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INTRODUCTION |
The CA1 region of the hippocampus in the mammalian brain is extremely sensitive to hypoxic-ischemic episodes (Petito and Pulsinelli 1984
). In vivo and ex vivo experiments have established that hypoxia, or a combination of hypoxia and aglycemia, can depress transiently synaptic transmission, induce excitotoxicity, and facilitate delayed neuronal death (Choi 1987
; Fujiwara et al. 1987
; Rothman and Olney 1986
; Urban et al. 1989
). It was demonstrated that the pharmacologically isolated N-methyl-D-asparate (NMDA)-mediated responses in the CA1 region of the rat hippocampus were potentiated significantly for
1 h by an (1-3 min) anoxic-aglycemic episode (Crépel et al. 1993
).
This novel form of potentiation shares certain electrophysiological properties with temporary suppression of glycolysis long-term potentiation (LTP) (Tekkok and Krjnevic 1995) and potentiation induced by high-frequency stimulation. Tetanus-induced LTP, referred to below as tetanus-LTP, was first reported as a possible physiological substrate for memory formation by Bliss and Lømo in 1973. Tetanus-LTP generally is described as a long-lasting increase in the amplitude of excitatory postsynaptic potential (EPSP) and/or population spike after brief, afferent tetanic stimulation (Gustafsson and Wigström 1988
). Although both tetanus-LTP and hypoxia-induced potentiation result in long-lasting changes in synaptic efficacy, certain important mechanistic differences between them already have been demonstrated. Unlike tetanus-LTP (Gustafsson and Wigström 1988
), hypoxia-induced potentiation is not synapse specific (Crépel et al. 1993b
; Ikeda et al. 1989
; Sanchez-Prieto and Gonzales 1988). Moreover, hypoxia-induced potentiation has been reported to be maintained not through the
-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated component of the EPSP as is tetanus-LTP (Kauer et al. 1988
; Muller et al. 1992
), but rather through the selective potentiation of the NMDA receptor-mediated component (Crépel et al. 1993a
). However, preliminary experiments (Durand and Lyubkin 1995
; Lyubkin et al. 1995
) conducted in the presence of 2 mM magnesium in the artificial cerebrospinal fluid (ACSF) to block NMDA response suggested that short episodes of hypoxia are capable of potentiating the AMPA-mediated synaptic response. It is therefore important to determine how hypoxia-induced potentiation could influence tetanus-induced potentiation and vice versa.
Although some studies have concentrated on the mechanisms underlying hypoxia and others of tetanus-LTP, very little is known about their interaction. The only study thus far of their interaction suggests that a period of hypoxia (5-8 min or until the disappearance of presynaptic volleys) can block the formation of tetanus-LTP if applied shortly after tetanus (Arai et al. 1990b
). The duration of the blocking effect by hypoxia on LTP formation is not known. This study also suggested that once tetanus-LTP is induced, hypoxia does not disrupt LTP maintenance because the field EPSP responses return to prehypoxic levels. However, in light of recent studies demonstrating the possibility of potentiation produced by short episodes of hypoxia (2 min) (for review see Hammond et al. 1994) and confirmed by our preliminary data (Durand and Lyubkin 1995
; Lyubkin et al. 1995
), hypoxia could potentiate still further synaptic pathways. The degree to which these two forms of potentiation interact with other therefore must be investigated to determine if a nonsynaptic specific potentiation such as hypoxia-induced potentiation could affect synapse specific potentiated pathways.
LTP induced by high-frequency stimulation has been suggested to be a prime neurophysiological paradigm to study memory in the mammalian brain (Hinton and Anderson 1981
; Teyler and Disscenna 1984). If hypoxia can erase tetanus-LTP by resetting previous potentiation levels and block formation of new tetanus-LTP, it could severely disrupt neuronal processing. This observation may have important clinical relevance in such areas of research as obstructive sleep apnea, stroke or sudden infant death syndrome, which in part is characterized by repeated exposure to hypoxic episodes (Berry et al. 1986
; Warner et al. 1987
).
Therefore, to clarify the interactive effects between hypoxia and tetanus-LTP, the first goal of this study was to examine whether hypoxia-induced potentiation resets synaptic efficacy in an independent, nonsynapse specific manner or whether it is additive and thus preserves the synaptic specificity associated with tetanus-LTP. The second goal of this study was to determine the effect of hypoxia on tetanus-LTP formation by inducing LTP after a hypoxic episode.
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METHODS |
Preparation of rat hippocampal slices
Experiments were performed using the hippocampal slice preparation described previously (Teyler 1980
). Adult male Sprague-Dawley rats (150-200 g) were anesthetized with ether and decapitated. The hippocampus was quickly dissected out and transversely cut into 400-µm slices. These slices then were incubated for 1 h at 25°C in oxygenated (95% O2-5% CO2) ACSF containing the following (in mM): 123 NaCl, 3.5 KCl, 1.25 NaH2PO4, 2.0 MgSO4, 2.0 CaCl2, 26 NaHCO3, and 10 dextrose, pH 7.45. After 1 h at room temperature, individual slices were placed in the oxygenated interface chamber, heated to 33°C, and perfused with ACSF at 12 ml/min. They were allowed to acclimate for 25 min before recording.
Extracellular recordings
Stimulus injections were accomplished using a two-pathway design. Two sets of orthodromic stimuli were delivered in an alternating manner, using fine tungsten electrodes, to the stratum radiatum region of the hippocampus (Fig. 1A). The intensity of the baseline current (applied at 0.5 Hz) for each pathway was fixed at 50% of the maximum field EPSP response. Tetanus-LTP was induced by a 1-s, 100-Hz stimulus with the same amplitude as the 0.5-Hz stimulus used to elicit baseline responses.

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| FIG. 1.
A: schematic of the hippocampal slice preparation showing stimulating and recording sites. Stimulation of the stratum radiatum gives rise to an orthodromic field potential population spike recorded in the dendritic layer, signaling synchronous activation of a number of CA1 pyramidal cells. All experimental protocols were administered to both ways equally to eliminate any experimental bias due to electrode placement. B: individual traces of field excitatory postsynaptic potential (EPSP) and presynaptic volley during the course of the experiment. C: time course of the field EPSP slopes recorded from 1 pathway during baseline (1), hypoxia, and after hypoxia. Synaptic transmission was blocked within 30-90 s after onset of hypoxia. After 8-12 min of recovery after hypoxia, the field EPSP slope was potentiated (2) by 27 ± 10% (n = 16; P < 0.01) after hypoxia. D: comparison of mean amplitudes of presynaptic volleys between baseline and hypoxia-induced potentiation averaged during the entire period of control baseline and last 10 min of hypoxia-induced potentiation. No significant difference was observed (n = 6).
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Field EPSP recordings were obtained from the dendritic CA1 region using a 5-10 M
glass micropipette filled with a 4 M NaCl solution. The slope of the descending portion of the population EPSP wave form was used to measure the dendritic response. The slope of the field EPSP was measured at 5, 15, and 30 s, then every 2 min until a stable tetanus-LTP response was obtained.
All experimental protocols were administered to both ways equally to eliminate any experimental bias due to electrode placement.
Oxygen depletion
Hypoxia was induced by replacing 95% O2-5% CO2 with 95% N2-5% CO2 for 2 min. Hypoxia-induced potentiation was recorded after the tissue was reoxygenated and the population EPSP returned to stable levels.
Occlusion experiments
For each occlusion experiment, an input/output curve was obtained. Baseline 0.5 Hz stimulating current was set to 30% of maximum response, and the 100-Hz, 1-s, tetanic current was set to 70% of maximum response. Electrical stimulation train of pulses were applied every 15 min. In cases where repeated tetanic stimuli produced a population spike, the current amplitude was decreased to 30% of maximum response. When no significant potentiation was observed after tetanus, the tetanic-stimulating current was increased 10%. This procedure was repeated until tetanus-LTP was occluded successfully. A final baseline was established; hypoxia was applied and measurements were taken as described above.
Data analysis
Field EPSP slopes were summed during the entire period of control baseline responses and during the last 10 min after hypoxia and tetanic stimulation. The magnitude of hypoxia-induced potentiation and tetanus-LTP were calculated relative to the prehypoxic/tetanic baselines, respectively. All data are reported as means ± SE of control baseline. The normality of a given sample distribution and equal variance between sample distributions were determined using the Shapiro-Wilks and Bartlett tests, respectively. For normal distributions with equal variances, the sample means were compared using the unpaired Student's t-test, and within sample differences were tested using a one-sample Student's t-test. Samples with either nonnormal distribution or unequal variances were compared using an unpaired, nonparametric Wilcoxon test, and within sample differences were tested using a one-sample, nonparametric sign-test. The errors bars in the figures indicate the standard error of the mean of the measurements.
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RESULTS |
Hypoxia-induced potentiation
The effects of oxygen deprivation on field EPSP were investigated by exposing the slices to a 2-min episode of hypoxia after a 30-min period of baseline population EPSP control responses. All experiments in which a stable control baseline was obtained were used for data analysis. During hypoxia, synaptic transmission was blocked within 30-90 s as the field EPSP responses decreased to nearly 0%. After a 8- to 12-min recovery period, the field EPSP responses stabilized and were significantly larger than the baseline responses: 27 ± 10% (n = 16; P < 0.01; Fig. 1, B and C). The potentiation observed was due to an increase in synaptic efficacy because the mean amplitude of the presynaptic volley was not significantly different during hypoxia-induced potentiation from control baseline (Fig. 1D). Therefore a short episode of hypoxia induced significant synaptic potentiation of the population EPSP in normal ACSF.
Effect of tetanus-LTP on hypoxia-induced potentiation
The effect of tetanus-LTP on hypoxia-induced potentiation was studied by inducing tetanus-LTP in one pathway with a 100-Hz, 1-s tetanus, which significantly potentiated the population EPSP slope by a mean value of 33 ± 3% (n = 10; P < 0.01). No effect was observed at the second pathway. This was followed 20 min later by a 2-min hypoxic episode. Within 30-90 s after the onset of hypoxia, synaptic transmission was blocked in both pathways. However, upon reoxygenation and a 10-min recovery period, field EPSP responses were significantly increased by 16 ± 5% (n = 10; P < 0.05) in the tetanized pathway and 19 ± 5% (n = 10; P < 0.01) in the control pathway with respect to the prehypoxic baseline. Therefore, hypoxia produced similar potentiation in both pathways. However, the total potentiation produced by a combination of tetanus and then hypoxia was 63 ± 13% (n = 10) which was significantly larger (P < 0.01) than hypoxia alone in the control pathway (Fig. 2, A and B). There was no change in the mean amplitude of the presynaptic volley for both pathways, indicating that tetanus-LTP and hypoxia-induced potentiation were synaptic events (Fig. 2C).

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| FIG. 2.
A: individual traces of the field EPSP and presynaptic volley during the course of the experiment. Number for each trace is indicated in B. B: time course of the field EPSP slopes recorded from 2 pathways (- -, - -; as shown in Fig. 1A). After 10 min of control (1), tetanic stimulation was delivered to pathway - -, which potentiated the EPSP slope by 33 ± 3% (n = 10; P < 0.01) (2) and had no significant effect on pathway - - (3). EPSP was monitored for 20 min and hypoxia was induced, resulting in an ~100% decrease in field EPSP (synaptic block) for both pathways. After an 8- to 12-min recovery period, the EPSP slope was potentiated by mean increase of 16 ± 5% (n = 10; P <0.05) for pathway - - (4) and 19 ± 5% (n = 10; P < 0.01) for pathway - - (5), relative to the prehypoxic baseline. Total potentiation produced in pathway - - by combination of long-term potentiation (LTP) and hypoxia (63 ± 13%; n = 10) was significantly larger than potentiation produced in pathway - - - by hypoxia alone (*P < 0.01). C: comparison of mean amplitudes of presynaptic volleys for both pathways between baseline, after tetanus, and during hypoxia-induced potentiation. , no significant difference was observed (applies to pathway - - and to - -; n = 5 for each).
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Occlusion experiments were performed to examine whether tetanus-LTP and hypoxia-induced potentiation share a common mechanism. Repeated tetanic stimulation produced synaptic saturation in a range of ~100-300%. This range is only an approximation because, in most experiments, the tetanic-stimulating current had to be decreased repeatedly due to the appearance of evoked population spikes in the dendritic response. Once tetanus-LTP was occluded, the tetanic-stimulating current was increased by 10% and applied again. A posttetanic baseline was established, and hypoxia was administered for 2 min. After recovery, hypoxia-induced potentiation was measured to be 23 ± 7% (n = 7; P < 0.05), which was not significantly different from normal hypoxia-induced potentiation (Fig. 3, A and B). Therefore, although tetanus-LTP was occluded effectively with repeated tetanic stimulation, hypoxia still produced significant potentiation of the field EPSP.

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| FIG. 3.
Time course of the field EPSP slopes for 1 experiment during a series of tetanic stimulations ( ) repeated every 12 min to produce LTP occlusion. When LTP was occluded, a baseline was established (1), the intensity of tetanic stimulation was increased 10% and delivered again (*). No effect was observed (2) and hypoxia was applied for 2 min. B: time course of pooled field EPSPs showing that after recovery, hypoxia-induced potentiation was measured to be 23 ± 7% (n = 7; P < 0.05) (3), which was not significantly different from normal hypoxia-induced potentiation in Fig. 1.
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Effects of hypoxia-induced potentiation on tetanus-LTP
The effect of hypoxia on tetanic LTP was studied by first applying hypoxia for 2 min after 20 min of baseline responses, allowing for recovery, and then 20 min later applying a high-frequency electrical stimulus. Hypoxia blocked synaptic transmission within 30-90 s, and field EPSP responses stabilized within 8-12 min upon reoxygenation.
Hypoxia significantly potentiated the population EPSP slope by an average value of 19 ± 5% (n = 10; P < 0.01). Twenty minutes later, electrical stimulation further increased the population EPSP slope by an additional 14 ± 4% (n = 10; P < 0.01; Fig. 4). Thus a 2-min hypoxic episode did not block tetanus-LTP formation 20 min after hypoxia. Shorter time intervals between hypoxia and tetanic stimulation were not used because
20 min were needed for the population EPSP to recover and stabilize for
10 min to establish a baseline.

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| FIG. 4.
Time course of the field EPSP slopes during control (1), 3 min of hypoxia, after hypoxia (2), and after 1-s, 100-Hz tetanus (3). Hypoxia blocked synaptic transmission within 30-90 s, and field EPSP responses stabilized within 8-12 min upon reoxygenation potentiated by mean value of 19 ± 5% (n = 10; P < 0.01) (2). Twenty minutes after hypoxia, the tetanus enhanced the field EPSP slopes further by 14 ± 4% (n = 10; P < 0.01) (3).
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Although hypoxia failed to block tetanus-induced-LTP formation, it significantly affected the magnitude of potentiation. Our results indicate that the magnitude of tetanus-induced LTP induced 20 min after hypoxia (15 ± 4%; n = 10) was significantly smaller (P < 0.01) relative to tetanus-LTP after normoxic conditions (33 ± 3%; n = 10; Fig. 5A).

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| FIG. 5.
A: comparison of tetanic-LTP induced after normoxic conditions with LTP induced 20 min after hypoxia. Magnitude of LTP induced 20 min after hypoxia (15 ± 4%; n = 10) was significantly smaller relative to normal LTP (33 ± 3%; n = 10; *P < 0.01). B: comparison of total potentiation produced by the combination tetanus and hypoxia as a test for synaptic saturation. Pathway stimulated by tetanus then hypoxia produced total potentiation of 63 ± 13% (n = 10), which was significantly larger (*P < 0.01) than total potentiation of 30 ± 8% (n = 10) produced by first hypoxia then tetanus in the second pathway.
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To test the possibility that synaptic saturation was responsible for the decrease in magnitude of tetanus-LTP after hypoxia, we compared the total potentiation produced by each pathway. For the first pathway, the tetanus was first applied and then followed by hypoxia, producing a total potentiation of 63 ± 13% (n = 10; Fig. 2B). For the second pathway, hypoxia was applied first then followed by LTP tetanus, producing a total potentiation of 30 ± 8% (n = 10; Fig. 4). Therefore, hypoxia significantly decreased (P < 0.01) the magnitude of tetanus-induced LTP, and the total synaptic potentiation was significantly smaller than the potentiation produced by tetanus then hypoxia in the first pathway (Fig. 5B).
Additionally, hypoxia blocked the transient, robust potentiation observed during the early phase of tetanus-LTP induction (Fig. 4,
). Figure 6 shows that 20 min after hypoxia, the tetanus failed to elicit a transient, robust potentiation as seen under normal conditions.

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| FIG. 6.
Time course of the early phase of tetanic LTP induction (60 s) is represented for 2 sets of experiments: tetanus after normoxic conditions ( , n = 10) and tetanus applied 20 min after hypoxia ( , n = 10). Tetanic stimulation 20 min after hypoxia failed to elicit a transient, robust potentiation as seen under normal conditions (*P < 0.05).
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DISCUSSION |
Previous studies of short periods of ischemia-induced potentiation of the pharmacologically isolated NMDA-mediated responses in the CA1 region of the rat hippocampus reported a mean increase of 40.1 ± 5% (n = 3) (Crépel et al. 1993b
) and 70 ± 13% (n = 12) (Crépel et al. 1993a
) of the field EPSP. In the present study, 2 min of 0% O2-hypoxia without aglycemia in normal ACSF potentiated the field EPSP by 27 ± 10% (n = 16; Fig. 2). Therefore, hypoxia alone is sufficient to produce significant potentiation of the field EPSP. In fact, preliminary data have shown that oxygen concentration
15% during hypoxia still can produce potentiation that is not significantly different in magnitude from the potentiation induced by 0% O2 hypoxia (Durand and Lyubkin 1995
).
Our results, however, were obtained in a solution containing 2 mM Mg. This concentration is known to block NMDA receptors at rest, suggesting that the AMPA-mediated transmission has been potentiated. This result was verified experimentally by adding 100 µM of D-2-amino-5-phosphonovaleric acid to the solution. Hypoxia-induced potentiation still was observed under these conditions (not shown). Previous researchers (Arai et al. 1990
; Crépel et al. 1994) did not observe potentiation of the AMPA-mediated response. Arai et al. also used a high concentration of Mg (2.5 mM), but the duration of the hypoxic episodes was significantly longer and could have affected the potentiation of the synaptic response. Crépel et al. (1994) used several pharmacological manipulations to separate carefully the NMDA/AMPA-mediated response and concluded that only the NMDA component of potentiated. It is possible, however, that the AMPA component was saturated and could therefore not be further potentiated.
A previous study that examined the interaction between tetanus-LTP and hypoxia (5-8 min or until the disappearance of presynaptic volleys) reported that hypoxia, applied
5 min after tetanus, does not disrupt tetanus-LTP maintenance because the field EPSP response returned to former tetanus-LTP levels upon reoxygenation (Arai et al. 1990b
). However, in light of the possibility of potentiation produced by short episodes of hypoxia (2 min), the interaction between the two forms of potentiation must be reanalyzed. Previous studies have shown that hypoxia produces a nonsynapse specific potentiation in the exposed hippocampal tissue (Ikeda et al. 1989
; Sanchez-Prieto and Gonzales 1988), whereas tetanus-LTP is a specific, associative interaction between a presynaptic and a postsynaptic population of neurons (Gustafsson and Wingström 1988). The results presented above suggest that hypoxia does not disrupt the synapse-specific tetanus-evoked potentiation but potentiates equally the control pathway (hypoxia alone) and the test pathway (tetanus followed by hypoxia) in the same slice (see Fig. 2B). The relative amount of synaptic weight is preserved after hypoxia. These results also suggest that hypoxia-induced potentiation of AMPA-mediated synaptic pathway does not share the same mechanisms with tetanus-induced LTP.
Occlusion experiments support this hypothesis and show that the mechanisms responsible for hypoxia-induced potentiation are independent of preexisting synaptic levels induced by high-frequency stimulation. Although tetanus-induced LTP was occluded effectively with repeated stimulation, hypoxia still produced significant potentiation of the field EPSP similar to normal hypoxia-induced potentiation (Fig. 3). The magnitude of hypoxia-induced potentiation was similar in three conditions: control and after the induction and the occlusion of tetanus-LTP. Therefore, hypoxia-induced potentiation is clearly independent of synaptic levels set by tetanus-LTP before hypoxia. Second, the results show that the hypoxia-induced potentiation interacts with previous levels of tetanus-LTP in a multiplicative manner. Therefore hypoxia-induced potentiation does not erase the synaptic specificity of tetanus-LTP.
Occlusion experiments also strongly suggest that hypoxia-induced potentiation and tetanus-induced LTP do not share the same mechanisms. During occlusion of tetanus-LTP, either the presynaptic release of glutamate or the postsynaptic second messenger systems are saturated or both. In the case of the saturation of vesicle release, glutamate released in the extracellular space still could produce potentiation. Previous studies have shown that there is a transient accumulation of glutamate in the synaptic cleft after hypoxia that may originate from cytoplasmic stores (Ikeda et al. 1989
; Sanchez-Prieto and Gonzales 1988) rather than from vesicular, presynaptic stores after high-frequency stimulation (Nicholls et al. 1987
). Therefore, one possible mechanistic difference that could explain the interaction between hypoxia-induced potentiation and tetanus-LTP is that hypoxia applied after tetanus-LTP could produce additional potentiation by triggering the release of glutamate from a different physiological pool. In the case of saturation of the second-messenger system, it is still possible to envisage that the glutamate released by hypoxia could active extrasynaptic receptors, which use a different second-messenger system.
The present study also explored the effect of hypoxia on tetanus-induced LTP by applying a hypoxic episode 20 min before tetanic stimulation (Fig. 4). Hypoxia did not effectively block tetanus-LTP formation as previously observed by Crépel and Ben-Ari (1996)
. Similarly, glycolysis-induced potentiation did not prevent the generation of tetanus-LTP (Tekkok and Krnjevic 1995
). However, hypoxia produced a significant decrease in the magnitude of potentiation (Fig. 5A). Total potentiation produced by the combination of tetanus-LTP then hypoxia on the second pathway was compared with the total potentiation in Fig. 4 to test whether synaptic saturation was responsible for the decrease in the magnitude of tetanus-LTP after hypoxia (Fig. 5B). Our results suggest that the pathway was not saturated and that hypoxia was directly responsible for the decrease in the magnitude of tetanus-LTP.
Additionally, hypoxia significantly affected the robust, transient potentiation occurring during early phase of tetanus-LTP induction. During the induction phase of normal tetanus-LTP, there is a considerable delay of ~2-3 s between tetanus and the initiation of tetanus-LTP followed by transient, robust posttetanic potentiation (PTP), which is independent of tetanus-LTP and is not blocked after tetanus-LTP occlusion (for review see Bliss and Collingridge 1993
; Gustafsson and Wigström 1990
). In the present study, the transient, robust potentiation after tetanus was not affected by successful occlusion of tetanus-LTP (Fig. 6), but was blocked 20 min after the administration of hypoxia. These data suggest that hypoxia modifies tetanus-LTP by acting presynaptically.
One possible explanation of the inhibition of tetanus-induced LTP by hypoxia is the depleted ATP-store hypothesis. ATP is needed for the mobilization and release of neurotransmitter (Baker and Knight 1978
; Dunn and Holtz 1983
; Sanchez-Prieto et al. 1987). Hypoxia has been shown to reduce ATP stores, resulting in the inhibition of synaptic transmission (Fredholm et al. 1984
; Lipton and Whittingham 1982
). By decreasing ATP levels, hypoxia also can affect the time course of transmitter synthesis, mobilization, and release, especially after high-frequency stimulation, which may reduce significantly vesicular ATP and transmitter stores.
Another possible explanation involves adenosine, which is produced during hypoxia when AMP accumulates and is dephosphorylated (Fredholm et al. 1983
, 1984
; Hagberg et al. 1985
). Adenosine can cause synaptic inhibition (Dunwiddie and Haas 1985
; Fowler 1990
; Fredholm and Dunwiddie 1988
) and also can inhibit tetanus-LTP (Arai et al. 1990a
; Mitchell et al. 1993
). It is unlikely, however, that adenosine alone could prevent tetanus-induced LTP 20 min after a short episode of hypoxia because, presumably, adenosine levels have returned to normal. Thus the combination of adenosine-induced inhibition and reduced ATP levels could explain the decrease in tetanus-LTP magnitude 20 min after hypoxia as well as the block of PTP during the early tetanus-LTP induction phase after tetanus.
Tetanus-LTP is a physiological mechanism that has been shown to control selectively synaptic strength (Hinton and Anderson 1981
; Teyler and Discenna 1984
). Although hypoxia modifies neuronal processing by general excitation, synaptic specificity associated with tetanus-LTP still is preserved. However, hypoxia can disrupt neuronal processing by inhibiting new modification of synaptic transmission. These findings may have important clinical implications in any field related to hypoxia, such as obstructive sleep apnea, which causes repeated hypoxic exposures such as sudden infant death syndrome, stroke, or obstructive sleep apnea (Berry et al. 1986
; Warner et al. 1987
).