Regulation of back-propagating action potentials in hippocampal neurons Daniel Johnston*, Dax A Hoffman?, Costa M Colbertzand Jeffrey C Magee

Protein kinase C has recently been shown to modulate the slow recovery from inactivation of Na+ channels in apical

dendrites of hippocampal CA1 pyramidal neurons. Moreover,

dendritic, A-type K+ channels have been found to be modulated by protein kinases A and C and by mitogen-

activated protein kinase. The electrical signalling ability of these dendrites is thus highly regulated by a number of

neurotransmitters and second-messenger systems.

Addresses *Division of Neuroscience, Baylor College of Medicine, 1 Baylor Plaza, Houston, Texas 77030-3498, USA; e-mail: dan@mossy.bcm.tmc.edu tMax-Planck-lnstitut fur medizinische Forschung, Jahnstrasse 29, D-691 20 Heidelberg, Germany; e-mail: dax@sunny.mpimf-heidelberg.mpg.de TDepartment of Biology and Biochemistry, University of Houston, Houston, Texas 77204-5513, USA; e-mail: cmc@colbert.biology.uh.edu 4Neuroscience Center, Louisiana State University Medical Center, 2020 Gravier Street, New Orleans, Louisiana 70112, USA; e-mail: jmagee@jmagee.neuro.Isumc.edu

Current Opinion in Neurobiology 1999, 9:288-292

http://biomednet.com/elecref/0959438800900288

0 Elsevier Science Ltd ISSN 0959-4388

Abbreviations [Ca2+li intracellular concentration of Ca*+ EPSP excitatory postsynaptic potential MAPK mitogen-activated protein kinase NMDA N-methyl-d-aspartate PDA phorbol 12,13-diacetate PKA CAMP-dependent protein kinase A PKC protein kinase C

Introduction In the past few years, it has become apparent that action potentials initiated near the soma of hippocampal and neo- cortical pyramidal neurons propagate not only along their axons but also back into apical and basal dendrites - so- called back-propagation [l”,Z]. The function of these back-propagating action potentials is not clear. It has been proposed that they play a role in associative synaptic plastic- ity by providing a feedback signal to synapses that unblocks NMDA receptors at concurrently activated synapses and activates voltage-gated CaZ+ channels [3’,4,5’]. The initia- tion and propagation of the action potentials depends on the properties and distribution of various types of voltage-gated ion channels in the axon, soma, and dendrites of these neu- rons. Here, we will review recent data on the modulation of dendritic Na+ and K+ channels by neurotransmitters and sec- ond-messenger systems and show how this modulation can alter the back-propagation of dendritic action potentials.

Voltage-gated ion channels in dendrites Neocortical and hippocampal pyramidal neurons possess a rich assortment of voltage-gated ion channels in their

dendrites. Identification of specific channel types and their distribution in hippocampal CA1 pyramidal neurons has recently been reviewed [6,7]. Na+ channels have an approximate uniform density across the soma and at least the first three-fourths of the apical dendritic tree [8,9]. The total density of Ca*+ channels also appears to be uni- form, although the specific types of Caz+ channels vary between soma and dendrites. Kf channels and inward rectifiers, on the other hand, have highly non-uniform distributions along dendrites [lO”,ll]. Little information is available about specific channel types or their distribu- tions in the basal dendrites other than that obtained from indirect fluorescence imaging experiments. These stud- ies suggest that action potentials back-propagate into the basal dendrites and elicit a rise in [Ca’+]i through the acti- vation of voltage-gated Ca2+ channels [l&13].

Modulation of dendritic Na+ channels Even though the density of Na+ channels appears to be approximately the same in the soma and apical dendrites, certain properties of these channels do vary. In particular, dendritic Na+ channels exhibit a remarkably long recovery time following inactivation [14,15], which has also been called ‘prolonged’ or ‘slow’ inactivation [ 16’1. After opening, channels appear to enter one of two inactivation states: one with a fast, and the other with a slow, rate of recovery. The fast recovery rate is on the order of 10 ms or less and accounts for the normally short refractory period of the action potential. The slow recovery rate, however, is more than two orders of magnitude slower than the FdSdSt recovery rate. Initial reports [14,15] indicated that dendritic Na+ channels show much more of this slow inactivation than somatic channels, which may explain why slow recovery from inactivation had not been described in previous stud- ies of somatic Na+ currents in these neurons [17,18]. Recently, Mickus et al. [ 16’1 have extended the initial find- ings by examining slow inactivation from channels at various distances along the apical dendrites and found that there is a gradual increase in the magnitude of slow inactivation with distance reaching a maximum at about 200 pm from the soma. The increase in slow inactivation with distance from the soma follows an approximate exponential relationship, with a space constant of 126 pm. The explanation for this gradual increase with distance is not known, but it is cer- tainly interesting from both a molecular and physiological point of view.

While making dendritic recordings of back-propagating action potentials, Spruston et ol. [19] noticed that the amplitudes of the action potentials decrease dramatically during a train. This behavior of trains has been studied in some detail by several groups [14,15,19-21,22’]. The con- clusion from recent studies is that the decline in

Regulation of back-propagating action potentials in hippocampal neurons Johnston et al. 289

amplitude during a train is attributable, in part, to this slow inactivation of dendritic Na+ channels. It appears, however, that transient K+ channels in dendrites (see below) also play a role [ 141.

Tsubokawa and Ross [22’] made the interesting observation that muscarinic agonists reduce this frequency-dependent decline in dendritic action potential amplitude during trains. Because muscarinic receptor activation has complex actions in hippocampal neurons, the biochemical mecha- nism for this effect was not clear from their study. Earlier, Tsubokawa and Ross [23] had demonstrated that phorbol esters reduce the frequency-dependent decline in action potentials, but the effect of the muscarinic agonist on the trains was suggested to be mediated by another biochemi- cal pathway and/or another ion channel. We decided to test directly the modulation of Na+ channels and found that phorbol esters reduce both the slow inactivation of dendrit- ic Na+ channels and the frequency-dependent decline in action potentials [24] (Figure 1). The fact that changes in slow inactivation of Na+ channels also leads to changes in the amplitudes of trains of action potentials strengthens the link between this property of Na+ channels and the firing behavior of the neuron. It is important to note, however, that there are potentially other ways in which trains of action potentials can be modulated, including through the modulation of muscarine-sensitive K-currents and hyper- polarization-activated (h) channels [ 111. Nevertheless, the slow inactivation of Na+ channels provides for a very long refractory period for action potentials in dendrites, espe- cially at sites greater than 200 pm from the soma. Neurotransmitters that lead to activation of protein kinase C (PKC) thus have the potential for greatly reducing this long refractory period and enhancing the repetitive fir- ing of back-propagating action potentials in dendrites.

Figure 1

Phorbol esters decrease the slow recovery from inactivation and decrease the activity- dependent decrease in dendritic action potential amplitude. (a) Naf currents in cell- attached patches. Brief depolarizations from holding potentials near resting potential evoke fast-inactivating inward Na+ currents. Cumulative inactivation as a result of the very slow recovery from inactivation decreases the magnitude of the currents when depolarizations are repeated at 50 ms intervals. Addition of PDA (10 PM) to the pipette solution greatly decreases the degree of cumulative inactivation. (b) Dendritic whole- cell recording (180 km from the soma). Antidromic action potentials repeated at 100 ms intervals show a profound decrease in amplitude over time. PDA added to the bath eliminates much of the activity-dependent attenuation. Adapted from [241.

Modulation of dendritic K+ channels Whereas the density of delayed rectifier K+ channels appears to be fairly uniform across the soma and apical dendrites, the density of transient, A-type K+ channels increases fivefold along the first three-fourths of the apical dendrites [lO”]. The transient K+ current in dendrites is activated near the resting potential, and it shows a fast rate of activation and a moderate, voltage-dependent rate of inactivation. Because of its fast activation and other prop- erties, the increasing density of A-type K+ channels acts to decrease the peak amplitude of back-propagating action potentials, to suppress the amplitude of excitatory postsy- naptic potentials (EPSPs), and to limit the occurrence of dendritically initiated action potentials. These transient K+ channels thus provide a brake for dendritic signal prop- agation. This brake, however, can be removed in a number of ways, including through voltage-dependent inactivation and phosphorylation by protein kinases. Recent work has explored in some detail the modulation of these A-type, K+ channels by neurotransmitters and second messengers.

Bath application of 8-bromo-CAMP to dendrites produces a lo-15 mV positive shift in the activation curve for the transient K+ current [25’]. This shift is partly reversed by the subsequent application of the kinase inhibitor H7, supporting the involvement of cAMP-dependent protein kinase A (PKA) (Figure 2). Two phorbol esters known to stimulate PKC, phorbol dibutyrate (PDBu) and phorbol 12,13-diacetate (PDA) [26], also shift the activation curve positively by 15 mV. The inactive phorbol 4-alpha appears to have no effect, supporting the conclusion that the activation of PKC by the phorbol esters mediates the shift in the activation curve. The effect of a positive shift in the activation curve by PKA and PKC is to decrease dendritic K+ currents and thereby increase the amplitude

:a) Cell-attached patches

Control

(b) Dendritic whole-cell recording Control

PDA (10pM)

2QmV L IOOms

5pA L 50 ms

PDA (1OyM)

290 Signalling mechanisms

Figure 2

(a) (i) Control

W 1 .oo

b----- 5(

V, = -5mV

(ii) &br-CAMP

%max g

25 ms

0.25 - 0.25

-100 -75 -50 -25 0 25 50 75 100

Membrane potential (mV)

-

Downregulation of transient channel (A-current) activation by 8-bromo-CAMP (8-br-CAMP). (a) Representative examples of isolated transient currents in (i) control recordings and (ii) recordings with 100 ,uM 8-br-CAMP included in the patch pipette (dark trace), scaled to demonstrate their fraction of maximal conductances, for a step from -85 to -5 mV. Under control conditions, nearly 50% of the available channels are activated by this voltage step. With 8-br-CAMP, only about 25% are activated. In the same patch, subsequent H7 (kinase inhibitor) application returned the fraction of channels activated back toward control levels - lighter trace in (ii). (b) Steady- state activation and inactivation curves for control and 8-br-CAMP conditions, and an activation curve with 8-br-CAMP in the pipette after bath application of 300 PM H7. Bath application of H7 shifted the 8-br-CAMP curve back toward control. (c) Time course of reversal of PKA effect by H7. V,, command voltage; % max g, O/o maximum conductance; V,,, act, voltage for l/2 maximum activation. Adapted from 125.1.

of action potentials. A decrease in A-type K+ currents by PKC has also been observed by Rudy and colleagues [27].

Both S-bromo-CAMP and phorbol esters also produce a small, but significant (-5 mV), positive shift in the inacti- vation curve and a small slowing of the rate of inactivation. Such a shift in the inactivation curve could increase slight- ly the number of channels available for activation at normal resting potentials, but this change would probably have lit- tle effect on action potential amplitude. If for some reason the neuron were more depolarized than the normal resting potential, then this effect on inactivation would tend to increase K+ currents and thus partly counteract the above

described increase in amplitude of action potentials.

Activation of both PKA and PKC can lead to activation of mitogen-activated protein kinase (MAPK) in neurons ([Z&29]; JP Adams et aL, unpublished data). Furthermore, inhibition of MAPK has been shown to block induction of long-term potentiation in these neurons [30]. Thus, we tested the effects of MAPK inhibitors on the transient K+ channels in dendrites. The inhibitors PD 098059 and LJO126-20 both produced a small, but significant, negative shift in the activation curve of S-10 mV ([31]; JP Adams eta& unpublished data). This shift led to an increase in the activation of transient K+ currents. The result suggests that MAPK is constitutively active in dendrites and that MAPK

activity reduces active K+ channels in the dendritic mem- brane. Biochemical studies have also led to the conclusion that constitutively active hlAPK exists in dendrites [JO].

In cell-attached patches from dendrites of CA1 pyramidal neurons, the total K+ current can be separated into a tran- sient component and a sustained component, reflecting A-type and presumably delayed-rectifier type K+ channels, respectively [lO”]. The activation curve for the transient channels in the dendrites is some lo-l.5 mV more negative than the activation curve for transient channels in the soma and proximal dendrites. The positive shift in the activation curve induced by 8-bromo-cAhlP or phorbol ester thus makes the activation curve of these dendritic channels very similar to those in the soma. The activation curve of the sustained K+ current, on the other hand, shows no such difference between soma and dendrites. Furthermore, the activation of the sustained current appears unaffected by

X-bromo-cAh4P or phorbol esters [ZS’]. Although this lack of effect is interesting in its own right, it also provides a useful control for the effects seen on the transient channels by these agents and indicates that the effects are unlikely to be attributable to some nonspecific effect on the mem- brane. One possible explanation for these results is that constitutivr activity of these kinases in the soma shifts the activation curve of the A-type K+ channels in the soma rel- ative to those in the distal parts of the dendrites.

Regulation of back-propagating action potentials in hippocampal neurons Johnston et al. 291

Functional consequences of K+ channel modulation in dendrites Activation of PKA, PKC, or MAPK thus decreases A-type Kf currents in dendrites by shifting their activation to more positive potentials. This means that for any given depolar- ization within the range of -SO to +50 mV there would be less outward K+ current. In particular, in the range of -25 to +25 mV, where the activation curve is the steepest, a 15 mV shift in the curve could result in a 50% or more decrease in transient current. Because this K+ current tends to dampen dendritic depolarizations, a decrease in the current should increase excitability. We tested this by measuring the amplitude of back-propagating action potentials before and during increases in PKA and PKC [ZS’].

Dendritic action potentials were measured at sites approx- imately ZOO-300 pm from the soma following antidromic stimulation of CA1 pyramidal neurons. The application of PDA increased the amplitude of the back-propagating action potentials by an average of 78% whereas &bromo- CAMP increased the amplitude by 51%. Little or no effect on amplitude was seen at more proximal sites (less than 200 pm from the soma). We also measured the rate of rise of the back-propagating action potentials, but no effect was seen with either compound. This suggests that the increase in amplitude results mostly from the decrease in the K+ current and not from an increase in Na+ current.

PKA and PKC can be increased by a number of neuro- transmitters. We tested the effect of isoproterenol, a beta-adrenoceptor agonist, and carbachol, a muscarinic receptor agonist, on the amplitude of back-propagating action potentials [32’] in a similar manner as with the direct activation of PKA and PKC described above. Isoproterenol, which will increase activation of PKA, increased action potential amplitude by an average of 56%, whereas carbachol, which will increase activation of PKC, produced a more modest increase of 19% (Figure 3). In both cases, there was no change in the rate of rise of the action potential, although in the carbachol experiments, the dendrites had to be hyperpolarized to remove residual Na+ channel inactivation before triggering the action potentials. Otherwise, carbachol also led to a small increase in the rate of rise of the action potential as a result of its effects on Na+ channels (see above). We also tested a dopamine Dl/DS receptor agonist, 6-Cl-PB, which should also increase PKA activity. In these experiments, there appeared to be two populations of neurons, one group that responded with a small increase in action potential ampli- tude and another group that showed no effect. It may be that the dopamine receptors are not expressed in all CA1 neurons or that the density of Dl/DS receptors is not large enough to produce sufficient intracellular PKA to affect dendritic K+ channels [33,34].

Conclusions In summary, dendritic signal propagation is dependent upon the distribution and properties of voltage-gated ion

Figure 3

(a) j lsoproterenol

\r IS0

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(a Carbachol

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Isoproterenol, carbachol, and a dopamine agonist increase dendritic action potential amplitude. (a) Bath application of 1 FM isoproterenol resulted in a 104% increase in amplitude, from 41 mV (‘Pre’) to 84 mV, of an antidromically initiated action potential recorded 220 pm from the soma. Wash-out of isoproterenol brought the action potential back down to pre-isoproterenol amplitude (38 mV; ‘Wash’). With a second application of isoproterenol (dark arrow labeled ‘Iso’), the amplitude again increased twofold to 80 mV. (b) In a different recording, 300 ym from the soma, isoproterenol again doubled the action potential amplitude from 25 to 50 mV. In this experiment, 300 pM H7, a generic kinase inhibitor, was included in the control saline during the wash-out of isoproterenol. The subsequent second application of isoproterenol failed to lead to a second increase in amplitude (dark arrow labeled ‘lso + H7’). (c) In a distal recording (300 pm), 1 PM carbachol increased the action potential amplitude by 81%, from 27 to 60 mV. In the carbachol experiments, cells were held hyperpolarized to -80 mV to remove Na+ channel inactivation (see text). Cd) One of the 6 out of 10 recordings where 6-Cl-PB led to an increase in amplitude. In a recording 220 pm from the soma, 10 KM 6-Cl-PB increased dendritic action potential amplitude by 26%, from 21 to 26.5 mV. The cells were held at -70 mV in all 6-Cl-PB experiments. Adapted from [32’].

channels. Both Na+ and K+ channels can be modulated by a number of neurotransmitters and second-messenger systems. The activation of PKA and PKC leads to an increase in dendritic excitability by removing a slow inactivation of Na+ channels (via PKC) and decreasing the activity of transient, A-type K+ channels (via PKA and PKC). The propagation of both action potentials and

292 Signalling mechanisms

synaptic potentials through the dendrites can thus be importantly modified by a variety of neuromodulatory synaptic inputs.

Acknowledgements This research was supported by National Institutes of Health (NIH) grants (MH48432, MH44754, MH11712, and NS37444), the Human Frontiers Science Program, and the Hankamer Foundation.

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