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Department of Psychology, McMaster University, Hamilton, Ontario, Canada
Submitted 15 March 2004; accepted in final form 22 August 2004
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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; Muller and Stead 1996).
Kirkwood and Bear (1994) proposed the idea of a dual threshold for synaptic plasticity such that LTD and LTP are associated with moderate and high levels of synaptic activity, respectively (see also Hansel et al. 1996). While it has been shown that intense synaptic activation can produce LTP, and moderate repetitive activation can produce LTD, it has also been proposed that the threshold, direction, and magnitude of synaptic change can be modulated in a homeostatic manner by prior synaptic activity. This regulation of synaptic activity has been termed "metaplasticity" (Abraham 1996; Abraham and Bear 1996). Without some control over the direction and magnitude of synaptic plasticity, changes in synaptic strength could be locked into a positive feedback loop leading to runaway LTP. In a model of plasticity in the visual cortex, Bienenstock, Cooper, and Munro (1982) proposed an algorithm that incorporates a sliding threshold (BCM model). Dudek and Bear (1992) have suggested that the sliding threshold in the BCM model may correspond to the sliding LTP-LTD crossover point observed in frequency-response experiments (Christie et al. 1995; Kirkwood et al. 1996; Wang and Wagner 1999). Furthermore, some neural network models have incorporated threshold adjustments that take into account the recent history of the synapse (Bear 1996; Bear et al. 1987; Bienenstock et al. 1982).
Metaplasticity has recently been documented in vivo. Abraham et al. (2001) have shown that the stimulation requirements for the induction of LTP were heterosynaptically modified as a function of the postsynaptic neuronal activity in the dentate gyrus of awake behaving rats. Tetanization of the medial perforant path induced LTP in this pathway and inhibited the subsequent induction of LTP in the lateral perforant path. Metaplasticity has also been shown using in vitro preparations. In the hippocampal CA1 region, both LTD and depotentiation can be facilitated when low-frequency conditioning stimulation is preceded by high-frequency priming stimulation (Holland and Wagner 1998). In hippocampal slices from the adult (50-to 65-day-old) mouse, LTD can be induced in the dentate gyrus (Wei and Xie 1999) or CA1 region (Wexler and Stanton 1993) only when high-frequency priming stimulation precedes the low-frequency conditioning stimulation. Similarly, associative LTD is facilitated in the rat dentate gyrus when a theta-frequency (5 Hz) priming stimulus precedes the conditioning stimulation (Christie and Abraham 1992).
Prior exposure to LFS can affect LTP induction as well. In area CA1, activation of synaptic inputs by LFS (Fujii et al. 1996), weak tetani, or single pulses (Huang et al. 1992) can suppress subsequent LTP induction, and these effects are N-methyl-D-aspartate receptor (NMDAR)-dependent. Although this effect runs counter to that predicted by the BCM model, it has also been shown that prior exposure to theta-frequency synaptic activity can reduce the threshold for LTP induction (Christie et al. 1995). Also, LTD has been shown in some preparations to be dependent on metabotropic glutamate receptor (mGluR) activation (e.g., Bashir and Collingridge 1994; Fitzjohn et al. 2001; Lin et al. 2000), and mGluR activation has been shown to prime LTP induction in the hippocampus (Cohen and Abraham 1996; Cohen et al. 1998) and dentate gyrus (O’Leary and O’Connor 1998).
Prior behavioral activity can also modulate the induction of LTP and LTD. Behavioral stress, for example, can inhibit LTP induction (Diamond et al. 1994; Foy et al. 1987; Shors et al. 1989) and facilitate LTD induction in area CA1 (Xu et al. 1997). Lebel et al. (2001) have also shown that olfactory learning inhibits subsequent LTP induction and facilitates LTD induction. Similarly, a persistent depotentiation can be induced in the hippocampus of freely moving rats after exploration of a new, nonstressful environment (Xu et al. 1998).
In the sensorimotor cortex of the awake behaving rat, multiple sessions of HFS must be delivered over consecutive days to the corpus callosum to induce maximal LTP effects (Trepel and Racine 1998), and multiple sessions of LFS are required for maximal LTD effects (Froc et al. 2000). Depotentiation is also observed in this preparation. After the induction of LTP, 1-Hz stimulation delivered daily for 10 day induces a depotentiation that is NMDAR-independent (Froc and Racine 2004). We have not determined, however, the interactions between the LTP- and LTD-inducing stimulation during the induction phase of these phenomena or the effects of HFS on newly depressed synapses. Consequently, our goal in the present experiments was to determine whether LFS delivered prior to HFS would prime the induction of LTP in the sensorimotor cortex or, conversely, whether HFS would prime the induction of LTD. We have chosen the sensorimotor cortex because it has been shown to express LTP, LTD, and a form of training-induced potentiation (Hodgson et al. 2000; Rioult-Pedotti et al. 1998), and it the most thoroughly tested neocortical site in chronic preparations (e.g., Froc and Racine 2004; Trepel et al. 1998). We are using chronic preparations because these phenomena may not be inducible in the slice. This form of LTP, in particular, is not observable within the time span of a slice experiment.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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All animal experiments were approved by the McMaster University Animal Research Ethics Board and were carried out in accordance with the Canadian Council on Animal Care Guide for the Care and Use of Laboratory Animals. Forty-six male Long-Evans rats (300–400 g), obtained from Charles River, were used in the following experiments. Rats were anesthetized using pentobarbital sodium (65 mg/kg ip) and received atropine (1.2 mg/kg ip) to prevent respiratory distress. Twisted wire bipolar electrodes were constructed from Teflon-coated stainless steel wire (120 µm diam), and the exposed tips were separated by 1.0 or 0.5 mm for cortical and white matter electrodes, respectively. All electrodes were placed in the right hemisphere. Recording electrodes were placed in the sensorimotor cortex 2.0 mm anterior to bregma and 4.0 mm lateral to the midline at a depth of 2.0 mm from the pial surface (M1 bordering on S1) (Paxinos and Watson 1997). Stimulating electrodes were placed in the nearby white matter 2.0 mm anterior to bregma and 2.0 mm lateral to the midline at a depth of 3.0 mm from the pial surface. Electrode depths were adjusted during surgery to maximize field response amplitudes. Electrodes were connected to gold-plated pins and inserted into a connector plug anchored to the skull surface with dental cement and four stainless steel screws. One screw in the right occipital bone served as a ground electrode.
Rats were housed individually on a 12 h/12 h-light/dark cycle and tested during the light cycle. A 2-wk recovery period preceded experimental testing.
Stimulation and recording
INPUT/OUTPUT TESTS. Recordings were taken during the quiet waking state with only occasional grooming or ambulation. Three baseline input/output (I/O) tests, separated by 48 h, were used to confirm the stability of the evoked responses. For I/O tests, single biphasic square-wave pulses, with a pulse duration of 0.1 ms, were delivered through constant current isolation units every 10 s. The pulses were applied at varying intensities to the white matter while the evoked field potentials were monitored in the cortex. During each I/O test, eight responses were sampled and averaged at each of 10 intensities (16, 32, 60, 100, 160, 250, 500, 795, 1,000, and 1,260 µA). Responses were filtered, digitized at 10 kHz, and stored on a computer hard drive. I/O measures were also collected immediately preceding the conditioning stimulation during the induction phases of all experiments and during the decay phase.
LTP. To induce LTP, 60 high-frequency trains were delivered once per day for either 10 or 15 day (for experiments 1 and 2, respectively). Each 24-ms train consisted of eight-pulses at 300 Hz, and trains were delivered once every 10 s. Pulse intensity was 1,260 µA. Daily input/output tests were recorded during the induction phase and for 7 day after the LTP induction procedure to confirm that the potentiation effects were long-lasting.
LTD AND DEPOTENTIATION. To induce LTD and depotentiation, LFS (1 Hz, 900 pulses, 1,260 µA) was delivered daily for 10 day immediately after baseline I/Os or the LTP induction regimen.
Experimental design
The first experiment examined the effects of combined, daily HFS and LFS on the induction of neocortical LTP and LTD. The second experiment dealt with the reversibility of established LTP by the subsequent application of LFS and the reversibility of established LTD by HFS.
COMBINED HFS/LFS STIMULATION. Following three baseline I/O measures, responses were matched in sets of four based on response morphology, after which animals in each set were randomly assigned to the four groups. An LTP control group (n = 10) received HFS alone for 15 day, and a second control group (n = 5) received no conditioning stimulation. The experimental groups received 15 day of both HFS and LFS, differing only in the order of presentation. The HFS-LFS animals (n = 5) received one session of HFS followed 2 min later by one session of LFS, every day for 15 day. The LFS-HFS animals (n = 5) received LFS followed 2 min later by HFS each day. The conditioning phase of this experiment was extended from 10 to 15 day to allow the experimental groups to reach asymptotic levels of LTP.
REVERSIBILITY OF LTP AND LTD. This experiment examined depotentiation by delivering LFS after potentiating responses to asymptotic levels (n = 5) and conversely, the reversibility of LTD by delivering HFS after depressing responses to asymptotic levels (n = 6). Both groups received 20 consecutive days of stimulation (10 day of HFS and 10 day of LFS), and differed only in the order of presentation. To verify the stability of the neocortical-evoked response, an LTP control group (n = 6) received HFS daily for 10 day and a fourth group (n = 6) received no stimulation.
Data analysis
Changes in responses were quantified by expressing the peak amplitudes of field potential components relative to the last baseline I/O. This was done at midrange intensities (250 and 500 µA), which typically reflect the largest potentiation and depression effects. For each animal, the early and late components were measured at fixed latencies corresponding to the peak of each component. The early component reflects changes in cell discharge associated with the potentiation of the monosynaptic population excitatory postsynaptic potential (EPSP), whereas the late components reflect polysynaptic activity (Chapman et al. 1998). Within animals, depotentiation and LTP effects were measured and analyzed at the same latencies. For the late components, the LTP effects, and thus the depotentiation effects, were maximal at longer latencies than the LTD effects. This is likely due to the fact that LTP recruits polysynaptic responses and broadens the field potential. The late component peaks and peak changes were most clear after the induction of LTP and LTD, so control responses were analyzed using the same mean latencies as the experimental animals. Because LTD effects peaked at somewhat shorter latencies than LTP effects, late components were measured at two latencies: late1 (11.0–21.0 ms) and late2 (17.4–34.0 ms). Changes in response amplitudes (in mV) were submitted to a two-way (group x session) mixed-design ANOVA.
Histology
Rats were anesthetized with urethan (2.0 g/kg) and perfused through the heart with formol-saline. Frozen brain sections were cut at 40 µm and stained with Cresyl violet to verify electrode placements.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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). The field potentials were as characterized by Chapman et al. (1998), who showed that both early and late components are generated by current sinks in upper layer V. In baseline recordings, the mean peak latencies of the early and late2 components of the field response were 7.5 ms (range: 4.3 to 10.0 ms) and 23.1 ms (range: 17.4 to 34.0 ms), respectively. Population spikes emerged most clearly after LTP induction, lasted for 2.0–9.0 ms, and were superimposed on the early monosynaptic component. Maximal LTD effects were typically observed at shorter latencies (late1 component: mean = 14.7 ms; range: 11.0–21.0 ms) than maximal LTP effects (late2). Latencies for the early, late1, and late2 components are identified in Fig. 1.
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All animals that received HFS showed typical LTP effects (Fig. 1) as previously characterized (Chapman et al. 1998; Trepel and Racine 1998). Both the early monosynaptic and late2 polysynaptic components showed changes in amplitude after LTP induction, yielding a significant group by session interaction [early: F(72,480) = 3.46, P < 0.001; late2: F(72,480) = 5.41, P < 0.001]. Although there was a clear increase in the amplitude of the polysynaptic component, there was a decrease and often a reversal in the amplitude of the monosynaptic component (Fig. 1), attributable to a potentiation of population spike activity (Chapman et al. 1998). As in previous studies (Chapman et al. 1998; Froc et al. 2000; Trepel and Racine 1998) the greatest potentiation effects were observed at intermediate test-pulse intensities (250–500 µA). The LTP effect observed in the late component reached asymptotic levels on the eighth day of conditioning for the LTP control animals.
There was a change in the amplitude of the early component in all stimulation groups, yielding a significant main effect of session [F(24,480) = 19.8; P < 0.001; Fig. 2A]. Again, this early component amplitude shift was presumably due to the increase in the number and magnitude of population spikes that are superimposed on the monosynaptic component (Chapman et al. 1998). The early component potentiation effect was similar in the HFS alone and combined stimulation groups, although there was a nonsignificant trend toward reduced potentiation in the HFS/LFS group. Both early and late components showed little decay after the cessation of conditioning stimulation.
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When the LFS preceded the HFS, there were no differences in either the early or late2 component amplitude changes compared with LTP controls. The LFS that would normally produce significant LTD or depotentiation effects (Froc et al. 2000) was ineffective when followed 2 min later by HFS.
Reversibility of maximal LTP and LTD
INITIAL POTENTIATION AND DEPRESSION. Typical LTP effects were produced by 10 day of HFS in all groups (Fig. 3). Latencies for the early, late1, and late2 components used in these analyses are indicated in Fig. 3. The greatest potentiation effects were observed at an intensity of 250 µA and reached asymptotic levels by the last day of conditioning. HFS induced a similar amount of LTP of the late2 component in all experimental groups (Fig. 4), yielding a significant main effect of session [F(11,143 = 39.47; P < 0.001]. There were no significant differences between LTP effects observed in the LTP control, LTP-LTD, and LTD-LTP groups, indicating that both the induction rate and asymptotic levels of LTP were similar in these groups. However, potentiation of the early component was significantly greater in the LTP control group than in the LTP–LTD group [F(10,80) = 15.35; P < 0.001]. The pattern of potentiation was otherwise similar between these groups.
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REVERSAL OF LTD. Ten days of LFS induced LTD of both early and late1 components in the LTD–LTP group. This depression was effectively reversed by subsequent HFS (Fig. 3A). The HFS, in fact, produced a significantly greater amplitude shift of the early component in the LTD–LTP group as compared with the LTP controls [F(10,90) = 2.78; P < 0.005], and this difference was still evident after 7 day of decay (Fig. 5, top). The late1 component was significantly decreased during the LTD phase compared with controls [Fig. 5B; F(12,120) = 5.12; P < 0.001]. Subsequently, 10 daily sessions of HFS increased this component from the depressed level to the baseline level observed prior to any conditioning (Fig. 5, middle). This potentiation effect required only three sessions of HFS to reach asymptote but returned to the depressed level after 7 day of decay. The magnitude of the late1 LTD effect in the LTD-LTP group was similar to the depotentiation observed in the LTP–LTD group, and there was no difference between these groups after the 7-day decay period (Fig. 5, middle).
The late2 component showed no depression in the LTD–LTP group and similar potentiation effects were observed in this component in the LTP phase of the LTP–LTD and LTD–LTP groups when the latter group was normalized to the last day of LFS (Fig. 4). After the 7-day decay period, there was no significant difference between responses observed in the LTD–LTP and LTP–LTD groups (Fig. 5C), but the LTD–LTP group decayed more rapidly than normal, and the LTP–LTD group showed a small increase in amplitude over the decay period. The faster decay observed in the experimental groups compared with the LTP controls was reflected in a significant group effect [F(2,13) = 5.39; P < 0.05].
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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Low-frequency (LTD-inducing) stimulation can modulate the effects of high-frequency (LTP-inducing) stimulation when both stimulus patterns are presented during the induction phase, and this effect is dependent on the order of presentation. It is, therefore unlikely that the differential increases in postsynaptic Ca2+ normally associated with LTD and LTP (Cummings et al. 1996; Hansel et al. 1996; Lynch et al. 1983; Malenka and Nicoll 1993; Mulkey and Malenka 1992; Zhang and Poo 2001) simply summate to determine the consequences for the synapse. Although normal LTP effects require 8–10 day of conditioning to reach asymptotic levels of potentiation, the HFS/LFS group showed significantly less potentiation after 10 day of conditioning and required 15 day to reach asymptote. The LFS appears to have suppressed the developing potentiation induced by the HFS, although it remains to be seen if the mechanisms of this effect and depotentiation of a fully induced, asymptotic, LTP are the same. During the first few sessions, there is little measurable LTP to affect, so latent effects in a downstream effector pathway is the likely target. HFS effects tend to be stronger than LFS effects, so it is not surprising that the depotentiation effect did not "clamp" the response amplitude at baseline levels. However, the potentiation effect showed a significantly slower rate of change across days of stimulation. It is not clear whether the weaker LTD effect is attributable to the stimulation protocol or reflects a true difference between LTP and LTD. It is also not clear what we should expect from such interactions. Theoretically, it might be an advantage if potentiation and depression (depotentiation) were not equivalent. This would make it difficult to fully erase stored information. The parameters of the LTP–LTD interactions, however, need to be more fully explored. It is possible that single-pulse LFS may not be the optimal pattern of activation for inducing LTD. Low-frequency paired-pulse stimulation, for example, has been shown to induce LTD in regions that were thought to be resistant to LTD induction by single-pulse LFS (Kemp and Bashir 1997, 1999; Kemp et al. 2000; Kourrich and Chapman 2003). Neocortical LTP is also known to be sensitive to the pattern of HFS stimulation (Werk and Chapman 2003).
Although the reverse order, with LFS leading, did not affect the rate of induction or the magnitude of subsequent LTP induction in the LFS/HFS group, 7 day after the cessation of the HFS, the LTP decay in the LFS/HFS group was greater than normal, reaching a level similar to that seen in the HFS/LFS group. This indicates that the longevity of the LTP effect may have been reduced by the prior exposure to LFS. This observation runs counter to the BCM rule, which would predict a priming effect of LFS on the subsequent induction of LTP.
We have previously found that although LTP in the sensorimotor neocortex of the awake, behaving rat is NMDAR dependent, LTD and depotentiation are not (Froc and Racine 2004). The NMDAR dependency of LTD in other preparations is less clear. Although an NMDAR-dependent form of LTD has been shown in area CA1 (e.g., Dudek and Bear 1992; Mulkey and Malenka 1992; Oliet et al. 1997), LTD has more frequently been shown to be dependent on mGluR-activation [e.g., in area CA1 of the rat hippocampus (Manahan-Vaughan 1997; Nicoll et al. 1998; Oliet et al. 1997; but see Selig et al. 1995b), dentate gyrus (O’Mara et al. 1995; but see Martin and Morris 1997) and visual neocortex (Haruta et al. 1994; Kato 1993)], suggesting that LTD and depotentiation in our preparation may also be mGluR dependent.
In an alternative hypothesis (Bortolotto et al. 1994, 1999), LFS restricts the subsequent induction of LTP through activation of a mGluR-dependent molecular switch. Although (RS)-
-methyl-4-carboxyphenylglycine (MCPG), an mGluR antagonist, blocks the induction of LTP at "naïve" synapses, it does not block the induction of further LTP once submaximal LTP has been induced. Moreover, this switch can be reset by LFS. Thus LFS delivered prior to and after (depotentiation) LTP induction can reset the switch thereby preventing the subsequent induction of LTP. These results are contrary to the BCM theory, which states that the prior induction of LTD by LFS should lower the threshold for LTP. Our observation that prior LFS decreases the longevity of subsequently induced LTP seems to support this alternative hypothesis. On the other hand, prior mGluR activation has been shown to prime the induction of LTP (Cohen et al. 1998) and to facilitate the longevity of LTP (Raymond et al. 2000).
Reversibility of maximal LTP and LTD
The second experiment in this study shows that asymptotic levels of LTP and LTD in the sensorimotor cortex are both reversible. Neither the magnitude nor the induction rate differed between the LTP induced on naive synapses and that induced after the induction of asymptotic LTD. After the induction of asymptotic LTD by LFS, HFS reversed this depression and returned evoked responses to baseline levels. However, this potentiation effect decayed below baseline levels in the 7 day after conditioning, suggesting that the prior LTD was not eliminated but was temporarily masked by the potentiation. The LTP longevity may have also been reduced. There was no difference in the asymptotic level of LTP or the rate of change during induction of LTP between the experimental groups and the LTP control group.
Similar to previous reports (Froc and Racine 2004; Froc et al. 2000), LTD induction affected the early component, but depotentiation did not. Determination of changes in the early component is difficult because LTD reduces the amplitude of the population EPSP, whereas LTP potentiates a group of population spikes with a polarity opposite to the population EPSP. The population EPSP is also potentiated, but this potentiation is typically masked by the population spikes (Chapman et al. 1998). While early component changes appear initially as decreased amplitudes, they often reverse in polarity and include multiple peaks. This change is indicative of an underlying potentiation in the cell discharge that is dissociable from polysynaptic changes (Chapman et al. 1998). The obvious expectation is that the population spike components should be depressed by depotentiation, but they are not, at least not significantly (Fig. 3B), suggesting that LTD and depotentiation may have differential effects on population spike activity. Depotentiation may preferentially affect newly potentiated polysynaptic components whereas LTD affects both monosynaptic and polysynaptic components. It is also possible that the enhanced discharge reflects an increase in excitability, but we have shown that these effects are specific to the activated lines (Trepel and Racine 1998), so any increase in excitability would have to be linked to the activated synapses. There is further evidence that de novo LTD may be mechanistically differentiable from depotentiation. While de novo LTD is inducible in calcineurin A knockout mice, depotentiation is not (Zhuo et al. 1999). According to Lee et al. (2000), LFS-induced depotentiation and LTD at naïve synapses both involve dephosphorylation of the GluR1 subunit of AMPARs but at different sites.
LTD mechanisms could be pre- or postsynaptic or both. LTD has been associated with a decrease in quantal size (Luthi et al. 1999; Nicoll et al. 1998), a decrease in glutamate release (Bolshakov and Sieglebaum 1994), and a postsynaptic decrease in AMPA receptor expression (Carroll et al. 1999a, b, 2001; Daw et al. 2000; Luthi et al. 1999; Man et al. 2000). Changes in NMDAR expression and/or function could also play a role (Grosshans et al. 2002; Montgomery and Madison 2002). LFS has been shown to decrease protein levels of the NR1 subunit of the NMDAR in vivo (Heynen et al. 2000), and LTD of the AMPAR-mediated excitatory postsynaptic current (EPSC) has been reported concomitantly with depression of the NMDAR-mediated EPSC (Selig et al. 1995a; Xiao et al. 1994, 1995; but see Carroll et al. 1999b). In paired recordings between CA3 pyramidal neurons, Montgomery and Madison (2002) have shown that whereas de novo LTD is NMDAR-dependent, depotentiation requires mGluR activation. Given that mGluR LTD does not occlude NMDAR LTD (Oliet et al. 1997) these two forms of LTD may involve different expression mechanisms. These mechanistic differences between LTD and depotentiation suggest that the molecular state of the synapse has been altered by the induction of LTP (Lee et al. 2000; Montgomery and Madison 2002). However, although LTP is NMDAR dependent in the neocortex of the awake behaving rat, the LTD and depotentiation induced by our protocols are not (Froc and Racine 2004). Chemical activation of mGluRs in cultured hippocampal neurons can produce a LTD that is associated with long-lasting loss of AMPA receptors from the membrane surface (Xiao et al. 2001). It remains to be seen whether or not LTD or depotentiation are mGluR dependent in our chronic preparation.
The HFS had a greater effect on the early component amplitude when 10 day of LFS preceded HFS, suggesting that prior exposure to the LTD-inducing stimulation had some enduring effect on subsequent LTP induction. Surprisingly, this effect was not observed in the late component. While LTD induction did not affect the magnitude of subsequently induced late component LTP, the LTP decayed faster.
Chronic preparations have many advantages over slice preparations. For example, the acquisition and decay of slowly developing phenomena can be seen and tracked, the structural correlates of these phenomena can be allowed time to develop, the phenomena can be observed within their natural circuitry with all systems intact, and the relationship between these phenomena and memory can be more easily investigated. The neocortical LTP phenomena that we have reported here and elsewhere (e.g., Trepel and Racine 1998) do not even become apparent until well past the time span of the longest slice experiments.
However, there are also many disadvantages to using chronic preparations. The responses are often not well characterized and can be quite difficult to characterize in the intact preparation. The neocortical field potential LTP and depotentiation effects can also be difficult to interpret because the multiple, potentiated population spikes overlap and mask the monosynaptic population EPSP. Evidence from previous work (Chapman et al. 1998) indicates that both the monosynaptic EPSP and population spikes are generated in Layer V pyramidal neurons, but we do not know to what extent the population spike potentiation is driven by the EPSP potentiation. We do, however, know that the population spike potentiation is specific to the activated lines (Trepel and Racine 1998), so there appears to be no widespread change in neuron excitability. An added problem is that large plasticity effects are also seen in the polysynaptic components, where the location of the critical underlying changes is not known.
Although more research is clearly needed to fully characterize neocortical responses in chronic preparations and ensure that the optimal induction protocols are being used to induce theses plasticity phenomena, it is clear from our data that LTD and LTP are capable of modulating the effects of one another in the awake behaving rat. That the effects of HFS and LFS could, at least partially, reverse each other suggests that they can act cooperatively to modify the functional state of the cortical network.
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ACKNOWLEDGMENTS |
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Present address of D. J. Froc: Dept. of Psychology, University of British Columbia, 2136 West Mall, Vancouver, British Columbia V6T 1Z4, Canada.
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FOOTNOTES |
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Address for reprint requests and other correspondence: R. J. Racine, Dept of Psychology, McMaster University, Hamilton, Ontario, L8S 4K1, Canada (E-mail: racine{at}mcmaster.ca)
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REFERENCES |
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