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This Article Abstract Full Text (PDF) All Versions of this Article: 94/5/3643    most recent 00548.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (2) Citing Articles via Google Scholar Google Scholar Articles by Cuellar, J. C. Articles by Merlin, L. R. Search for Related Content PubMed PubMed Citation Articles by Cuellar, J. C. Articles by Merlin, L. R.

REPORT

Contrasting Roles of Protein Kinase C in Induction Versus Suppression of Group I mGluR-Mediated Epileptogenesis In Vitro

¹Department of Physiology and Pharmacology and ²Department of Neurology, State University of New York Downstate Medical Center, Brooklyn, New York

Submitted 25 May 2005; accepted in final form 21 July 2005

	ABSTRACT

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Activation of group I metabotropic glutamate receptors (mGluRs) elicits persistent ictaform discharges in guinea pig hippocampal slices, providing an in vitro model of epileptogenesis. The induction of these persistent ictaform bursts is prevented by L-cysteine sulfinic acid (CSA), an agonist at phospholipase D (PLD)–coupled mGluRs. Studies described herein examined the role of protein kinase C (PKC) in both the group I mGluR–mediated induction and CSA-mediated suppression of this form of epileptogenesis. Intracellular recordings were performed from CA3 stratum pyramidale and synchronized burst length was monitored. In the presence of 50 µM picrotoxin, a -aminobutyric acid type A antagonist, 250- to 500-ms synchronized bursts were elicited. (S)-3,5-Dihydroxyphenylglycine (DHPG, 50 µM), an agonist at group I mGluRs, increased the burst length to 1–3 s in duration, a change that persisted after agonist washout. This persistent change in burst length was elicited in the presence of 10 µM chelerythrine, a PKC inhibitor, indicating that DHPG-induced epileptogenesis is PKC independent. However, although PLD activation with CSA (100 µM) was highly effective at suppressing group I mGluR–mediated induction of burst prolongation, CSA application in the presence of chelerythrine was no longer effective and resulted in the expression of persistent ictaform bursts. These data suggest that CSA-mediated suppression of group I mGluR–induced epileptogenesis is PKC dependent. We propose that CSA mediates its effect by PLD-driven activation of PKC, which may desensitize the phospholipase C–linked group I mGluRs and thereby prevent group I mGluR–induced epileptogenesis.

	INTRODUCTION

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Selective group I metabotropic glutamate receptor (mGluR) activation elicits a long-lasting change in hippocampal network activities, converting interictal-length synchronized bursts into ictal-length discharges that persist long after removal of the mGluR agonist (Merlin and Wong 1997). The induction of persistent ictaform discharges likely represents an in vitro model of epileptogenesis, the process in which normal cortex becomes persistently predisposed to produce ictal discharges. The intracellular signaling pathways critically involved in mGluR-induced epileptogenesis have yet to be determined.

The group I mGluRs (mGluR1 and mGluR5) are G-protein–linked receptors that, via phospholipase C activation, hydrolyze phosphatidylinositol 4,5-bisphosphate (PIP2) to produce inositol trisphosphate and diacylglycerol. These lead to intracellular calcium mobilization and protein kinase C (PKC) activation, respectively, with numerous downstream sequelae. Thus any electrophysiological effect elicited by activation of group I mGluRs may be dependent on any or all of these signal transduction pathways.

We recently reported that L-cysteine sulfinic acid (CSA) can prevent group I mGluR–induced epileptogenesis, although it has no effect on the expression of ictaform discharges once they are fully induced (Rico and Merlin 2004). We also provided evidence suggesting that this antiepileptogenic effect is mediated by activation of phospholipase D (PLD)-coupled mGluRs. The pathway by which PLD activation interferes with group I mGluR–mediated activities may involve the activation of PKC (Catania et al. 1991; Nishizuka 1995). In the studies presented herein, we examined the role of PKC activation in both the group I mGluR–mediated induction and the PLD-mediated suppression of DHPG-induced epileptogenesis. Portions of this work have appeared in abstract form (Griffith and Merlin 2005).

	METHODS

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Guinea pigs (2 to 4 wk old) were anesthetized with halothane and decapitated in compliance with the Guide for the Humane Care and Use of Animals. Brains were promptly removed from the cranium and placed in ice-cold artificial cerebrospinal fluid (ACSF) containing (in mM): 124 NaCl, 26 NaHCO₃, 5 KCl, 1.6 MgCl₂, 2.0 CaCl₂, and 10 D-glucose. The hippocampus was dissected free and transverse slices 400 µm thick were prepared with a Vibratome (Technical Products International), then transferred to nylon mesh in an interface recording chamber maintained at 35.5°C and bubbled with a gas mixture of 95% O₂-5% CO₂ to pH 7.4.

Intracellular recordings from the CA3 stratum pyramidale were obtained using glass microfilament electrodes filled with 2 M potassium acetate and pulled to a resistance of 25–100 M. Data were amplified and digitized using an Axoclamp 2B and A/D converter (Axon Instruments), then stored for later analysis using pClamp software (Axon Instruments). Hyperpolarizing current was injected as needed to suppress excessive intrinsically generated activity, allowing for better visualization of the synchronized network activity. Cells were excluded from analysis if they failed to meet any of the following criteria: action potential amplitude of 50 mV, resting membrane potential (before drug exposure) of at least –60 mV, and/or production of rhythmic synchronized interictal bursts of 250-ms duration on exposure to picrotoxin.

Pharmacological agents were transiently bath applied as indicated. DHPG, CSA, and chelerythrine were obtained from Tocris Cookson (Ellisville, MO); all other agents were from Sigma (St. Louis, MO). Picrotoxin, a -aminobutyric acid type A (GABA_A) antagonist, was present throughout all recordings to elicit baseline synchronized bursts of interictal length. When chelerythrine was used, it was introduced 10 min in advance of mGluR agonist. Significance of changes within a slice was determined using the paired Student’s t-test, each slice serving as its own control. Comparisons between groups were made using the unpaired t-test; across multiple groups, ANOVA with post-ANOVA Newman–Keuls multiple comparison test was performed. P < 0.05 was deemed significant. Data are reported as means ± SE; n refers to number of slices tested. Burst length was measured from onset of depolarization until return to initial membrane potential at the end of the oscillatory discharge.

	RESULTS

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Chelerythrine does not block DHPG-mediated induction of persistent prolonged bursts

Bath application of 50 µM picrotoxin (PTX) elicited synchronized bursts under 500 ms in duration in the CA3 pyramidal cell network of guinea pig hippocampal slices. Addition of 50 µM DHPG, a group I mGluR agonist, for 40 min gradually converted these brief interictal bursts into persistent ictaform discharges 0.8–2.5 s in length. At the end of a 40-min agonist application, burst length increased from 342 ± 15 ms (before DHPG introduction) to 1,048 ± 101 ms (at 40 min; n = 6, P < 0.05). On removal of the agonist, burst length typically continued to increase for 40–80 min before reaching a plateau length (burst duration at 60 min washout 1,119 ± 94 ms, n = 6, Fig. 1A). In an additional five slices, the burst prolongation elicited consisted of a mixed pattern predominantly composed of bursts 1,114 ± 183 ms long with interspersed markedly prolonged discharges 2–12 s in length.

View larger version (27K): [in this window] [in a new window]   FIG. 1. Chelerythrine does not prevent (S)-3,5-dihydroxyphenylglycine (DHPG)–induced burst prolongation. Example of time course of persistent increase in epileptiform burst duration induced by 40-min application of 50 µM DHPG. Continuous intracellular recording from CA3 pyramidal cell; each filled circle represents an epileptiform burst. A1: control experiment with DHPG alone. B1: DHPG applied in the presence of 10 µM chelerythrine (CHEL), a protein kinase C (PKC) inhibitor. Traces in A2 and B2 correspond to bursts plotted in A1 and B1, respectively; calibration bars apply to both sets of traces. PTX, picrotoxin-induced baseline burst before introduction of DHPG or chelerythrine; DHPG, DHPG-induced persistent prolonged burst at 1-h washout of DHPG. Vm just before burst generation in traces displayed in A2 and B2, in order, is –60, –59, –61, and –75 mV.

Chelerythrine also did not significantly affect the transient increase in burst frequency typically seen during the DHPG-induced development of ictaform discharges. At 10 min of exposure to DHPG, the epileptiform burst frequency increased from 0.13 ± 0.01 to 0.38 ± 0.01 Hz in controls (n = 6) and from 0.12 ± 0.01 to 0.36 ± 0.04 Hz in the presence of chelerythrine (n = 6). Furthermore, at 1-h washout the burst frequency returned to baseline in both cases (0.13 ± 0.01 Hz control vs. 0.14 ± 0.01 Hz chelerythrine, n = 6 for each).

Chelerythrine prevents CSA-mediated suppression of DHPG-induced burst prolongation

Coapplication of 50 µM DHPG and 100 µM CSA for 40 min resulted in a substantially reduced enhancement of epileptiform burst length when compared with DHPG application alone (P < 0.05). Initial bursts of 363 ± 32 ms were 387 ± 74 ms at the end of a 40-min application of DHPG + CSA (n = 6). At 1-h washout of both agents, a mild but statistically significant persistent burst prolongation appeared (529 ± 52 ms, range 365–710 ms; n = 6, P < 0.05; Fig. 2A). CSA had no effect on DHPG-mediated modulation of burst frequency; bursts initially recurred at 0.11 ± 0.01 Hz, accelerated to 0.37 ± 0.05 Hz at 10-min DHPG in the presence of CSA, and returned to 0.14 ± 0.04 by 1-h washout (n = 6).

View larger version (27K): [in this window] [in a new window]   FIG. 2. Chelerythrine prevents cysteine sulfinic acid (CSA)–mediated suppression of burst prolongation. Example of time course of change in epileptiform burst length induced by coapplication of DHPG and 100 µM CSA, an agonist of the phospholipase D (PLD)–coupled metabotropic glutamate receptor (mGluR). A1: DHPG and CSA alone. B1: DHPG and CSA applied in the presence of 10 µM CHEL. Traces in A2 and B2 correspond to bursts plotted in A1 and B1, respectively; first burst taken before DHPG or CHEL introduction and second burst after 1-h washout of DHPG. Vm for each of the 4 traces in A2 and B2, in order, is –65, –74, –64, and –62 mV; calibration bars apply to both sets of traces.

View larger version (17K): [in this window] [in a new window]   FIG. 3. PLD-mediated suppression of mGluR-induced epileptogenesis is PKC dependent: proposed mechanism. A: summary data; n = 6 for all groups. PTX group: burst length just before introduction of DHPG; DHPG group: measured at 1-h washout. Control, 50 µM DHPG alone; CSA, DHPG coapplied with 100 µM CSA; CSA/CHEL, DHPG and CSA applied in the presence of 10 µM CHEL. Whereas significant burst prolongation was elicited in all 3 cases, ANOVA analysis revealed that the burst prolongation induced in the presence of CSA is significantly suppressed compared with the other groups. B: proposed PKC-dependent mechanism for PLD-induced suppression of group I mGluR-mediated responses. PA, phosphatidic acid; DAG, diacylglycerol; IP3, inositol trisphosphate; PLC, phospholipase C. Arrows indicate activation or generation, whereas line with "T" ending indicates inhibition (PKC effect on PLC). Dashed line indicates presumed IP3 dependency of epileptiform burst induction, indirectly suggested by the data presented here (PKC independence of burst induction). Italicized DAG and PKC from group I mGluR activation suggest pools of DAG and PKC distinct from those elicited by activation of PLD-coupled mGluRs, with each PKC pool having distinct effects arising from either differences in PKC isoforms, intracellular localization, timing of activation, or/and amount activated (see DISCUSSION for more details).

	DISCUSSION

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We have been investigating the induction and maintenance properties of group I mGluR–induced persistent burst prolongation. Our data thus far reveal that the induction process is independent of N-methyl-D-aspartate (NMDA) and -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor activation (Galoyan and Merlin 2000; Merlin 1999), more strongly dependent on mGluR5 than on mGluR1 activation (Merlin 2002), and requires new protein synthesis (Merlin et al. 1998). By contrast, the sustained expression of the ictaform bursts no longer depends on protein synthesis (Merlin et al. 1998) and is neither mediated by GABA_B suppression (Huszár and Merlin 2004) nor NMDA potentiation (Galoyan and Merlin 2000), but rather appears to be primarily dependent on potentiated mGluR1-mediated responses (Merlin 2002; Merlin and Wong 1997), possibly by the mGluR1-linked activation of the persistent current I_mGluR(V) (Chuang et al. 2002; Wong et al. 2005).

Despite the fact that group I mGluRs can activate PKC, our current data suggest that neither the induction nor sustained expression of mGluR-mediated ictaform bursts is PKC dependent. Therefore it is likely that the mGluR5-driven, protein synthesis–dependent induction process does not require PKC activation as part of the underlying signal transduction pathway that elicits persistent ictaform bursts and may instead be more dependent on inositol trisphosphate (IP3) production and intracellular calcium mobilization. This is consistent with studies by Zhao et al. (2004) in which PKC inhibitor failed to suppress DHPG-induced prolonged bursts elicited in mouse slices. Our data revealing a lack of effect of chelerythrine on the maintenance of fully induced bursts further suggest that the mGluR1-dependent expression of I_mGluR(V) is likely to be PKC independent as well.

PLD-mediated suppression of epileptogenesis requires PKC activation

CSA has multiple sites of action, among which is activation of PLD-coupled mGluRs (Boss et al. 1994). We previously demonstrated (Rico and Merlin 2004) that the CSA-mediated suppression of group I mGluR–induced epileptogenesis is blocked by PCCG-13, a selective antagonist at PLD-coupled mGluRs (Pellicciari et al. 1999), implicating PLD activation in the suppression of group I mGluR–induced epileptogenesis.

There are at least two possible routes by which PLD activation may result in suppression of group I mGluR–mediated responses: 1) PLD-mediated internalization of group I mGluRs (Bhattacharya et al. 2004) or 2) PLD-driven enhanced PKC activation with secondary desensitization of group I mGluRs (Catania et al. 1991; Fig. 3B). The PKC dependency of the PLD-mediated suppression, demonstrated by our data, supports the latter hypothesis.

One might be inclined to presume that PLD activation itself is PKC dependent. However, it has been shown that the activation of PLD does not require PKC-dependent phosphorylation, but rather merely an association with PKC (Park et al. 1998), and chelerythrine is not likely to interfere with this association. Therefore the ability of chelerythrine to prevent PLD-mediated suppression of mGluR-induced epileptogenesis implicates a different PKC-dependent mechanism linking PLD activation to mGluR suppression. Figure 3B illustrates a route by which this may occur. PLD activation catalyzes the formation of phosphatidic acid from phosphatidylcholine (Löffelholz 1989). Phosphatidic acid may directly elicit numerous effects; alternatively, it can be converted to diacylglycerol, which may then boost the activation of conventional PKCs (cPKCs) (Nishizuka 1995). cPKC activation can then desensitize group I mGluRs by suppressing phospholipase C (PLC) activation (Catania et al. 1991). Others have shown that the group I mGluR–induced epileptogenic response is likely to be PLC dependent (Chuang et al. 2001).

Why then does not group I mGluR–driven PKC activation elicit negative feedback to prevent mGluR-induced epileptogenesis? There are a number of possibilities. 1) The group I and PLD-coupled mGluRs may activate different PKC isoforms and/or PKC at different microdomains of the cell (Delmas et al. 2004), with the PLD-induced PKC being more effective at eliciting suppression of the group I mGluR–mediated response. 2) There may be a threshold level of PKC that needs to be activated, so that only the combined PKC activation elicited by coactivation of both group I and PLD-coupled mGluRs is effective at suppressing the group I mGluR–induced epileptogenic effect. 3) The timing of the PKC activation by the PLD-coupled mGluR versus the group I mGluR may differ, making the PLD-induced PKC activation more effective at suppressing group I mGluR–induced epileptogenesis.

If any of the above hypotheses is true (alone or in combination), the group I mGluRs and PLD-coupled mGluRs are likely to be localized on the same cells. Group I mGluRs are expressed in hippocampal pyramidal cells, interneurons, and glia (Biber et al. 1999; Blümcke et al. 1996; Fotuhi et al. 1994). PLD-coupled mGluRs are less well characterized, but mGluR-induced PLD responses have been evoked in cortical astrocytic cultures (Servitja et al. 1999). It has yet to be determined whether the key cells involved in mGluR-induced epileptogenesis are pyramidal or glial. However, it is unlikely that receptors on interneurons are critically involved here given that the epileptogenic response can be elicited by group I mGluR activation in the presence of complete blockade of GABAergic inhibition with GABA_A and GABA_B antagonists (Huszár and Merlin 2004).

Thus we have presented evidence that PLD-mediated activation of PKC underlies the efficacy of CSA in preventing group I mGluR–induced epileptogenesis in vitro. Because PLD activation is effective against induction but not maintenance of this mGluR-induced epileptogenesis (Rico and Merlin 2004), it would suggest that mGluR5 may be more sensitive to this type of desensitization than mGluR1. Further studies will be required to examine this pathway in more detail.

	GRANTS

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This work was supported by National Institute of Neurological Disorders and Stroke Grant NS-40387 to L. R. Merlin.

	ACKNOWLEDGMENTS

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The authors thank K. Perkins and T. Sacktor for assistance.

	FOOTNOTES

 
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Address for reprint requests and other correspondence: L. R. Merlin, SUNY Downstate Medical Center, 450 Clarkson Avenue, Box 29, Brooklyn, NY 11203 (E-mail: Lisa.Merlin{at}downstate.edu)

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This Article Abstract Full Text (PDF) All Versions of this Article: 94/5/3643    most recent 00548.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (2) Citing Articles via Google Scholar Google Scholar Articles by Cuellar, J. C. Articles by Merlin, L. R. Search for Related Content PubMed PubMed Citation Articles by Cuellar, J. C. Articles by Merlin, L. R.