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© The Rockefeller University Press,
0021-9525/2003/11/511 $8.00
The Journal of Cell Biology, Volume 163, Number 3, 511-523
Article |
Ca2+ influx–independent synaptic potentiation mediated by mitochondrial Na+-Ca2+ exchanger and protein kinase C
Address correspondence to Bai Lu, Section on Neural Development and Plasticity, NICHD, NIH, Building 49, Rm. 6A80, 49 Convent Dr., Bethesda, MD 20892-4480. Tel.: (301) 435-2970. Fax: (301) 496-1777. email: bailu{at}mail.nih.gov
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Abstract |
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Activity-dependent modulation of synaptic transmission is an essential mechanism underlying many brain functions. Here we report an unusual form of synaptic modulation that depends on Na+ influx and mitochondrial Na+-Ca2+ exchanger, but not on Ca2+ influx. In Ca2+-free medium, tetanic stimulation of Xenopus motoneurons induced a striking potentiation of transmitter release at neuromuscular synapses. Inhibition of either Na+ influx or the rise of Ca2+ concentrations ([Ca2+]i) at nerve terminals prevented the tetanus-induced synaptic potentiation (TISP). Blockade of Ca2+ release from mitochondrial Na+-Ca2+ exchanger, but not from ER Ca2+ stores, also inhibited TISP. Tetanic stimulation in Ca2+-free medium elicited an increase in [Ca2+]i, which was prevented by inhibition of Na+ influx or mitochondrial Ca2+ release. Inhibition of PKC blocked the TISP as well as mitochondrial Ca2+ release. These results reveal a novel form of synaptic plasticity and suggest a role of PKC in mitochondrial Ca2+ release during synaptic transmission.
Key Words: synaptic plasticity; neuromuscular junction; mitochondria; Na+-Ca2+ exchanger; Ca2+ influx
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Introduction |
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Although it is generally believed that presynaptic forms of plasticity are due to a prolonged elevation of intracellular concentrations of free Ca2+ ([Ca2+]i) after the termination of tetanus, the precise molecular mechanisms for the enhancement of transmitter secretion remain unclear. At the resting nerve terminals, [Ca2+]i is generally <100 nM. This is accomplished by the Ca2+ ATPase, which effectively pumps Ca2+ out of the terminals, and by the plasmalemmal Na+-Ca2+ exchanger, which allows entry of three Na+ in exchange for the efflux of one Ca2+ (Blaustein and Lederer, 1999; Garcia and Strehler, 1999). The key step in triggering transmitter secretion is an elevation of terminal [Ca2+]i. This could be achieved by a number of mechanisms. First, a well-established mechanism is the action potential–driven membrane depolarization, leading to Ca2+ influx through voltage-gated Ca2+ channels. The second and more complex mechanism is the release of Ca2+ from intracellular organelles. One class of such organelles is the ER. Two types of ligand-gated Ca2+ channels are involved in Ca2+ release from the ER: the IP3 receptor, operated by inositol 1,4,5-trisphosphate (IP3), and the ryanodine receptor, gated by Ca2+ as well as cyclic ADP ribose (Berridge, 1998). Although still a fairly new concept, transmitter secretion triggered or modulated by Ca2+ release from the ER has been shown in a number of synapses (Smith and Cunnane, 1996; Cochilla and Alford, 1998; Mothet et al., 1998; Yang et al., 2001). The other class of organelles is mitochondria, which represents a transient storage mechanism for Ca2+. An accumulation of Ca2+ in the mitochondria induced by certain stimuli is released when the stimulus is terminated (Tang and Zucker, 1997; Melamed-Book and Rahamimoff, 1998). Under physiological conditions, mitochondrial Ca2+ release is achieved primarily by the Na+-Ca2+ exchanger on the mitochondrial membranes. It has been recently shown that the massive secretion of transmitters at the NMJ induced by 
-latrotoxin is mediated by the mitochondrial Na+-Ca2+ exchanger (Tsang et al., 2000). Finally, when cells are overloaded with Na+ and extracellular Ca2+ is high, the plasmalemmal Na+-Ca2+ exchanger may operate in a "reverse mode" to allow Ca2+ entry into the cells (Zhong et al., 2001).
Many forms of activity-dependent synaptic plasticity require Ca2+ influx. Using a cultured neuromuscular synapse preparation in which Ca2+ influx has been completely prohibited, we report here a novel form of synaptic plasticity that would be difficult to reveal in normal circumstances. A train of tetanic stimulation induces a robust potentiation of neurotransmitter release, as well as an increase in [Ca2+]i, at the developing NMJ in the absence of extracellular Ca2+. Detailed analyses using both pharmacological and molecular approaches indicate that this synaptic potentiation is independent of Ca2+ release from ER ryanodine or IP3 receptors, but requires Na+ influx. The increase in Na+ concentration in the nerve terminals triggers Ca2+ efflux through the mitochondrial Na+-Ca2+ exchanger, leading to the tetanus-induced synaptic potentiation (TISP). In addition, inhibition of PKC dramatically attenuated TISP as well as mitochondrial Ca2+ release. We also show that blockade of the mitochondrial Na+-Ca2+ exchanger inhibits the synaptic potentiation and [Ca2+]i increase in normal extracellular Ca2+. Thus, this form of synaptic plasticity may occur during the bursting activity at the NMJ in vivo. Our studies may also help understand the contribution of mitochondria and PKC in transmitter release and provide a useful model to investigate molecular mechanisms for transmitter release without the interference of Ca2+ influx.
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Results |
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10-fold increase in SSC frequency could be induced by stimulation at 2–10 Hz (Fig. 1 C, left). At 50 Hz, the synaptic potentiation reached a new level, and stimulation frequency >50 Hz did not induce further potentiation (unpublished data). In medium containing normal [Ca2+]o, synaptic efficacy was increased almost immediately after the application of the tetanus (Fig. 1 A). In Ca2+-free medium, the SSC frequency began to rise 1–2 min after the tetanus, and the maximal enhancement was usually observed 5–10 min later (Fig. 1 C, middle). After the peak, the SSC frequency gradually decreased, but it never returned to baseline for as long as the recording can be held (up to 60 min).
Dependence on Na+ influx and the rise of intracellular Ca2+
Two effects are elicited by tetanic stimulation of presynaptic neurons in normal conditions: repetitive firing of high frequency action potentials and large influx of Ca2+. As the TISP was completely independent of Ca2+ influx, we tested the role of action potentials in this unusual form of plasticity. Firing of action potentials results from a rapid and large Na+ influx, followed by a delayed efflux of K+ ions. To determine whether the TIPS is mediated by Na+ influx, we reduced Na+ concentration in the extracellular medium ([Na+]o) by half (from 115 mM to 57.5 mM), by replacing Na+ with N-methyl-D-glucamine (NMDG) (Simasko, 1994). Patch recordings were made on the nerve terminals distal to the synapses made between motor axons and muscle cells (Fig. 2 A). At this low [Na+]o, electric stimulation could still reliably induce action potentials, with lower amplitudes (Fig. 2 C). Moreover, action potentials could be recorded at these terminals during the entire course of the tetanic stimulation, suggesting that action potentials fully invaded the presynaptic terminals (Fig. 2 B). Under the low [Na+]o conditions, however, the effect of tetanus was dramatically reduced (Fig. 3 A). SSC frequency increased by 68-fold after tetanic stimulation in normal Na+ medium, but showed only fivefold increase when [Na+]o was reduced to 57.5 mM (Fig. 3 B). To test whether Na+ influx into the nerve terminals is required for TISP, we inhibited Na+ channels at the terminals by rapid perfusion of tetrodotoxin (TTX, 0.5 µM) to a very restricted area around the nerve terminals. TTX at this concentration completely blocked Na+ channels, and therefore action potentials, in the spinal neurons (unpublished data). TTX was applied through a fine glass pipette positioned near the synapse under recording by gravity. A suction pipette was placed in the opposite side of the perfusion pipette to remove excess TTX. This method has been shown to restrict drug exposure to a very small area at terminals/axons (Stoop and Poo, 1995). As shown in Fig. 3 C, application of tetanus during TTX perfusion elicited virtually no potentiation, whereas subsequent application of the same tetanus induced a robust potentiation in the same neuron during perfusion of Ringer solution. Quantitative analysis indicated that local TTX perfusion virtually prevented the tetanus-induced potentiation (Fig. 3 D). A similar brief perfusion of Ringer solution to naïve synapses had no effect on TISP (Fig. 3 D). These results strongly suggest that Na+ entry into the nerve terminals is important for TISP.
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We next tested whether a rise in intracellular Ca2+ concentration ([Ca2+]i) is required for TISP. Membrane-permeable EGTA (EGTA/AM) was used to buffer [Ca2+]i. The effectiveness of tetanus was markedly reduced when cells were pretreated with EGTA/AM for >30–60 min. The synaptic efficacy increased only threefold in 0.1 mM EGTA/AM, and the increase in SSC frequency was further attenuated when 1 mM EGTA/AM was used (Fig. 5 A). Similar effects were achieved when [Ca2+]i was buffered by another Ca2+ chelator, the membrane-permeable BAPTA/AM, for >30 min (Fig. 5 B). Interestingly, robust synaptic potentiation was induced by tetanus when the membrane-impermeable BAPTA was loaded directly into the postsynaptic muscle cells through the patch pipette (pipette concentration, 1 mM; Fig. 5 B). These results suggest that although independent of Ca2+ influx, TISP still requires an increase in [Ca2+]i in the presynaptic neurons but not in the postsynaptic muscle cells. To determine whether the increase in SSC frequency truly reflects an enhanced transmitter release, and whether TISP is completely independent of postsynaptic muscle cells, we examined transmitter release at free nerve terminals using FM dye destaining techniques (Betz et al., 1992; Ryan et al., 1993). FM 1-43 dye was loaded into synaptic vesicles in the presynaptic terminals by exposing neurons to high K+ loading solution (60 mM K+, 2 mM Ca2+) for 3 min in the presence of FM 1-43 (2 µM), followed by extensive washes in Ca2+-free medium. Fluorescent spots, which represent clusters of recycled vesicles labeled by FM dye, were quite stable in the Ca2+-free medium for a long period of time, suggesting that baseline SSC does not lead to significant FM dye destaining (Fig. 5 D). TISP was initiated by tetanic stimulation of the cell body of presynaptic neurons in the absence of extracellular Ca2+. A marked destaining of FM dye was observed at NMJ as well as free nerve terminals (Fig. 5 D). Thus, the induction of TISP is completely independent of postsynaptic muscle cells.
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cleavage. Pretreatment of the nerve-muscle cocultures with the PLC- inhibitor U73122 (5 µM) did not block TISP (Fig. 6 B, a). Application of the IP3 receptor inhibitor Xestospongin C (XeC, 1 µM) (Gafni et al., 1997) also had no effect (Fig. 6 B, a). We also used heparin, a more specific and reliable inhibitor of the IP3 receptor. As heparin is a hydrophilic molecule incapable of entering cells through bath application, we loaded it into the presynaptic neurons through embryo injection techniques (Yang et al., 2001). The presence of heparin in presynaptic neurons was indicated by the fluorescence of coinjected rhodamine dextran. Tetanic stimulation induced very similar synaptic potentiation in both heparin-positive and -negative synapses (Fig. 6 B, a). In the second series of experiments, we determined whether TISP could still occur after ER Ca2+ stores are completely exhausted. Thapsigargin is known to inhibit ER Ca2+-ATPase activity and therefore has frequently been used to deplete ER Ca2+ stores (Thastrup et al., 1990). With a few minutes of delay, the application of thapsigargin in Ca2+-free conditions induced a marked increase in SSC frequency due to the release of Ca2+ from the ER Ca2+ stores. Within 60–80 min or so, the SSC frequency returned to control levels as a consequence of the depletion of ER Ca2+. Tetanic stimulation at this point could still induce the synaptic potentiation (Fig. 6 A). Taken together, these results strongly indicate that the TISP was not mediated by the release of Ca2+ from the ryanodine or IP3 receptor stores.
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Requirement for mitochondrial Na+-Ca2+ exchanger
Tetanic stimulation rapidly increases the concentration of intracellular Na+, which triggers the exchange of cytoplasmic Na+ with Ca2+ in the mitochondria (Friel, 2000; Gunter et al., 2000). The requirement of intracellular Ca2+ as well as Na+ influx, and the independence of Ca2+ influx and ER Ca2+ stores, suggests that the TISP is mediated by mitochondrial Ca2+. To test this hypothesis, we first uncoupled mitochondrial membrane potential by the protonophore carbonyl cyanide 4-(trifluoromethoxy) phenyl hydrazone (FCCP, 1 µM), which depolarizes and depletes Ca2+ from mitochondria. Application of FCCP in Ca2+-free conditions induced a huge increase in SSC frequency, which returned to control levels in 20–50 min (Fig. 7, A and B). FCCP also caused a transient and slow drift of membrane potential, which was recovered within minutes (Fig. 7 A). Compared with the effect of thapsigargin on ER Ca2+ stores, the depletion of mitochondria Ca2+ by FCCP had a faster onset and higher magnitude, but lasted for a relatively shorter period of time. Importantly, tetanic stimulation 40 min after FCCP application could no longer induce synaptic potentiation (Fig. 7 A). Quantitative analysis indicated that FCCP treatment elicited a transient, 67-fold increase in SSC frequency, and TISP failed to occur when the tetanic stimulation was applied after the effect of FCCP subsided (Fig. 7 B). These data suggest that the release of Ca2+ from mitochondria is critical for TISP.
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We next examined whether tetanic stimulation elicits an increase in [Ca2+]i via the mitochondrial Na+-Ca2+ exchanger. Ca2+ imaging was performed by confocal microscopy using the cell-permeable Ca2+ indicator fluo-4. Cells in the nerve-muscle cultures were loaded with this indicator, and tetanic stimulation was applied to neuronal soma through a loose-patch pipette (touched, but not sealed) to induce action potentials. We determined the fluo-4 fluorescence in Ca2+-free medium (Fig. 8 A, inset) and normalized it to averaged basal fluorescence before stimulation. The change in fluorescence (
F/F0) was plotted against time. Tetanic stimulation evoked a gradual increase of [Ca2+]i at nerve terminals (Fig. 8 B), with the time course very similar to that of TISP. This increase was significantly attenuated in low [Na+]o (57.5 mM, Fig. 8 B). Moreover, pretreatment with CGP markedly attenuates the tetanus-induced mitochondrial Ca2+ release (Fig. 8 B). The basal [Ca2+]i level in the terminals, however, was not affected by CGP (see Fig. 10 C). In the presence of the IP3 receptor inhibitor XeC, tetanus still induced the same magnitude of increase in [Ca2+]i (Fig. 8 B). Thus, in zero [Ca2+]o conditions, tetanus-induced increase in intracellular Ca2+ is mediated by the mitochondrial Na+-Ca2+ exchanger. These results, together with the findings that TISP could be attenuated by FCCP and CGP, strongly support the model that tetanic stimulation induces Ca2+ release through the mitochondrial Na+-Ca2+ exchanger at the nerve terminals, leading to a marked potentiation of transmitter release.
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Discussion |
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Although our study demonstrated that transmission and synaptic plasticity could occur without Ca2+ influx, it seems that a rise of presynaptic [Ca2+]i is still necessary. This is quite different from the Ca2+-independent vesicle fusion in the cell body of DRG neurons reported recently (Zhang and Zhou, 2002). Vesicle fusion, as measured by membrane capacitance recording, was induced by membrane depolarization in Ca2+-free medium. Fura-2 measurements could not detect any change in [Ca2+]i under these conditions. Even intracellular dialysis with BAPTA for 10 min could not block this secretion. It was therefore concluded that a Ca2+-independent but voltage-dependent vesicular secretion may exist in the cell body of the DRG neurons (Zhang and Zhou, 2002). As the authors pointed out, the depolarization-induced vesicle fusion was not observed in a number of other cells tested. In our system, depolarization of the nerve terminals in Ca2+-free conditions by rapid perfusion of high K+ solution could not induce transmitter release at the neuromuscular synapses. Although the present study also found an increase in vesicle fusion in the absence of Ca2+ influx, we attribute this phenomenon to Na+ influx driven by action potentials and Ca2+ release through mitochondrial Na+-Ca2+ exchanger. It will be interesting to determine whether mitochondrial Ca2+ release also contributes to the depolarization-induced vesicle fusion seen in DRG cell bodies.
Mitochondria are observed in virtually all nerve terminals. It has long been thought that the function of the terminal mitochondria is to provide energy necessary for synaptic vesicle cycling. However, a number of studies have demonstrated that high frequency stimulation could induce mitochondrial Ca2+ release at the motoneuron terminals, and this could go on over a period of 10 min after the cessation of the stimulation (David et al., 1998; David, 1999). The release of mitochondrial Ca2+ has been shown to enhance transmitter release induced by repetitive stimulation or drug application (Tang and Zucker, 1997; Scotti et al., 1999; Tsang et al., 2000). As these experiments were done in normal extracellular Ca2+, loading of Ca2+ into the mitochondria during stimulation and unloading after stimulation is thought to be the mechanism for the transient increase in [Ca2+]i (Tang and Zucker, 1997; Melamed-Book and Rahamimoff, 1998). Mitochondria are therefore proposed to serve as a Ca2+ buffering system that controls the extent of cytosolic Ca2+ rise in the nerve terminals (Stuenkel, 1994; Tang and Zucker, 1997; David et al., 1998; David, 1999). We found, however, that FCCP could induce mitochondrial Ca2+ release when Ca2+ influx was completely prohibited. Thus, resting mitochondria contain substantial amounts of Ca2+, and the release of this Ca2+ is sufficient to enhance transmitter release at NMJ. Another advance by the present study is to demonstrate synaptic modulation by Ca2+ release through the mitochondrial Na+-Ca2+ exchanger. Several previous studies have suggested that the plasmalemmal Na+-Ca2+ exchanger, but not the one on mitochondria, is important for presynaptic Ca2+ regulation (Scotti et al., 1999; Zhong et al., 2001). We show that in Ca2+-free medium, inhibition of the mitochondrial Na+-Ca2+ exchanger prevented the tetanus-induced increase in [Ca2+]i and greatly attenuated TISP. Thus, our study reveals a previously unexpected role of the mitochondrial Na+-Ca2+ exchanger in modulation of transmitter release.
A form of plasticity most relevant to the present study is PTP. Using the crayfish NMJ as a model system, Tang and Zucker (1997) have investigated the mechanism for PTP in detail. Inhibition of mitochondrial Ca2+ uptake or release by tetraphenylphosphonium (TPP+), carbonyl cyanide m-chlorophenylhydrazone (CCCP), or ruthenium red all block PTP and the "residual Ca2+" in the nerve terminals after tetanic stimulation. They proposed that mitochondria accumulate Ca2+ during tetanic stimulation (as a consequence of Ca2+ influx) and release Ca2+ back to the cytoplasm after the tetanus. In a later study, they found that the specific plasmalemmal Na+-Ca2+ exchanger inhibitor KB R7943 significantly reduced PTP as well as Ca2+ accumulation caused by Na+ influx (Zhong et al., 2001). In contrast, the specific mitochondrial Na+-Ca2+ exchanger inhibitor CGP had no effect on either PTP or Ca2+ accumulation. It was therefore concluded that the plasmalemmal Na+-Ca2+ exchanger acting in reverse mode is the key mediator for PTP, and the mitochondrial Na+-Ca2+ exchanger is not involved in this form of plasticity. The TISP described in the present study is very different from PTP. First, TISP does not involve residual Ca2+ resulting from tetanus-induced Ca2+ influx. Rather, it can be induced in the complete absence of Ca2+ influx. Second, the kinetics of TISP is quite different from that of PTP. PTP occurs right after the termination of tetanus and gradually decreases over time. In Ca2+-free medium, TISP occurs several minutes after the termination of the tetanus, peaks around 10 min, and lasts for a much longer period of time (>1 h). Third, TISP and PTP are mediated by very different mechanisms. We demonstrated that TISP requires the mitochondrial Na+-Ca2+ exchanger, while Zhong et al. (2001) showed that PTP is completely independent of the molecule. Taken together, the present study has identified a new form of synaptic plasticity and elucidated its underlying mechanisms.
Tetanic stimulation has also recently been shown to induce LTP at the NMJ (Wan and Poo, 1999). Injection of BAPTA, EGTA, or a peptide inhibitor for the Ca2+-dependent phosphatase calcineurin into postsynaptic muscle cells blocks this LTP. Thus, the induction of LTP requires Ca2+ influx and perhaps calcineurin activity in postsynaptic muscle cells. We found that TISP in the absence of Ca2+ influx could also last for a long period of time (for >1 h, or as long as the recording could be held, SSC frequency never returned to the baseline levels before tetanus). However, introduction of BAPTA or PKC inhibitor into postsynaptic muscle cells could not prevent TISP. FM dye destaining experiments also indicate that tetanic stimulation of neuronal soma elicited a robust transmitter release in free nerve terminals. Thus, TISP described in this study is independent of postsynaptic muscle cells.
At a variety of synapses, activation of PKC potentiates transmitter release primarily in steps downstream of Ca2+ influx (Majewski and Iannazzo, 1998). Given the same magnitude of [Ca2+]i rise, two factors control the fusion of synaptic vesicles and the release of transmitters: the number of readily releasable vesicles (also called the readily releasable pool) and the release probability of these vesicles. Using chromaffin cells and cultured hippocampal neurons as model systems, PKC has been implicated in the potentiation of synaptic transmission by increasing the size of the readily releasable pool (Gillis et al., 1996; Stevens and Sullivan, 1998). At calyx-type synapses in the brain stem, PKC is thought to facilitate vesicle exocytosis by increasing the probability of release (Yawo, 1999; Wu and Wu, 2001). These conclusions, however, were based on experiments using phorbol ester as a PKC activator. A recent study indicated that phorbol ester–induced potentiation of transmitter release is mediated not by PKC but by Munc-13, a protein localized in the presynaptic active zone and involved in priming vesicles to fusion competence (Rhee et al., 2002). PKC may also modulate voltage-gated ion channels, leading to an increase in presynaptic Ca2+ influx (Fu and Huang, 1994; Byrne and Kandel, 1996). By eliminating Ca2+ influx into the nerve terminals, we were able to address the role of PKC in transmitter release induced by Ca2+ released from mitochondria. Inhibition of presynaptic PKC by several specific PKC inhibitors markedly attenuated the tetanus-induced Ca2+ release from mitochondria and virtually prevented TISP, while activation of PKC rapidly increased the [Ca2+]i and potentiated transmitter release in Ca2+-free medium. Our results therefore support the notion that PKC is required for optimal function of the mitochondrial Na+-Ca2+ exchanger at nerve terminals.
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Materials and methods |
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FM 1-43 imaging
The FM dye experiments were performed essentially as previously described (Wang et al., 2001). FM 1-43 (Molecular Probes) was loaded into the spinal neurons by incubating 1-d-old cultures with high K+ loading solution containing KCl (60 mM), NaCl (57.6 mM), CaCl2 (2 mM), Hepes (10 mM, pH 7.6), and FM 1-43 (2 µM) for 3 min. Cells were then rinsed with Ca2+-free medium and imaged with a Noran Odyssey II confocal unit, using a laser with a band pass excitation filter around 488 nm and a 515-nm long pass emission filter. Four 640 x 480 pixel frames were averaged (123 ms), and images were acquired at one image/10 s. The fluorescence images were stable with minimum bleach for >10 min in Ca2+-free medium. After acquiring 12 images (2 min) as baseline, FM 1-43 destaining was initiated by tetanus, and acquisition was continued for another 8 min. Fluorescence intensity was measured using a region-of-interest tool outlining the varicosities, corrected for photo bleaching, and post hoc normalized to initial fluorescence (F/F0).
Ca2+ imaging
Cells from 1-d-old cultures were loaded with Ca2+ indicators for 30–60 min. Fluo-4 (Molecular Probes; final concentration, 5 µM) was used for terminal [Ca2+]i changes in Ca2+-free medium, whereas Oregon green 488 BAPTA-5N, AM (Molecular Probes; final concentration, 5 µM) was used for Ca2+ imaging in normal medium. Cells were extensively washed after loading the Ca2+ indicators in respective media, and then excited at 488 nm. The fluorescence images were acquired at the same rate using the same procedures as described in the previous paragraph.
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Acknowledgments |
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This work is supported by the National Institute of Child Health and Human Development Intramural Research Program.
Submitted: 7 July 2003
Accepted: 17 September 2003
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References |
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