurophysiol 53:652-669
[Abstract/Free Full Text] .- Glanzman DL, Kandel ER, Schacher S (1989) Identified target motor neuron regulates neurite outgrowth and synapse formation of Aplysia sensory neurons in vitro. Neuron 3:441-450[ISI][Medline].
- Hawkins RD, Kandel ER, Siegelbaum SA (1993) Learning to modulate transmitter release: themes and variations in synaptic plasticity. Annu Rev Neurosci 16:625-665[ISI][Medline].
- Klein M, Shapiro E, Kandel ER (1980) Synaptic plasticity and the modulation of the Ca2+ current. J Exp Biol 89:117-157
[Free Full Text] .- Rayport SG, Schacher S (1986) Synaptic plasticity in vitro: cell culture of identified. Aplysia neurons mediating short-term habituation and sensitization. J Neurosci 6:759-763[Abstract].
- Regehr WG, Delaney KR, Tank DW (1994) The role of presynaptic calcium in short-term enhancement at the hippocampal mossy fiber synapse. J Neurosci 14:523-537[Abstract].
- Santarelli L, Montarolo P, Schacher S (1996) Neuropeptide localization in varicosities of Aplysia sensory neurons is regulated by target and neuromodulators evoking long-term synaptic plasticity. J Neurobiol 31:297-308[ISI][Medline].
- Smith PD, Liesegang GW, Berger RL, Czerlinski KG, Pjoldolsky RJ (1984) A stopped-flow investigation of calcium ion binding by ethylene glycol bis(beta-aminoethyl ether)-N,N'-tetraacetic acid. Anal Biochem 143:188-195[ISI][Medline].
- Sudhof TC (1995) The synaptic vesicle cycle: a cascade of protein-protein interactions. Nature 375:645-653[Medline].
- Swandulla D, Hans M, Zipser K, Augustine GJ (1991) Role of residual calcium in synaptic depression and posttetanic potentiation: fast and slow calcium signaling in nerve terminals. Neuron 7:915-926[ISI][Medline].
- Trudeau LE, Castellucci VF (1993) Excitatory amino acid neurotransmission at sensory-motor and interneuronal synapses of Aplysia californica. J Neurophysiol 70:1221-1230
[Abstract/Free Full Text] .
Copyright © 1998 Society for Neuroscience 0270-6474/98/18218770-10$05.00/0
This article has been cited by other articles:
D. Fioravante, R.-Y. Liu, A. K. Netek, L. J. Cleary, and J. H. Byrne
Synapsin Regulates Basal Synaptic Strength, Synaptic Depression, and Serotonin-Induced Facilitation of Sensorimotor Synapses in Aplysia
J Neurophysiol, December 1, 2007; 98(6): 3568 - 3580.
[Abstract] [Full Text] [PDF]
G. Houeland, A. Nakhost, W. S. Sossin, and V. F. Castellucci
PKC Modulation of Transmitter Release by SNAP-25 at Sensory-to-Motor Synapses in Aplysia
J Neurophysiol, January 1, 2007; 97(1): 134 - 143.
[Abstract] [Full Text] [PDF]
P. Lovell and L. L. Moroz
The largest growth cones in the animal kingdom: an illustrated guide to the dynamics of Aplysia neuronal growth in cell culture
Integr. Comp. Biol., December 1, 2006; 46(6): 847 - 870.
[Abstract] [Full Text] [PDF]
Y.-J. Sung, F. Wu, S. Schacher, and R. T. Ambron
Synaptogenesis regulates axotomy-induced activation of c-Jun-activator protein-1 transcription.
J. Neurosci., June 14, 2006; 26(24): 6439 - 6449.
[Abstract] [Full Text] [PDF]
D. L. Glanzman
The Cellular Mechanisms of Learning in Aplysia: Of Blind Men and Elephants
Biol. Bull., June 1, 2006; 210(3): 271 - 279.
[Abstract] [Full Text] [PDF]
Y. Wu, F. Kawasaki, and R. W. Ordway
Properties of Short-Term Synaptic Depression at Larval Neuromuscular Synapses in Wild-Type and Temperature-Sensitive Paralytic Mutants of Drosophila
J Neurophysiol, May 1, 2005; 93(5): 2396 - 2405.
[Abstract] [Full Text] [PDF]
O. Khabour, J. Levenson, L. C. Lyons, L. S. Kategaya, J. Chin, J. H. Byrne, and A. Eskin
Coregulation of Glutamate Uptake and Long-Term Sensitization in Aplysia
J. Neurosci., October 6, 2004; 24(40): 8829 - 8837.
[Abstract] [Full Text] [PDF]
Y. Ezzeddine and D. L. Glanzman
Prolonged Habituation of the Gill-Withdrawal Reflex in Aplysia Depends on Protein Synthesis, Protein Phosphatase Activity, and Postsynaptic Glutamate Receptors
J. Neurosci., October 22, 2003; 23(29): 9585 - 9594.
[Abstract] [Full Text] [PDF]
J. K. Rose, K. R. Kaun, S. H. Chen, and C. H. Rankin
GLR-1, a Non-NMDA Glutamate Receptor Homolog, Is Critical for Long-Term Memory in Caenorhabditis elegans
J. Neurosci., October 22, 2003; 23(29): 9595 - 9599.
[Abstract] [Full Text] [PDF]
E. G. Antzoulatos, L. J. Cleary, A. Eskin, D. A. Baxter, and J. H. Byrne
Desensitization of Postsynaptic Glutamate Receptors Contributes to High-Frequency Homosynaptic Depression of Aplysia Sensorimotor Connections
Learn. Mem., September 1, 2003; 10(5): 309 - 313.
[Abstract] [Full Text] [PDF]
Y. Zhao and M. Klein
Modulation of the Readily Releasable Pool of Transmitter and of Excitation-Secretion Coupling by Activity and by Serotonin at Aplysia Sensorimotor Synapses in Culture
J. Neurosci., December 15, 2002; 22(24): 10671 - 10679.
[Abstract] [Full Text] [PDF]
T. D. Gover, X.-Y. Jiang, and T. W. Abrams
Persistent, Exocytosis-Independent Silencing of Release Sites Underlies Homosynaptic Depression at Sensory Synapses in Aplysia
J. Neurosci., March 1, 2002; 22(5): 1942 - 1955.
[Abstract] [Full Text] [PDF]
A. S. Bristol, T. M. Fischer, and T. J. Carew
Combined Effects of Intrinsic Facilitation and Modulatory Inhibition of Identified Interneurons in the Siphon Withdrawal Circuitry of Aplysia
J. Neurosci., November 15, 2001; 21(22): 8990 - 9000.
[Abstract] [Full Text] [PDF]
