Skip to main content
NCBI home page
The Journal of Physiology logoLink to The Journal of Physiology
. 1998 Dec 1;513(Pt 2):467–475. doi: 10.1111/j.1469-7793.1998.467bb.x

Role of protein kinase C in the induction of homosynaptic long-term depression by brief low frequency stimulation in the dentate gyrus of the rat hippocampus in vitro

Y Wang *, J Wu *, M J Rowan †, R Anwyl *
PMCID: PMC2231306  PMID: 9806996

Abstract

  1. Enhancement of the induction of long-term depression (LTD) of excitatory postsynaptic currents (EPSCs) by a priming stimulus was investigated in the medial perforant pathway of the dentate gyrus of the hippocampus in vitro.

  2. In control, LTD could be induced by a conditioning low frequency stimulation (LFS) consisting of sixty, although not thirty or fewer, stimuli at 1 Hz applied at a holding potential of −40 mV.

  3. A conditioning LFS of just five stimuli at 1 Hz was found to induce LTD if preceded 1–5 min, but not 15 min, by a priming LFS of five stimuli at 1 Hz, −40 mV, which did not by itself induce LTD.

  4. A low concentration of the protein kinase C (PKC) activator (−)-indolactam V, which did not itself induce LTD, reduced the threshold for the number of stimuli inducing LTD following the priming stimulus, while a high concentration of (−)-indolactam V directly induced a depression of the test excitatory postsynaptic current (EPSC), which occluded LFS-induced LTD. This suggests that the priming of LTD and also the direct induction of LTD involves the activation of PKC.

  5. The pseudosubstrate peptide inhibitor PKC19–36 inhibited the induction of LTD by the priming protocol and by the control induction conditioning protocol.

  6. These experiments demonstrate that a covert synaptic change involving generation of PKC is very effective in producing conditions whereby LTD is induced by very brief synaptic stimulation.

Long-term depression (LTD) is a long-lasting activity-dependent reduction in excitatory glutamatergic transmission which can be induced by a period of low frequency presynaptic stimulation (LFS) (reviewed by Bear & Malenka, 1994; Linden, 1994). The standard method for induction of homosynaptic LTD of field excitatory potentials is 5–15 min of LFS at 1−5 Hz in CA1 hippocampus in vitro (Dudek & Bear, 1992; Mulkey & Malenka, 1992). Two types of protocol have recently been discovered that in the hippocampus result in the induction of LTD in vitro by a much briefer duration of presynaptic stimulation, and which therefore may be of greater physiological significance. The first protocol consists of a combination of LFS with depolarization of the postsynaptic cell. Stimulation at 10 Hz for 2 s in CA1 (Cummings et al. 1996) or 1 Hz for 60 s in the dentate gyrus (Wang et al. 1996, 1997) was found to result in the induction of a large magnitude LTD of excitatory postsynaptic currents (EPSCs) in cells held at −40 to −60 mV. The second protocol that enhanced the induction of LTD involves a priming stimulus preceding the LFS. High frequency stimulation (HFS) preceding LFS resulted in an enhancement of the amplitude of LTD in CA1, both in experiments in which the priming HFS resulted in the induction of long-term potentiation (LTP) (Wagner & Alger, 1995) and in experiments in which the priming HFS resulted in the induction of only short-term potentiation (STP) (Wexler & Stanton, 1993).

In the present study, we have carried out an investigation of priming of LTD in the dentate gyrus in vitro. We have shown in previous studies that large amplitude LTD can be induced routinely by LFS in the dentate gyrus, in both juvenile and adult animals (O'Mara et al. 1995a, b; Wang et al. 1997). We present evidence that a brief LFS can act as a priming stimulus for LFS-induced LTD, and that the priming is mediated via activation of protein kinase C (PKC). Because of the difficulty in obtaining LTD in vivo in the dentate gyrus, perhaps because of the very prominent inhibitory tone in this region (Doyere et al. 1996), we routinely added picrotoxin to our bathing media, as in previous studies (O'Mara et al. 1995a, b; Wang et al. 1997), which may facilitate induction of LTD.

METHODS

All experiments were carried out on transverse slices of the rat hippocampus (Wistar; age, 2–3 weeks; weight, 40–80 g). The brains were rapidly removed after decapitation and placed in cold oxygenated (95 % O2-5 % CO2) media. Slices were cut at a thickness of 350 μm using a Campden vibroslice, and placed in a holding container containing oxygenated media at room temperature (20–22°C). The slices were then transferred as required to a submerged recording chamber and continuously superfused at a rate of 8 ml min−1 at 32°C.

The control media contained (mM): NaCl, 120; KCl, 2.5; NaH2PO4, 1.25; NaHCO3, 26; MgSO4, 2.0; CaCl2, 2.0; and D-glucose, 10. All solutions contained 100 μM picrotoxin (Sigma) to block GABAA-mediated activity. Additional drugs used were D-2-amino-phosphonopentanoate (AP5, Tocris Cookson), (−)-indolactam V (LC Labs), (+)-indolactam V (LC Labs), and PKC19–36 (Calbiochem). The patch clamp electrode (resistance, 5–8 MΩ) contained (mM): potassium gluconate, 130; KCl, 10; EGTA, 10; CaCl2, 1; MgCl2, 3; Hepes, 20; MgATP, 5; NaGTP, 0.5; and 2(triethylamino)-N-(2,6-dimethylphenyl)acetamide (QX 314), 5; pH 7.2 (using KOH).

Whole-cell recordings from dentate granule cells were made using an Axopatch 1D amplifier (3 kHz low-pass Bessel filter), as described previously (O'Connor et al. 1995). Series resistance (Rs) measured 12–25 MΩ, as measured directly from the amplifier. Rs was also measured directly in several cells from the peak amplitude of the resistive current Ic (without low-pass filtering), as Rs=VR/Ic, where VR is the amplitude of the test pulse, usually 10 mV. The mean input resistance was 258 ± 24 MΩ(number of cells (n) = 63) and the mean resting potential −71 ± 3 mV (n= 68). The input resistance was monitored continuously, and the recording terminated if it varied by more than 10 %. Test EPSCs were recorded at a holding potential of −70 mV in response to stimulation of the medial perforant pathway at a control frequency of 0.05 Hz, with the stimulation intensity adjusted to evoke an EPSC which was about 30 % of the maximum amplitude, usually about 50–100 pA. Control homosynaptic LTD was evoked by LFS consisting of sixty stimuli at 1 Hz, under voltage clamp, with the cell held at −40 mV. The amplitude of LTD was measured 30 min post-LFS. Full experiments were carried out provided that certain criteria were met. These included a resting membrane potential of at least −65 mV, a high input resistance (at least 200 MΩ), and a low threshold and steep input-output curve for the EPSCs.

Recordings were analysed using the Strathclyde electrophysiological software (Dr J. Dempster, Strathclyde University, UK). Values are the mean ±s.e.m., and Student's t test was used for statistical comparisons.

RESULTS

Induction of LTD of EPSCs by LFS

Control LTD without priming stimulation was induced by a conditioning LFS applied presynaptically at a frequency of 1 Hz with the postsynaptic cell held at −40 mV. Sixty continuous stimuli applied at 1 Hz induced a large amplitude LTD (Fig. 1A). It can be seen that the LTD attained a peak amplitude averaging 37 ± 3 % (n= 12, P < 0.005). LTD of a similar magnitude could be induced up to 30 min following formation of a whole-cell clamp. Although LTD developed rapidly (peak amplitude in ∼1 min) in seven out of the twelve cells, LTD developed relatively slowly in the remaining five cells, with a peak amplitude being attained in 10–15 min. Thus the group mean shown in Fig. 1A attained a time to peak of 4 min. A similar slow development of LTD has previously been observed in CA1 hippocampus using a brief induction protocol (10 Hz, 2 s) in depolarized cells (Cummings et al. 1996). Thirty conditioning stimuli at 1 Hz did not induce LTD at −40 mV (Fig. 1B), the EPSCs measuring 105 ± 3 % (n= 6, P > 0.05) following LFS, demonstrating that the threshold number of stimuli at 1 Hz required for LTD induction is between about thirty and sixty.

Figure 1. Induction of LTD by conditioning LFS.

Figure 1

Open in a new tab

A, 60 conditioning stimuli applied at a frequency of 1 Hz and at a holding potential of −40 mV (indicated by arrow) induced LTD of test EPSCs, recorded under whole-cell patch clamp recording conditions at −70 mV (n= 12). The traces show an EPSC prior to (a), and following (b), induction of LTD. B, 30 conditioning stimuli applied at 1 Hz and at −40 mV did not induce LTD (n= 6).

Priming stimulation reduces the threshold for LTD induction

The priming protocol consisted of five stimuli at 1 Hz, at −40 mV (the priming LFS), followed by an interval of 1–15 min prior to applying a further conditioning LFS, at −40 mV. The five priming stimuli did not alone induce significant short-term depression or LTD, the EPSC averaging 98 ± 7 % (n= 15, P > 0.05) during the 5 min following the five priming stimuli (Fig. 2A and C). The effect of such priming stimuli is shown in Fig. 2A, in which five priming stimuli followed, after an interval of 5 min, by a further five conditioning stimuli, resulted in the induction of a large LTD measuring 46 ± 4 % (n= 5, P < 0.01). Thus the priming protocol reduced the threshold for the induction of maximal or near-maximal LTD from between thirty and sixty to only five conditioning stimuli. In order to determine whether the effects of the priming are time dependent, the interval between the priming LFS and the conditioning LFS was varied, with intervals of 1 or 15 min between the priming stimuli and the conditioning stimuli. The magnitude of the induced LTD was found to be lower with an interval of 1 or 15 min compared with 5 min between the priming and conditioning LFS. If only a 1 min interval was allowed between the five priming stimuli and the five conditioning pulses, LTD measured 20 ± 5 % (n= 5, P < 0.05) (Fig. 2B), while a 15 min interval between priming stimuli and conditioning LFS did not induce LTD, the EPSCs measuring 101 ± 4 % (n= 5, P > 0.05) following LFS (Fig. 2C).

Figure 2. Enhancement of LTD induction by a priming protocol.

Figure 2

Open in a new tab

An initial 5 priming stimuli at 1 Hz, −40 mV, were applied, followed, after a variable interval of 1–15 min, by a further 5 stimuli at 1 Hz, −40 mV (n= 5). A, 5 priming stimuli followed, after an interval of 5 min, by 5 conditioning stimuli, induced large amplitude LTD. Traces show an EPSC before (a) and after (b) induction of LTD. B, 5 priming stimuli followed, after an interval of 1 min, by 5 conditioning stimuli, induced a small amplitude LTD (n= 5). C, 5 priming stimuli followed, after an interval of 15 min, by 5 conditioning stimuli, did not induce LTD (n= 5). Traces show an EPSC before (a) and after (b) the lack of induction of LTD.

Weak PKC activation reduces the threshold for LTD induction following a priming LFS, and strong PKC activation directly induces LTD

A simple explanation for the ability of priming to enhance LTD induction is that the priming stimuli result in the activation of an intracellular messenger which is slow to be generated or to have an enhancing action on LTD induction. We investigated the effect of one likely candidate for the priming messenger, PKC. The effects of PKC activation were investigated by the application of the selective PKC activator (−)-indolactam V (Fujiki et al. 1984; Golard et al. 1993; Boxall et al. 1996).

(−)-Indolactam V was allowed to diffuse into the cell from the patch pipette. At a low concentration (25 μM) in the patch electrode, (−)-indolactam V did not alter the baseline test EPSCs but did reduce the number of conditioning stimuli required to induce LTD following a priming stimulation. In a control priming set of experiments at −40 mV, five priming stimuli at 1 Hz followed after 5 min by two conditioning stimuli at 1 Hz did not induce LTD, the EPSCs measuring 108 ± 8 % (n= 6, P > 0.05) following LFS (Fig. 3A). However, in the presence of 25 μM (−)-indolactam V, five priming stimuli followed after 5 min by two conditioning stimuli at 1 Hz did induce significant LTD, which measured 21 ± 3 % (n− 6, P < 0.01) (Fig. 3B).

Figure 3. A low concentration (25 μM) of the PKC activator (−)-indolactam V enhances the induction of LTD by priming stimulation.

Figure 3

Open in a new tab

A, a protocol of 5 priming stimuli followed by 2 conditioning stimuli at −40 mV did not induce LTD (n= 5). Traces show the EPSC prior to induction of LTD (a) and following induction of LTD (b). B, in the presence of a low concentration of (−)-indolactam V (25 μM), applied intracellularly via the patch pipette, LTD was induced by an identical protocol (n= 5).

At high concentrations (200 μM) in the patch pipette (−)-indolactam V induced a depression in the EPSC evoked at the test frequency and measured at the holding potential. The depression was initiated within 2 min of forming the whole-cell patch and stabilized within 5–8 min at a level of 37 ± 3 % (n 7equals; 5, P < 0.01) (Fig. 4A). No change in input resistance was associated with the indolactam-induced depression of the EPSC. The (−)-indolactam V-induced depression appeared to be generated by induction of LTD, as it occluded LFS-induced LTD. Thus subsequent LFS (60 stimuli at 1 Hz) at −40 mV did not result in the induction of LTD in these experiments, the EPSC being further reduced by only 3 ± 3 % (n= 5). These experiments demonstrate that strong activation of PKC results in the direct induction of LTD at the test stimulation frequency.

Figure 4. A high concentration (200 μM) of the PKC activator (−)-indolactam V induced a depression of the EPSC which occluded LFS-induced LTD.

Figure 4

Open in a new tab

A, a high concentration (200 μM) of indolactam V initiated the induction of LTD within a couple of minutes of formation of the whole-cell patch, and maximal LTD was attained 5 min after patch formation, even whilst stimulation was only at the test frequency. Application of LFS (60 stimuli at −40 mV) failed to induce further LTD (n= 5), showing occlusion of the LFS-induced LTD by the (−)-indolactam V-induced LTD. B, the inactive isomer (+)-indolactam V did not induce run-down of the EPSC at the test frequency, although application of LFS (60 stimuli at 1 Hz, −40 mV) led to LTD induction (n= 5).

The inactive stereoisomer (+)-indolactam V was ineffective at inducing a depression of the EPSC. A high concentration of (+)-indolactam (200 μM) did not directly induce LTD (EPSC = 100 ± 9 %, n= 5), but LFS consisting of sixty stimuli at 1 Hz, −40 mV, induced LTD of 30 ± 4 % (n= 5, P < 0.05) (Fig. 4B).

Inhibition of PKC blocks LTD induction by the priming and prolonged LFS protocols

Verification of the role of PKC activation in the induction of LTD was accomplished by the use of the PKC inhibitory peptide PKC19–36 (House & Kemp, 1987), which was added to the patch pipette solution at a concentration of 100 μM. PKC19–36 did not alter the amplitude of the test EPSC as it diffused into the cell. However, the induction of LTD by the priming protocol of five stimuli at 1 Hz followed, after an interval of 5 min, by a further five stimuli at 1 Hz, was completely blocked by PKC19–36, LTD measuring 1 ± 4 % (n= 6, P > 0.05) (Fig. 5A). The inhibitory PKC peptide also completely blocked the induction of LTD by sixty stimuli at 1 Hz, LTD measuring 5 ± 3 % (n= 5, P > 0.05) following LFS (Fig. 5B).

Figure 5. The PKC inhibitor PKC19–36, applied intracellularly from the patch pipette, inhibited the induction of LTD.

Figure 5

Open in a new tab

A, PKC19–36 inhibited the induction of LTD by the priming protocol of 5 priming stimuli followed after 5 min by 5 conditioning stimuli (n= 5). B, PKC19–36 inhibited the induction of LTD by LFS consisting of 60 stimuli at 1 Hz, −40 mV (n= 5).

DISCUSSION

The present experiments show that LTD can be induced by a very brief period of stimulation if optimal induction conditions are employed. It is not necessary to use prolonged LFS, which has been used in most previous studies to induce LTD in CA1 (Mulkey & Malenka, 1992; Dudek & Bear, 1992; Bolshakov & Siegelbaum, 1994; Selig et al. 1995; Xiao et al. 1995) and the dentate gyrus (O'Mara et al. 1995a, b). One important parameter which has been found in the present study to reduce greatly the threshold number of stimuli for LTD induction is priming.

Priming

The use of the term priming of LTD in the present context refers to the ability of prior synaptic activity that does not itself induce LTD to induce LTD by a later conditioning stimulation. Thus a covert priming stimulation is reducing the threshold for LTD induction by conditioning stimulation. The present study is, to our knowledge, the first demonstrating a facilitation of homosynaptic LTD by a low frequency priming stimulus. In the present studies, a LFS priming protocol was very effective in lowering the threshold for LTD induction. While the threshold number of stimuli at 1 Hz that induced LTD in control experiments was between thirty and sixty, this was lowered to less than five stimuli following the priming. A similar lowering of the threshold of synaptic plasticity has previously been observed in the CA1, in which full depotentiation of LTP was observed if just four stimuli at 100 Hz were applied at the trough of carbachol-induced θ activity (Huerta & Lisman, 1995). Thus the combination of mild depolarization of the cell plus a priming stimulus allows the induction of LTD with a very small number of stimuli. Enhancement of homosynaptic LTD and depotentiation has also previously been demonstrated by a HFS priming protocol in CA1 in vitro (Wexler & Stanton, 1993; Wagner & Alger, 1995). Such priming by HFS was found to be covert in the studies of Wagner et al. (1995), with application of the HFS, even in the presence of AP5, successfully priming LTD. Priming of associative LTD by LFS has been documented between two different pathways in the dentate gyrus in vivo (Christie & Abraham, 1992). In this latter study, associative LTD (that occurring in the lateral perforant pathway when LFS was delivered out of phase with brief HFS trains in the medial perforant pathway) was only induced if the lateral perforant pathway received 5 Hz priming stimulation (Christie & Abraham, 1992).

Role of PKC

The use of the PKC activator (−)-indolactam V in the present studies provided evidence that an increase in PKC is involved in both the priming of LTD and the direct induction of LTD. Thus a low concentration of (−)-indolactam V, which would be expected to stimulate a relatively low level of PKC, and which did not alter the baseline test EPSCs, lowered the number of conditioning stimuli required to induce LTD in the priming protocol. Moreover, a high concentration of (−)-indolactam V, which would be expected to strongly stimulate PKC, directly induced LTD in the present study. The enhancement by (−)-indolactam V may be produced by an additive effect of the PKC generated by (−)-indolactam V and that generated by the subthreshold LFS, or, alternatively, by a synergistic action of the indolactam V-activated PKC and a second LFS-induced intracellular messenger. In previous studies, extracellular application of the the PKC activator phorbol 12,13-diacetate, which produced a large enhancement of synaptic transmission of field EPSPs, was found to be able to substitute for high frequency synaptic transmission in priming synapses to exhibit enhanced homosynaptic LTD in CA1 (Stanton, 1995). LTD induction in the cerebellum was also directly induced by stimulation of PKC with (−)-indolactam V (Boxall et al. 1996).

Further support for an essential role of activation of PKC in LTD induction was established by the finding in the present study that the induction of LTD, both by the priming protocol and by the control protocol, was blocked by the PKC inhibitor PKC19–36. Previous studies in CA1 have shown that PKC19–36 prevented the induction of a metabotropic glutamate receptor (mGluR)-dependent LTD, although not an NMDA receptor (NMDAR)-dependent LTD, in CA1 (Oliet et al. 1997). LTD in the cerebellum was also blocked by PKC inhibitors (Linden & Connor, 1991; Hemart et al. 1995).

The magnitude of the priming-induced LTD was found to be greater with a 5 min priming interval between the priming and conditioning stimuli than with a 1 or 15 min interval. This optimal interval of 5 min may reflect the maximal level of PKC induced by the priming stimulus.

Role of mGluR

The receptor most likely to be involved in the stimulation of PKC is the mGluR. We have previously shown that activation of mGluRs is essential for homosynaptic LTD induction in the dentate gyrus (O'Mara et al. 1995a), with the mGluR agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid ((1S,3R)-ACPD) directly inducing LTD, and the mGluR antagonist (+)-α-methyl-carboxyphenylglycine (MCPG) preventing LTD induction. Activation of mGluR has also been shown to be required for the induction of an NMDAR-independent LTD in CA1, with MCPG inhibiting the induction of LTD (Bolshakov & Siegelbaum, 1994; Oliet et al. 1997). mGluR group I are known to be linked to phospholipase C and thence activation of PKC. We therefore hypothesize that the priming LFS results in mild activation of mGluRs and subsequent stimulation of PKC at a concentration below that which directly induces LTD. The LTD induced by the combination of priming and conditioning LFS would then be generated by the additive action of PKC generated by the priming and by the conditioning LFS.

Different forms of LTD

Several distinct forms of LTD, with different modes of induction, appear to be present in the hippocampus. In CA1, two distinct forms of LTD have been described. The induction of one type was NMDAR dependent and mGluR independent, involved a protein phosphatase cascade, and was postsynaptically induced and expressed. A second type was NMDAR independent, dependent on activation of mGluRs, Ni2+-sensitive Ca2+ channels and PKC generation, prevented by blocking GABAA inhibition, independent of phosphatase inhibition, postsynaptically induced and presynaptically expressed (Oliet et al. 1997). Both types of LTD induction were independent of nitric oxide (NO) production (Selig et al. 1995; Oliet et al. 1997). A LTD that we have previously investigated in several studies in the medial perforant pathway of the dentate gyrus appears to be a third distinct type of LTD. It is NMDAR independent, and dependent on mGluR activation (O'Mara et al. 1995a), activation of Ni2+-sensitive Ca2+ channels (Wang et al. 1997), NO production (Wu et al. 1997) and release of Ca2+ from intracellular stores (O'Mara et al. 1995a; Wang et al. 1997). The induction of such LTD is not prevented by blocking GABAA inhibition (O'Mara et al. 1995a; Wang et al. 1997), and appears to be postsynaptically expressed, as it is not associated with a change in paired pulse depression (authors’ unpublished observations).

In conclusion, the present experiments demonstrate that hippocampal LTD can occur in two stages; an initial activity produces an underlying and enduring trace, which can then act at a later time in conjunction with synaptic activity to produce a stronger long-lasting synaptic depression.

Acknowledgments

This work was supported by grants from the Health Research Board, Ireland; The Wellcome Trust; and the European Union, DGXII.

References

  1. Bear MF, Malenka RC. Synaptic plasticity: LTP and LTD. Current Opinion in Neurobiology. 1994;4:389–399. doi: 10.1016/0959-4388(94)90101-5. [DOI] [PubMed] [Google Scholar]
  2. Bolshakov VY, Siegelbaum SA. Postsynaptic induction and presynpatic expression of hippocampal long-term depression. Science. 1994;264:1148–1152. doi: 10.1126/science.7909958. [DOI] [PubMed] [Google Scholar]
  3. Boxall AR, Lancaster B, Garthwaite J. Tyrosine kinase is required for long-term depression in the cerebellum. Neuron. 1996;16:805–813. doi: 10.1016/s0896-6273(00)80100-2. [DOI] [PubMed] [Google Scholar]
  4. Christie BR, Abraham WC. Priming of associative long-term depression in the dentate gyrus by theta frequency synaptic activity. Neuron. 1992;9:79–84. doi: 10.1016/0896-6273(92)90222-y. [DOI] [PubMed] [Google Scholar]
  5. Cummings JA, Mulkey RM, Nicoll RA, Malenka RC. Ca2+ signalling requirements for long-term depression in the hippocampus. Neuron. 1996;16:825–833. doi: 10.1016/s0896-6273(00)80102-6. [DOI] [PubMed] [Google Scholar]
  6. Doyere V, Errington ML, Laroche S, Bliss TVP. Low frequency trains of paired stimuli induce long-term depression in area CA1 but not in dentate gyrus of the intact rat. Hippocampus. 1996;6:52–57. doi: 10.1002/(SICI)1098-1063(1996)6:1<52::AID-HIPO9>3.0.CO;2-9. 10.1002/(SICI)1098-1063(1996)6:1<52::AID-HIPO9>3.3.CO;2-Q. [DOI] [PubMed] [Google Scholar]
  7. Dudek SM, Bear MF. Homosynaptic long-term depression in area CA1 of the hippocampus and effects of N-methyl-D-aspartate receptor blockade. Neuron. 1992;9:967–975. doi: 10.1073/pnas.89.10.4363. 10.1016/0896-6273(92)90248-C. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Fujiki H, Suganuma M, Nakayasu M, Tahira T, Endo Y, Shuda K, Sugimura T. Structure-activity studies on synthetic analogues (indolactams) of the tumor promotor teleocidin. Gann Monograph on Cancer Research. 1984;75:866–870. [PubMed] [Google Scholar]
  9. Golard A, Role LW, Siegelbaum SA. Protein kinase C blocks somatostatin-induced modulation of calcium current in chick sympathetic neuron. Journal of Neurophysiology. 1993;70:1639–1643. doi: 10.1152/jn.1993.70.4.1639. [DOI] [PubMed] [Google Scholar]
  10. Hemart N, Daniel H, Jaillard D, Crepel F. Receptors and second messengers involved in long-term depression in rat cerebellar slices in vitro; a reappraisal. European Journal of Neuroscience. 1995;7:45–53. doi: 10.1111/j.1460-9568.1995.tb01019.x. [DOI] [PubMed] [Google Scholar]
  11. House C, Kemp BE. Protein kinase C contains a pseudosubstrate protype in its regulatory domain. Science. 1987;238:1726–1728. doi: 10.1126/science.3686012. [DOI] [PubMed] [Google Scholar]
  12. Huerta PT, Lisman JE. Bidirectional synaptic plasticity induced by a single burst during cholinergic theta oscillation in CA1 in vitro. Neuron. 1995;15:1053–1063. doi: 10.1016/0896-6273(95)90094-2. 10.1016/0896-6273(95)90094-2. [DOI] [PubMed] [Google Scholar]
  13. Linden DJ. Long-term depression in the mammalian brain. Neuron. 1994;12:457–472. doi: 10.1016/0896-6273(94)90205-4. 10.1016/0896-6273(94)90205-4. [DOI] [PubMed] [Google Scholar]
  14. Linden DJ, Connor JA. Participation of postsynaptic PKC in cerebellar long-term depression in culture. Neuron. 1991;15:1393–1401. doi: 10.1126/science.1721243. 10.1016/0896-6273(95)90017-9. [DOI] [PubMed] [Google Scholar]
  15. Mulkey RM, Malenka RC. Mechanisms underlying induction of homosynaptic long-term depression in area CA1 of the hippocampus. Neuron. 1992;9:967–975. doi: 10.1016/0896-6273(92)90248-c. 10.1016/0896-6273(92)90248-C. [DOI] [PubMed] [Google Scholar]
  16. O'Connor J, Rowan MJ, Anwyl R. Tetanically induced LTP involves a similar increase in the AMPA and NMDA receptor components of the excitatory postsynaptic current: Investigations of the role of mGlu receptors. Journal of Neuroscience. 1995;15:2013–2020. doi: 10.1523/JNEUROSCI.15-03-02013.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. O'Mara S, Rowan MR, Anwyl R. Metabotropic glutamate receptor-induced homosynaptic long-term depression and depotentiation in the dentate gyrus of the rat hippocampus in vitro. Neuropharmacology. 1995a;34:983–989. doi: 10.1016/0028-3908(95)00062-b. 10.1016/0028-3908(95)00062-B. [DOI] [PubMed] [Google Scholar]
  18. O'Mara S, Rowan MR, Anwyl R. Dantrolene inhibits long-term depression and depotentiation of synaptic transmission in the rat dentate gyrus. Neuroscience. 1995b;68:621–624. doi: 10.1016/0306-4522(95)00233-9. 10.1016/0306-4522(95)00233-9. [DOI] [PubMed] [Google Scholar]
  19. Oliet SHR, Malenka RC, Nicoll RA. Two distinct forms of long-term depression coexist in CA1 hippocampal pyramidal cells. Neuron. 1997;18:969–982. doi: 10.1016/s0896-6273(00)80336-0. 10.1016/S0896-6273(00)80336-0. [DOI] [PubMed] [Google Scholar]
  20. Selig DK, Lee H-K, Bear MF, Malenka RC. Reexamination of the effects of MCPG on hippocampal LTP, LTD and depotentiation. Journal of Neurophysiology. 1995;74:1075–1082. doi: 10.1152/jn.1995.74.3.1075. [DOI] [PubMed] [Google Scholar]
  21. Stanton PK. Transient protein kinase C activation primes long-term depression and suppresses long-term potentiation of synaptic transmission in hippocampus. Proceedings of the National Academy of Sciences of the USA. 1995;92:1724–1728. doi: 10.1073/pnas.92.5.1724. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Wagner JJ, Alger BE. GABAergic and developmental influence on homosynaptic LTD and depotentiation in rat hippocampus. Journal of Neuroscience. 1995;15:1577–1586. doi: 10.1523/JNEUROSCI.15-02-01577.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Wang Y, Rowan MJ, Anwyl R. Evidence that long-term depression induction in the rat hippocampus in vitro requires Ca2+ influx via Ni2+-sensitive Ca2+ channels and Ca2+ release from intracellular stores. The Journal of Physiology. 1996;495.P:50P. [Google Scholar]
  24. Wang Y, Rowan MJ, Anwyl R. Induction of LTD is NMDAR-independent, but dependent on Ca influx via low voltage gated Ca channels and release of Ca from intracellular stores in the dentate gyrus in vitro. Journal of Neurophysiology. 1997;77:812–825. doi: 10.1152/jn.1997.77.2.812. [DOI] [PubMed] [Google Scholar]
  25. Wexler EM, Stanton PK. Priming of homosynaptic long term depression in hippocampus by previous synaptic activity. NeuroReport. 1993;4:591–594. doi: 10.1097/00001756-199305000-00034. [DOI] [PubMed] [Google Scholar]
  26. Wu J, Rowan MR, Anwyl R. Evidence for involvement of the neuronal isoform of nitric oxide synthase during induction of long-term potentiation and long-term depression in the rat dentate gyrus in vitro. Neuroscience. 1997;78:393–398. doi: 10.1016/s0306-4522(97)84911-1. 10.1016/S0306-4522(97)84911-1. [DOI] [PubMed] [Google Scholar]
  27. Xiao M-Y, Karpefors M, Gustafsson B, Wigstrom H. On the linkage between AMPA and NMDA receptor-mediated EPSPs in homosynaptic long-term depression in the hippocampal CA1 region of young rats. Journal of Neuroscience. 1995;15:4496–4506. doi: 10.1523/JNEUROSCI.15-06-04496.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from The Journal of Physiology are provided here courtesy of The Physiological Society

RESOURCES