Department of Ophthalmology, Yale University School of Medicine, New Haven, CT 06520-8061, USA
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Abstract |
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Introduction |
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To investigate these questions, we examined the effects of the PKA inhibitors (9R,10S,12S)-2,3,9,10,11,12-hexahydro-10-hydroxy-9-methyl-1-oxo-9,12-epoxy-1H-dindolo[1,2,3-fg:3',2',1'kl]pyrrolo[3,4-1][1,6]benzodiazocine-10-carboxylic acid, hexyl ester (KT5720) and 8-chloroadenosine-3',5'-monophosphoro-thioate, Rp-isomer (Rp-8-Cl-cAMPS) on LTP and LTD, the most commonly accepted models for neuronal plasticity in the visual cortex, and compared them to the effects of the PKG inhibitor ß-phenyl-1,N2-etheno-8-bromoguanosine-3',5'-monophosphoro-thioate, Rp-isomer (Rp-8-Br-PET-cGMPS). We also examined the effects of the PKA activator 8-chloroadenosine-3',5'-mono-phosphoro-thioate, Sp-isomer (Sp-8-Cl-cAMPS). While the role of PKA (Frey et al., 1993; Huang et al., 1994
; Weisskopf et al., 1994
; Blitzer et al., 1995
; Brandon et al., 1995
; Salin et al., 1996
; Tzounopoulos et al., 1998
; Otmakhova et al., 2000
) and PKG (Zhuo et al., 1994
; Arancio et al., 2001
; Kleppisch et al., 1999
) in LTP and LTD has been studied extensively in hippocampus and other tissues, this is the first time that the effect of PKA and PKG inhibitors on LTP and LTD and the role of activators have been studied in the visual cortex. It is also the first time that this set of comparisons has been made in the same series of experiments on the same tissue.
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Materials and Methods |
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Coronal slices were made from rat visual cortex. SpragueDawley rats (1830 days old) were anesthetized with halothane and decapitated soon after the disappearance of a tail reflex. The brain was rapidly removed and immediately placed in fresh, ice-cold, oxygenated dissection buffer containing (mM) sucrose 215; KCl 2.5; NaH2PO4 1.25; NaHCO3 26; dextrose 10; MgCl2 2.8; CaCl2 1.0. After the brain stayed in the dissection buffer for 2 min, a block of visual cortex was dissected and glued to the microslicer tray. Coronal slices were sectioned at 400 µm in a fresh, ice-cold oxygenated dissection buffer using a DSK 1000 microslicer. The slices were quickly and carefully transferred to a submersion holding chamber that contained fresh artificial cerebrospinal fluid (ACSF, in mM: NaCl 124; KCl 5.0; NaH2PO4 1.25; NaHCO3 26; dextrose 10; MgCl2 1.3; CaCl2 2.5) bubbled with 95% O2/5% CO2 at room temperature. The slices recovered in the holding chamber for at least 1 h before the experiments. For recording, slices were then transferred to a submersion-type recording chamber mounted on the stage of an upright microscope (BX50WI, Olympus) and held fixed by a grid of parallel nylon threads and perfused with ACSF at a rate of 34 ml/min. All experiments were carried out at room temperature (2225°C). Drugs were applied by gravity.
Field potentials were recorded in layer II/III with glass electrodes (<1 M) filled with ACSF by electrically stimulating layer IV with a bipolar matrix stimulating electrode (no. MX21XEP, Frederick Haer and Co.) placed in the center of the cortical thickness. Changes in the amplitude of the maximal negative field potential (FP) were used to measure the magnitude of LTP and LTD.
Slices were stimulated at 0.05 Hz with a constant current pulse (200 µs duration) at 1535 µA, which yielded 5060% of the maximal response. Stimulation for LTP or LTD was applied after 20 min of stable baseline recording. LTP was induced by theta-burst stimulation (TBS) consisting of 10 bursts at 5 Hz, each burst containing five pulses at 100 Hz, repeated for five times at 0.1 Hz. LTD was induced by low-frequency stimulation (LFS) for 15 min at 1 Hz. Every six or nine samples were averaged and field potential amplitudes were then normalized to baseline and expressed as the mean ± SEM. An unpaired Students t-test was used to compare FP amplitudes measured in any two different groups, and a paired Students t-test was used to compare responses obtained before and after drug treatments in the same group. Differences were considered significant at the level of P < 0.05. The P value for LTP or LTD was calculated by comparing FP amplitude at the time point 30 min after LTP or LTD induction with that at 2 min before LTP or LTD induction, unless indicated otherwise. Slices were interleaved for control and drug-treated groups.
All the drugs were applied by bath perfusion. Sp-8-Cl-cAMPS and Rp-8-Br-PET-cGMPS were purchased from BioLog (La Jolla, CA) and prepared as 1000x stocks in distilled water and aliquoted and stored at -20°C. KT5720 (BioMol, Plymouth Meeting, PA) was prepared as a 1000x stock solution in DMSO and also aliquoted and stored at -20°C. Rp-8-Cl-cAMPS (BioLog) was directly dissolved in ACSF to its final concentration before experiments. The stocks were diluted in ACSF to achieve their final concentrations. Concentrations were chosen to be 16100 times greater than the Ki for the protein being antagonized, and two to five times smaller than the Ki for other relevant proteins that might be affected. Other chemicals were purchased from Sigma (St Louis, MO).
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Results |
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One of two different selective and membrane-permeant PKA inhibitors, KT5720 (Kase et al., 1987) or Rp-8-Cl-cAMPS (Gjertsen et al., 1995
), was bath applied for 20 min starting at 15 min before LTP induction by TBS. Although short-term potentiation (STP) was observed, both drugs resulted in the blockade of LTP, whereas the interleaved control slices exhibited normal LTP (Fig. 1A
). Unexpectedly, Rp-8-Br-PET-cGMPS, a selective and membrane-permeant PKG inhibitor (Butt et al., 1995
), also completely blocked LTP (Fig. 1B
). However, neither of these two protein kinase inhibitors affected basal synaptic transmission at the concentrations used in our experiments. Perfusing slices with either KT5720 or Rp-8-Br-PET-cGMPS (Fig. 1C,D
) for 30 min did not significantly affect the amplitude of the field potential in the absence of stimuli to induce LTP or LTD. Thus, both PKA and PKG are required for LTP induction in the visual cortex, but do not have an obvious effect on basal synaptic transmission.
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Discussion |
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The role of the PKA signaling pathway in the late phase of LTP in hippocampus and other tissues is well documented (Frey et al., 1993; Huang et al., 1994
; Nguyen and Kandel, 1996
; Abel et al., 1997
; Bolshakov et al., 1997
). Our results support the point that PKA is also required for the early phase of LTP (Blitzer et al., 1995
; Otmakhova et al., 2000
), since PKA inhibitors block the induction of LTP, and a PKA activator induces LTP by itself. In an attempt to determine whether TBS-induced LTP and potentiation induced by the PKA activator share common mechanisms, we found that LTP induced by repeated TBS occluded Sp-8-Cl-cAMPs-induced potentiation, but application of Sp-8-Cl-cAMPs did not occlude TBS-induced LTP. One explanation for this phenomenon is that PKA activity is not saturated by Sp-8-Cl-cAMPs, even at 50 µM. An alternative explanation is that more than one signaling pathway is required for LTP induction in the visual cortex, so that TBS can still induce LTP even when the cAMP/PKA pathway is saturated. In fact, both CaMKII and p42/44 mitogen-activated protein kinase (MAPK) are reported to contribute to LTP in the visual cortex (Kirkwood et al., 1997
; Cristo et al., 2001
).
Our results agree with the report of Hensch et al. (Hensch et al., 1998) who found that LTP of extracellular field potentials is absent in visual cortical slices from PKA RIß-deficient mice. The present study also indicates that PKA activity is not required for the maintenance of LTP, since application of the PKA inhibitor KT5720 at 30 min after LTP induction does not reduce the magnitude of LTP. This is consistent with the study in hippocampus showing that PKA is transiently activated during LTP (Roberson and Sweatt, 1996
). Our result that a PKA activator produces a potentiation of synaptic transmission that develops gradually after the removal of the activator also suggests that transient activation of PKA initiates a cascade of events. Thus the activity of PKA is not necessary to be kept at high level during the maintenance of LTP.
In contrast to PKA, the role of the cGMP/PKG signaling pathway in LTP is controversial. The discrepancies between the previous reports might be attributed to differences in the experimental conditions. One important variable is the selectivity and membrane permeability of those cGMP analogs and inhibitors used in those studies. Son et al. found that perfusion with 8-Br-cGMP, a cGMP analog, for 5 or 10 min before weak tetanic stimulation resulted in long-lasting potentiation, while perfusion with 8-Br-cGMP for 15 min before weak tetanic stimulation resulted in no long-lasting potentiation at all. However, perfusion with 8-pCPT-cGMP, a different cGMP analog that is more membrane permeable and more selective for activation of PKG, for 15 or even 30 min before weak tetanic stimulation produced robust LTP (Son et al., 1998). Another important variable might be the protocol for LTP induction. Parent et al. reported that activation of cyclic nucleotide-gated ion channel (CNG) 1 contributed to LTP induction by TBS but not to that by tetanic stimulation (Parent et al., 1998
). Most cGMP analogs have effects on CNGs to a different extent. Thus we chose Rp-8-Br-PET-cGMPs, a more selective and more membrane permeable PKG inhibitor that does not affect CNG at the concentration used in this study, to determine the role of PKG in LTP in the present experiments. The results show that the PKG inhibitor can completely block TBS-induced LTP. These results agree with some studies in the hippocampus (Zhuo et al., 1994
; Arancio et al., 1995
; Malen and Chapman, 1997
) and clearly demonstrate that the cGMP/PKG signaling pathway is required for the early phase of LTP in visual cortex. In hippocampus, it was reported that cGMP acted directly in the presynaptic neuron to produce LTP (Son et al., 1998
; Arancio et al., 2001
). But in the visual cortex, cGMP has postsynaptic facilitating effects on both excitatory synaptic transmission and NMDA response (Wei et al., 2002
), so it will be intriguing to determine whether PKG contributes to LTP in the visual cortex by presynaptic or postsynaptic mechanisms.
Of greater interest were the results from LTD experiments. LTD has been suggested to be simply a reversal of LTP, specifically that LTD and depotentiation share a common mechanism. An attractive hypothesis is that LTP and LTD reflect the phosphorylation and dephosphorylation, respectively, of a common set of synaptic proteins (Lisman, 1989; Bear and Malenka, 1994
). If this is true, inhibitors of the relevant protein kinases should block LTP and may facilitate or even produce LTD by themselves (Kameyama et al., 1998
), but at least should not block LTD. In our case, neither PKA nor PKG inhibitors produced LTD by themselves, though they blocked LTP. To the contrary, inhibitors of PKA blocked LTD, which is consistent with the results from visual cortical (Hensch et al., 1998
) and hippocampal slices of PKA RIß-deficient mice (Brandon et al., 1995
) and results from the hippocampus of mice lacking the Cß1 catalytic sub-unit of PKA (Qi et al., 1996
). So far little is known about the mechanisms of PKA action in LTD. If basal synaptic transmission is governed by PKA, down-regulation of PKA activity would induce LTD and subsequent application of electrical LTD-induction protocols would produce no further depression (Kameyama et al., 1998
). But this is not true in our case, because the PKA inhibitor KT5720 did not significantly change basal synaptic transmission when it was applied in the same manner as in the LTD experiments. Kato et al. reported that intracellular calcium release through inositol-1,4,5-trisphosphate (IP3) facilitates induction of LTD in visual cortex (Kato et al., 2000
), and PKA is well demonstrated to be a major regulator of intracellular calcium release by phosphorylation of IP3 receptors (Haug et al., 1999
; Bugrim, 1999
). Thus one possibility is that PKA takes part in LTD induction through regulation of intracellular Ca2+ release by IP3 receptors. An alternative possibility that could account for our results is that PKA plays a role in both LTD and LTP by modulating NMDA receptors. Because inhibition of PKA blocks both LTP and LTD, the simplest hypothesis is that PKA inhibitors affect a common component of mechanisms for LTP and LTD. Both LTP and LTD in the pathway from layer IV to layer II/III in visual cortex are NMDA receptor-dependent (Kirkwood and Bear, 1994a
,b
). So NMDA receptors would be an attractive target for PKA in this hypothesis. It has been demonstrated that the NMDA receptor 1 subunit (NR1) can be phosphorylated by PKA on serine 890 and 897 (Tingley et al., 1997
). In addition, NMDA channel activity can be enhanced by PKA but is limited by PP1, and PKA is bound to PP1 by Yotiao, an NMDA receptor-associated protein (Westphal et al., 1999
). Thus once PKA is inhibited, the function of NMDA channel will be depressed by PP1 so that LTP or LTD is blocked.
The current study also allows us to relate our results on LTP and LTD with previous results on ocular dominance plasticity (Beaver et al., 2001), and to ask what role LTP and LTD may play in plasticity in the whole animal. PKA inhibitors abolish both LTP and LTD and ocular dominance plasticity. PKG inhibitors abolish LTP but not LTD, and do not affect ocular dominance plasticity. The simple suggestion from this is that LTP is not sufficient to support ocular dominance plasticity, or LTD is more important for ocular dominance plasticity than LTP. Antonini and Stryker (Antonini and Stryker, 1993
, 1996
) looked at the anatomical correlates of ocular dominance plasticity, and found that terminals from the deprived eye retract over the first week, well before the terminals of the non-deprived eye expand. If LTD is associated with retraction of terminals and LTP with expansion, and retraction has to occur before expansion to liberate space for the expansion, then blockage of LTD will prevent ocular dominance plasticity, but blockage of LTP may not. A similar result has been found in the process of retraction of connections from the retina within the lateral geniculate nucleus to form eye-specific layers. This retraction does not occur in mice mutant for class I major histocompatibility complex, and LTD is absent, while LTP is enlarged (Huh et al., 2000
). However, as we noted, all the experiments in the present study were carried out at room temperature. Reservations might be necessary for us to draw conclusions regarding in vivo conditions, since synaptic transmission in the visual cortex, like other mammalian physiological functions, can be affected by changes in temperature (Volgushev et al., 2000
).
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Notes |
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Address correspondence to: Nigel W. Daw, Department of Ophthalmology, Yale University Medical School, New Haven, CT 06520-8061, USA. Email: nigel.daw{at}yale.edu.
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References |
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