The Journal of Neurophysiology Vol. 80 No. 3 September 1998, pp. 1547-1551
Copyright ©1998 by the American Physiological Society

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Activation of Protein Kinase C Increases Neuronal Excitability by Regulating Persistent Na⁺ Current in Mouse Neocortical Slices

Nadav Astman, Michael J. Gutnick, and Ilya A. Fleidervish

Department of Physiology and Zlotowski Center for Neuroscience, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beersheva 84105, Israel

	ABSTRACT

Abstract Introduction Methods Results Discussion References

Astman, Nadav, Michael J. Gutnick, and Ilya A. Fleidervish. Activation of protein kinase C increases neuronal excitability by regulating persistent Na⁺ current in mouse neocortical slices. J. Neurophysiol. 80: 1547-1551, 1998. Effects of the protein kinase C activating phorbol ester, phorbol 12-myristate 13-acetate (PMA), were studied in whole cell recordings from layer V neurons in slices of mouse somatosensory neocortex. PMA was applied intracellularly (100 nM to 1 µM) to restrict its action to the cell under study. In current-clamp recordings, it enhanced neuronal excitability by inducing a 10- to 20-mV decrease in voltage threshold for action-potential generation. Because spike threshold in neocortical neurons critically depends on the properties of persistent Na⁺ current (I_NaP), effects of PMA on this current were studied in voltage clamp. After blocking K⁺ and Ca²⁺ currents, I_NaP was revealed by applying slow depolarizing voltage ramps from 70 to 0 mV. Intracellular PMA induced a decrease in I_NaP at very depolarized membrane potentials. It also shifted activation of I_NaP in the hyperpolarizing direction, however, such that there was a significant increase in persistent inward current at potentials more negative than 45 mV. When tetrodotoxin (TTX) was added to the bath, blocking I_NaP and leaving only an outward nonspecific cationic current (I_cat), PMA had no apparent effect on responses to voltage ramps. Thus PMA did not affect I_cat, and it did not induce any additional current. Intracellular application of the inactive PMA analogue, 4-PMA, did not affect I_NaP. The specific protein kinase C inhibitors, chelerythrine (20 µM) and calphostin C (10 µM), blocked the effect of PMA on I_NaP. The data suggest that PMA enhances neuronal excitability via a protein kinase C-mediated increase in I_NaP at functionally critical subthreshold voltages. This novel effect would modulate all neuronal functions that are influenced by I_NaP, including synaptic integration and active backpropagation of action potential from the soma into the dendrites.

	INTRODUCTION

Abstract Introduction Methods Results Discussion References

The dynamics of neocortical circuit function depend on the excitability of individual neurons as well as on the synaptic interactions between them. Neocortical neuronal excitability may be modulated by a variety of ligands that regulate voltage-gated channels through activation of protein kinase C (PKC). Although most attention in this regard has focused on K⁺ channel regulation (Krnjevic et al. 1971; McCormick et al. 1993), there is considerable evidence that PKC-mediated phosphorylation of the Na⁺ channel may also be of considerable functional significance. Studies at the channel level have shown that this regulation results in a decrease in Na⁺ channel availability (Cantrell et al. 1996; Lotan et al. 1990; Numann et al. 1991); this would be expected to reduce neuronal excitability. Recent reports, however, indicate that in hippocampus, PKC activation increases dendritic excitability and thereby reverses the activity-dependent reduction in dendritic action-potential propagation (Colbert and Johnston 1998; Tsubokawa and Ross 1997).

In the present study, we sought to determine the effect of PKC activation on neocortical neurons. We found that, although exposure to phorbol esters causes a decrease in persistent Na⁺ current (I_NaP) at depolarized voltages, it also leads to a marked decrease in threshold for action-potential generation. This paradoxical effect is related to a hyperpolarizing shift in the voltage dependence of I_NaP activation. Portions of this work were previously presented in abstract form (Fleidervish et al. 1997).

	METHODS

Abstract Introduction Methods Results Discussion References

CD1 mice of either sex, postnatal day 7 to postnatal day 28, were anesthetized with pentobarbital sodium (60 mg/kg) and decapitated. Brains were removed, and 400-µm-thick coronal slices of somatosensory cortex were prepared as previously described (Fleidervish et al. 1996; Fleidervish and Gutnick 1996). Recordings were made in a small (300 µl) interface-type recording chamber, where slices were continuously perfused with artificial cerebrospinal fluid whose composition was (in mM) 124 NaCl, 3 KCl, 2 CaCl₂, 2 MgSO₄, 1.25 NaH₂PO₄, 26 NaHCO₃, and 10 glucose (pH 7.3 at 32 ± 0.5°C when bubbled with a 95% O₂-5% CO₂ gas mixture).

Whole cell recordings from 108 layer V neurons were made using the patch-clamp technique (Hamill et al. 1981) as modified for "blind" recording in slices (Blanton et al. 1989). Patch pipettes, pulled from borosilicate glass capillaries (Hilgenberg, Germany) on a Narishige PP83 puller, had resistances of 1.5-3.5 M. The pipette solution for persistent sodium current recording consisted of (in mM) 135 CsCl, 4 NaCl, 2 MgCl₂, and 10 N-2-hydroxyethylpiperazine-N'-2-ethansulfonic acid (HEPES, cesium salt), pH 7.25. Care was taken to maintain membrane access resistance as low as possible (usually 3-4 M and always <10 M); series resistance was 80% compensated using the built-in circuitry of an Axopatch-1D amplifier (Axon Instruments). Command voltage protocols were generated, and data were acquired on-line with an Axolab 1100 A/D interface. Data were low-pass filtered at 2 kHz (3 dB, 4-pole Bessel filter) and sampled at 5-10 kHz digitalization frequency. Before data acquisition, linear leak current was subtracted using the built-in circuits of the amplifier.

An Axoclamp-2A amplifier in a Bridge mode was used for current-clamp experiments. The pipette solution contained (in mM) 135 K gluconate, 2 MgCl₂, and 10 HEPES (potassium salt), pH 7.25. Data were low-pass filtered at 10 kHz (3 dB, 4-pole Bessel filter) and sampled at 20 kHz digitalization frequency. Voltages in Fig. 1 have not been corrected for liquid junction potential.

View larger version (34K): [in this window] [in a new window]   FIG. 1. Phorbol 12-myristate 13-acetate (PMA) causes an increase in neuronal excitability. A: in a current-clamp whole cell recording from layer V neuron, PMA (100 nM) increases neuronal excitability. Note, that as PMA diffuses into the cell, an initially just threshold depolarizing current step of 165 pA elicits progressively longer trains of spikes. Top traces: membrane voltage. Middle traces: intracellularly applied current pulse. Bottom traces: time differential of the voltage trace. Note that the increase in excitability is associated with a small decrease in spike overshoot potential and in maximal upstroke velocity. B: in the same neuron, PMA induces a shift of the voltage threshold for action-potential generation from 39 to 58 mV over 50 min. Note, that the current necessary to elicit a spike decreases from 165 to 65 pA. Spikes have been truncated at 30 mV. C: time course of the effect of 100 nM PMA on the voltage of spike threshold in 7 neurons. Note that the time course of the effect varied somewhat from cell to cell, and that in one neuron, threshold was not changed. D: effect of 23-min exposure to 100 nM intracellular PMA on spike amplitude and rate of depolarization, and on apparent input resistance and membrane time constant. Shown are means ± SE, n = 7. The changes in amplitude, dV/dt and Rin were statistically significant (paired t-test, P < 0.05).

Data were analyzed using PClamp 5.5 and Microcal Origin 3.78 software. Spike amplitudes were measured from threshold to peak. Apparent input resisitance (R_in) was determined as the slope of neuronal voltage-current curve measured in the hyperpolarizing the (linear) range. Membrane time constant (_m) was determined by an exponential fit to the decay of the voltage response following a small hyperpolarizing current step.

The protein kinase C activator, phorbol 12-myristate 13-acetate (PMA; Sigma) was applied intracellularly through the patch pipette to limit its action to the neuron under study. 4- phorbol 12-myristate 13-acetate (Sigma) was used as a negative control. The specific PKC inhibitor chelerythrine (Biomol) was applied to the bath solution. The specific PKC inhibitor calphostin C (Biomol) was added to the pipette solution. Bath applied tetrodotoxin (TTX; Sigma; 1 µM) was used to block Na⁺ currents, and CdCl₂ (200 µM) was used to block Ca²⁺ currents.

	RESULTS

Abstract Introduction Methods Results Discussion References

Figure 1 shows a current-clamp recording from a representative layer V neuron with PMA (100 nM) included in the pipette solution. As the phorbol ester diffused into the cell, neuronal excitability increased (Fig. 1A), such that a given depolarizing current step evoked progressively longer and longer trains of spikes. This was closely associated with a hyperpolarizing shift in the voltage threshold for action-potential generation (Fig. 1B). Immediately upon establishment of whole cell recording, spike threshold of this cell was 39 mV. As PMA continued to diffuse into the neuron, however, spike threshold gradually decreased until it finally reached a new steady value between 55 and 60 mV (Fig. 1B), which is close to the activation threshold of fast Na⁺ current in neocortical neurons (Fleidervish et al. 1996). As is illustrated in Fig. 1C, a similar effect of PMA on voltage threshold was observed in six of the seven layer 5 neurons tested, although the time course and extent of the effect varied from neuron to neuron. These effects were caused by the phorbol ester, because threshold voltage was stable for hours in recordings under the same experimental conditions but without PMA in the pipette (n = 10 cells). Figure 1D shows that the PMA-induced hyperpolarizing shift in threshold was not accompanied by an increase in action-potential amplitude or maximal depolarization rate, as might be expected if the availability of Na⁺ current underlying the action potential itself were to increase. Indeed, in most neurons, including that shown in Fig. 1, PMA caused a slight progressive decrease in spike overshoot and a slight reduction in maximal rate of rise. These observations indicate that the threshold decrease occurred despite a parallel reduction in the overall availability of Na⁺ channels, which is consistent with previous reports that PKC-mediated Na⁺ channel phosphorylation causes a decrease in Na⁺ current (Cantrell et al. 1996; Lotan et al. 1990; Numann et al. 1991).

View larger version (27K): [in this window] [in a new window]   FIG. 2. Protein kinase C (PKC) activation by PMA decreases INaP at depolarizing potentials and shifts its activation to more negative potentials. A: in a voltage-clamp recording with PMA (100 nM) included into the pipette solution, instantaneous current-voltage (I-V) curve during a slow (35 mV/s) depolarizing ramp was checked every minute. Note that while PMA diffuses into the cell, the inward currents decrease at depolarizing voltages and increase at potentials more hyperpolarizing than 45 mV. K+ currents were blocked by using Cs+ as the main intracellular monovalent cation, and Ca2+ currents were blocked by adding 200 µM Cd2+ to the bath. Access resistance 4 M; leakage subtracted. B: when tetrodotoxin (TTX; 1 µM) was added to the bath solution, PMA did not affect the instantaneous I-V curve. C: PKC inhibitor, chelerythrine (20 µM), when added to the bathing solution, prevented PMA effect on INaP.

In previous reports, increased neocortical neuronal excitability due to the actions of various neuromodulators has generally been ascribed to decreased K⁺ conductance (Krnjevic et al. 1971; McCormick et al. 1993). Figure 1D shows, however, that the PMA-induced effect on voltage threshold we report was not associated with the changes in apparent input resistance and membrane time constant that would be expected if K⁺ conductances were reduced. Indeed, enhanced neuronal excitability caused by a decrease in K⁺ conductance would be expected to be associated with an increase in apparent input resistance, and to entail a reduction in the current required to reach spike threshold (McCormick et al. 1993); it would not, however, be expected to alter the threshold voltage itself, which, in neocortical neurons, depends primarily on the availability of I_NaP (Crill 1996; see, for review, Taylor 1993).

Results of the current-clamp experiments strongly suggested that PKC activation by PMA affects neuronal excitability via modulation of I_NaP, whose prominence in neocortical neurons is well documented (Alzheimer et al. 1993a; Connors et al. 1982; Stafstrom et al. 1985). We therefore examined the effect of intracellularly applied PMA on I_NaP in voltage clamp mode by applying 2-s depolarizing voltage ramps from 70 to 0 mV; a rising rate slow enough to entirely inactivate the fast Na⁺ current (Fig. 2A) (Alzheimer et al. 1993b; Fleidervish and Gutnick 1996). When K⁺ currents were blocked by intracellular Cs⁺ and Ca²⁺ currents were blocked with bath-applied Cd²⁺, the resultant instantaneous current-voltage (I-V) curve was inward from around 55 mV due to activation of I_NaP (Alzheimer et al. 1993b; Fleidervish and Gutnick 1996). At potentials more positive than 35 mV, I_NaP was superimposed on a large outward current, I_cat (Alzheimer 1994; Fleidervish and Gutnick 1996).

Intracellular exposure to PMA (100 nM to 1 µM) had a dual effect on I_NaP. Starting from the first minutes of breaking into the cell, there was a decrease in I_NaP amplitude at very depolarized membrane potentials. Also, the activation of I_NaP shifted in the hyperpolarizing direction, such that there was a significant increase in I_NaP at potentials more negative than 45 mV (Fig. 2A).

The PMA effect on I_NaP was via PKC activation, because the inactive PMA analogue, 4-PMA, had no apparent effect on I_NaP (n = 6 neurons; data not shown). Furthermore, in slices that were preincubated for >1 h with the specific PKC inhibitor chelerythrine (20 µM; n = 6), intracellularly applied PMA did not affect I_NaP (Fig. 2C). In slices bathed in TTX (1 µM) I_NaP was completely blocked (Fig. 2B). Under these conditions, the intracellular PMA had no evident effect on the surviving responses to voltage ramps (Fig. 2B), indicating that PKC activation did not affect I_cat, and that its effect on the instantaneous I-V curve was not due to induction of an additional current.

Figure 3A shows the time course of the PMA effect on I_NaP as determined in 11 neurons. Current amplitudes at 55 mV and at 35 mV were used as measures of I_NaP availability at these potentials (Fig. 3, inset). Values have been normalized to the initial amplitude at 35 mV, because, at this potential, I_NaP is near maximal activation, yet it does not overlap with I_cat (Fig. 2B). At 35 mV, after a short delay, PMA caused a steady decrease in I_NaP such that, after 10 min, only 45 ± 11% (mean ± SE) of the initial current amplitude remained. By contrast, at 55 mV, I_NaP gradually increased from near zero to ~25% of the initial amplitude at 35 mV. These effects of intracellular PMA were not observed in neurons exposed to the specific PKC inhibitors chelerythrine (preincubation as above, n = 7, Fig. 3B), and calphostin C (10 µM in the pipette solution, n = 7, data not shown).

View larger version (23K): [in this window] [in a new window]   FIG. 3. A: time course of the PMA effect on INaP. Inset: superimposed responses to voltage ramps at 1 and 6 min from the beginning of PMA exposure. Dashed lines show the voltages at which INaP amplitude was measured. Graph: circles and squares plot the means of INaP amplitudes at 35 and 55 mV, respectively, as a function of the recording time (n = 11 cells). The current values are normalized to INaP amplitude at 35 mV at the 1 min of recording. B: as in A, but after slice was incubated for at least 1 h in chelerythrine (20 µM; n = 7 cells).

	DISCUSSION

Abstract Introduction Methods Results Discussion References

Our data demonstrate that PKC activation by intracellular PMA lowers spike threshold and thereby increases the excitability of layer V neocortical neurons. This finding was unexpected because several studies have shown that PKC activation causes a decrease in the availability of fast-inactivating Na⁺ channels (Cantrell et al. 1996; Lotan et al. 1990; Numann et al. 1991). Indeed, we find that I_NaP, which reflects a distinct kinetic mode of these same Na⁺ channels (Alzheimer et al. 1993a; Patlak and Ortiz 1985), is also decreased by exposure to PMA. However, I_NaP is only reduced at membrane potentials more depolarized than spike threshold; that is, voltages where the persistent fraction of the Na⁺ current has virtually no influence on the neuron's behavior because it is so much smaller than the fast-inactivating I_Na and I_K. The functionally significant effect of PKC activation was a leftward shift in the I_NaP activation curve, which in any event is ~10 mV more negative than that of the transient I_Na (Brown et al. 1994; French et al. 1990). We propose that the consequent increase in persistent inward current at subthreshold voltages was responsible for the hyperpolarizing shift in spike threshold and the change in voltage trajectory toward threshold. It is important to note that the Na⁺ channel kinetics in neocortical neurons is such that at threshold potential, only a small fraction of the total transient I_Na is available for activation (Fleidervish et al. 1996). The voltage dependence of I_Na inactivation is very steep, however. Thus a PKC-mediated shift in I_NaP activation serves to compensate for the overall reduction in Na⁺ channel availability and can account for the observed enhancement of neuronal excitability.

In direct measurements of I_NaP, the effect of PMA appeared within 4-5 min, whereas the effect on spike threshold in current-clamp recordings evolved over a longer time period. This discrepancy may reflect the time necessary for PMA to diffuse from the somatic pipette to the spike initiation zone, which is likely to be quite distant in the axons of pyramidal neurons (Colbert and Johnston 1996; Stuart et al. 1997).

Various modulators may regulate neocortical excitability by activating one or another isozyme of PKC, and the molecular details underlying the novel effect on I_NaP we report here have yet to be elucidated. The extreme diversity within the broad family of PKC (Dekker and Parker 1994; Nishizuka 1988), as well as differences in experimental conditions, may explain the difference between our findings with phorbol ester and the recent report by Mittmann and Alzheimer (1998) that in isolated neocortical neurons at room temperature, activation of muscarinic receptors depressed I_NaP without a voltage shift in activation.

The functional consequences of regulating I_NaP are likely to be very significant, because of the role this persistent inward current plays not only in determining spike threshold and firing properties, but also in synaptic integration and regulation of dendritic excitability. In this last regard, it is interesting that in hippocampal pyramidal cells, activity-dependent reduction in dendritic spike amplitude, which has been attributed to a reduction in Na⁺ channel availability (Colbert et al. 1997; Jung et al. 1997), is reversed both by carbachol (Tsubokawa and Ross 1997) and by phorbol esters that activate PKC (Colbert and Johnston 1998).

	ACKNOWLEDGEMENTS

  We thank Dr. U. Heinemann for helpful discussions.

  This research was supported by a grant from the German-Israeli Foundation for Scientific Research and Development.

	FOOTNOTES

  Address for reprint requests: I. A. Fleidervish, Dept. of Physiology, Faculty of Health Sciences, Ben Gurion, University of the Negev, Beer Sheva 81405, Israel.

  Received 13 March 1998; accepted in final form 8 June 1998.

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