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Volume 17, Number 10,
Issue of May 15, 1997
pp. 3476-3487
Copyright ©1997 Society for Neuroscience
Arachidonic Acid Inhibits Transient Potassium Currents and
Broadens Action Potentials during Electrographic Seizures in
Hippocampal Pyramidal and Inhibitory Interneurons
Sotirios Keros and
Chris J. McBain
Laboratory of Cellular and Molecular Neurophysiology, National
Institute of Child Health and Human Development, National Institutes of
Health, Bethesda, Maryland 20892-4495
 ABSTRACT
- INTRODUCTION
- MATERIALS AND METHODS
- RESULTS
- DISCUSSION
- FOOTNOTES
- REFERENCES
ABSTRACT 
The transient outward potassium current was studied in outside-out
macropatches excised from the soma of CA1 pyramidal neurons and stratum
(st.) oriens-alveus inhibitory interneurons in rat hippocampal slices.
Arachidonic acid dose dependently decreased the charge transfer
associated with the transient current, concomitant with an increase in
the rate of current inactivation. Arachidonic acid (AA) did not
affect the voltage dependence of steady state inactivation but did
prolong the period required for complete recovery from inactivation.
The effects of AA were mimicked by the nonmetabolizable analog
of AA, 5,8,11,14-eicosatetraynoic acid, suggesting that
metabolic products of AA were not responsible for the observed
blocking action. In addition, AA blocked st. oriens-alveus-lacunosum-moleculare interneuron transient currents but
not currents recorded from basket cell interneurons. In current clamp
experiments, AA was without effect on the action potential waveform of CA1 pyramidal neurons under control recording conditions. In voltage-clamp experiments, the use of a test pulse paradigm, designed to mimic the action potential voltage trajectory, revealed that the transient current normally associated with a single spike deactivates too rapidly for AA to have an effect. Transient
currents activated by longer duration "action potential" waveforms,
however, were attenuated by AA. Consistent with this finding was
the observation that AA broadened interictal spikes recorded in
the elevated [K+]o model of epilepsy. These
data suggest that AA liberated from hippocampal neurons may act
to block the transient current selectively in both CA1 pyramidal
neurons and inhibitory interneurons and to broaden action potentials
selectively under pathological conditions.
Key words:
arachidonate;
potassium currents;
stratum oriens
interneurons;
fatty acids;
interictal spikes;
CA1
INTRODUCTION
The freely diffusible, lipid soluble fatty acid
arachidonic acid (AA) is an important second messenger in a wide
variety of cell types. AA and its metabolic products have been
shown to modulate a large number of ligand- and voltage-gated ion
channels in a variety of systems (for review, see Bevan and Wood, 1987 ;
Ordway, 1991). AA can be liberated from cell membranes either
through a direct action of phospholipase A2 or through the combined
action of phospholipase C and diacylglycerol lipase. Metabolism of
AA by a cyclooxygenase enzyme occurs extremely rapidly and can
produce 20 distinct, short-lived but extremely potent intermediates
(e.g., the prostaglandins, prostacyclins, and thromboxanes).
Modulation of a variety of voltage-dependent potassium channels by
AA is well documented (Meves, 1994). AA has been shown to
activate a large conductance (160 pS) K+ channel directly
in cardiac atrial muscle (Kim and Clapham, 1989) and a small
conductance (23 pS) K+ channel in smooth muscle (for
review, see Ordway et al., 1991). The lipoxygenase metabolites of
AA also activate the cardiac, muscarinic-activated
K+ channel, stimulate BKCa channels in rat
pituitary tumor cells (Duerson et al., 1996), and modulate S-type
K+ channels in Aplysia (Piomelli et al., 1987).
In central neurons, AA either depresses or enhances
K+ currents through lipoxygenase or cyclooxygenase
metabolites (Keyser and Alger, 1990; Schweitzer et al., 1990; Zona et
al., 1993).
The molecular identities of the channels modulated by AA are
largely unknown. Recently, however, AA has been shown to inhibit currents directly through channels formed by members of the Kv4 (Shal) subfamily of voltage-dependent potassium
channels, whereas other members of Shaker subfamilies were
relatively insensitive to AA (Villaroel and Schwarz, 1996;
however, see Honore et al., 1994). Kv4.2 protein is strongly expressed
across the somatodendritic axis of hippocampal CA1 pyramidal neurons
(Sheng et al., 1992; Maletic-Savatic et al., 1995), and recent evidence
suggests that the predominant A-type transient current throughout
principal neurons of the CNS arises from channels formed by Kv4.2
(Serodio et al., 1994). Taken together this would suggest that a large fraction of the transient current in CA1 pyramidal neurons may be
through Kv4.2-containing channels and therefore may be subject to
AA modulation. To test this hypothesis, we made recordings from
outside-out macropatches excised from the somata of a variety of
neuronal types in the hippocampal slice preparation and studied the
modulation of the transient current contained in these patches by
AA.
MATERIALS AND METHODS
Hippocampal slices were prepared as described previously
(Maccaferri and McBain, 1995). Briefly, Sprague Dawley rats (postnatal days 8-22) were killed by decapitation after deep anesthesia using isoflurane following National Institutes of Health animal welfare guidelines. The brain was removed and placed in ice-cold artificial CSF, composed of (in mM): 130 NaCl, 24 NaHCO3,
3.5 KCl, 1.25 NaH2PO4, 1 CaCl2, 3 MgSO4, and 10 glucose, saturated with 95% O2
and 5% CO2, pH 7.4. Transverse hippocampal slices
~300µm thick were cut using a Vibratome (Oxford series 1000;
Polysciences, Warrington, PA) and incubated at room temperature for a
recovery period of at least 1 hr before use.
All voltage-clamp recordings were performed at room temperature using
outside-out macropatches excised from the somata of the appropriate
cell type. Patch electrodes were fabricated from thin-walled
borosilicate glass (TW150; World Precision Instruments) and had
resistances of 2-6 M when filled with (in mM): 130 K-gluconate, 10 NaCl, 2 Na2ATP, 0.3 NaGTP, 10 HEPES, and
0.6 EGTA, buffered to pH 7.4 and ~275 mOsm. In some experiments 10 mM
bis(2-aminophenoxy)ethane-N,N,N ,N-tetra-acetic acid
(BAPTA) was added to the internal solution (see text for details).
Glutathione (5 mM) was included and Mg2+ was
excluded from the intracellular solution to prevent a loss of N-type
inactivation caused by cysteine oxidation (Ruppersberg et al., 1991).
Biocytin (0.2-0.4%) was routinely added to the recording electrode
for post hoc identification of the recorded cell. Individual
neurons were visually identified using a near infrared charge-coupled
device camera. First, tight seals (>1 G) were obtained from
visually identified cells in the CA1 stratum (st.) pyramidale or st.
oriens-alveus as described previously (Maccaferri and McBain, 1995).
After establishment of the whole-cell configuration, the electrode was
slowly withdrawn from the slice over the course of several minutes to
ensure the formation of a large macropatch of membrane. Slices and
outside-out patches were perfused with media of the following
composition (in mM): 130 NaCl, 24 NaHCO3, 3.5 KCl, 1.25 NaH2PO4, 1 CaCl2, 3 MgSO4, 0.2 CdCl2, and 10 glucose and
tetrodotoxin (TTX, 0.5-1 µM) saturated with 95%
O2 and 5% CO2, pH 7.4. Series resistances in
whole-cell voltage-clamp experiments were calculated from the
capacitive current peak (unfiltered) in a 10 mV voltage step and were
in the range of 10-30 M; membrane potentials were not corrected for
these errors. For current-clamp recordings, the whole-cell recording
configuration was used. Solutions were identical to those described
above, with the exception that TTX and Cd2+ were omitted.
Data were collected using either an Axopatch 1D or an Axopatch 200A
amplifier (Axon instruments, Burlingame, CA) modified to permit bridge
balance compensation in the current clamp mode. Signals were filtered
at 2 kHz and digitized at 5-10 kHz on a Pentium-based computer using
the pClamp suite of programs (Axon Instruments). Data are presented as
the mean ± SEM.
Drugs and solutions. Arachidonic acid was obtained as a
sodium salt (Sigma, St. Louis, MO). Arachidonic acid was made fresh daily before use by dissolving in water; the solution was sonicated for
3-5 min and then vortexed for a further 2 min. The solution was
aliquoted, frozen, and used as required. If used from frozen, arachidonic acid was thawed and sonicated for 5 min and vortexed for 1 min before use. Fresh arachidonic acid was made every 3 hr.
5,8,11,14-Eicosatetraynoic acid (ETYA; Calbiochem, La Jolla, CA) was
dissolved in ethanol to make a stock solution of 10 mM immediately before use. The final concentration of ethanol in solutions
containing ETYA was 0.1%. For experiments involving ETYA, 0.1%
ethanol was routinely added to all control solutions. Ethanol (0.1%)
was without effect on the transient currents recorded from hippocampal
neurons.
Histological methods. After electrophysiological recordings,
slices were fixed in 4% paraformaldehyde (>24 hr), immersed in 30%
sucrose/PBS and resectioned into ~75 µm sections on a freezing microtome. Biocytin staining was revealed using an avidin-horseradish peroxidase reaction (Vectastain avidin-biotin complex standard kit)
and enhanced using NiNH4SO4 (1%) and
CoCl2 (1%). Slices were mounted and dehydrated on
gelatin-coated glass slides for camera lucida reconstruction.
RESULTS
Transient outward potassium currents in
outside-out macropatches
Because of the large physical profile and multiple dendritic
branch points of hippocampal neurons, most voltage-clamp data obtained
from whole-cell voltage-clamp experiments are subject to considerable
space-clamp error (Spruston et al., 1994; Thurbon et al., 1994). In the
present experiments, outside-out macropatches excised from the cell
bodies of pyramidal neurons and inhibitory interneurons were used for
all voltage-clamp experiments to minimize such errors. Typically,
patches excised from hippocampal neurons possessed a sufficiently large
number of channels to permit the study of macroscopic transient
currents. In general, macropatches excised from cells deep within the
slice yielded patches containing the largest transient currents
compared with those excised from more superficial cells. Although
transient currents usually dominated the total outward current in
pyramidal neuron macropatches (Fig. 1), the transient
current was typically studied in isolation by use of the voltage
protocol shown in Figure 1. By alternating a prepulse to  110 or 30
mV (or 40 mV, 100 msec), the total current (sustained plus transient)
or the isolated sustained current component, respectively, could be
activated in the patch by a test pulse to +40 mV. The transient current
was subsequently isolated by digital subtraction of the sustained
current from the total current. In a typical experiment, 18 test
pulses, which alternated between a prepulse to either 30 or 110 mV,
were delivered to a patch in both control or drug-treated conditions.
After isolation of each transient current trace, the nine traces were
then summed and averaged to yield the isolated and averaged transient
current (Fig. 1, right panel). Transient currents in
outside-out macropatches possessed amplitudes ranging from 100 pA to 2 nA (mean amplitude, 465 ± 70 pA; Vtest = +40 mV; n = 47). Inactivation of the transient current
could be fit by a single exponential with a time constant of 23.3 ± 1.2 msec (Fig. 1B, dotted line; n = 47), suggesting that only a single transient current component was
present in the outside-out macropatches. Transient current amplitude
was a steep function of the test potential (Fig.
2A). Currents were activated at
potentials positive to 60 mV, and in most patches the calculated
conductances were nonsaturating at test potentials up to +70 mV (data
not shown). Because of the nonsaturating nature of the transient
current conductance, we were unable to determine the half-activation
voltage from conductance-voltage plots of the voltage dependence of
activation in the majority of patches. In four patches, however,
maximal conductance was reached at the most positive potentials, and
the mean half-activation potential of the transient current in these
patches was 7.5 ± 2.2 mV (k, 20.7 ± 1.0;
n = 4) (data not shown). Steady state inactivation was
studied using depolarizing test pulses to a fixed voltage (+40 mV)
preceded by a series of prepulse conditioning potentials ranging from
120 to 10 mV. The transient current was completely inactive at
prepotentials positive to 40 mV. As the prepotential was made
progressively more negative, the transient current amplitude increased
(Fig. 2B). The relative amplitudes of the currents
were plotted and fitted with a Boltzmann equation to generate the
steady state inactivation curve (Fig. 2B)
Half-inactivation of the transient current occurred at 72.1 ± 1.8 mV (k, 8.8; n = 8), a value close to
that reported previously for transient currents in cultured hippocampal
neurons (Ficker and Heinemann, 1992).
Fig. 1.
Isolation of the transient current in outside-out
macropatches excised from hippocampal pyramidal neurons.
A, Transient currents were isolated from the total
outward current by alternating prepulses to 30 and 110 mV before a
test pulse to +40 mV. Inclusion of a prepulse to 30 mV resulted in
the complete inactivation of the transient current and left only the
isolated sustained current phenotype. In contrast, inclusion of a
prepulse to 110 mV activated both transient and sustained current
phenotypes. Digital subtraction of the family of currents obtained with
a prepulse at 30 mV (nine trials) from those obtained with a prepulse
to 110 mV (nine trials) yielded the isolated transient current.
B, The isolated transient currents were then averaged to
generate the mean current for analysis. Under control conditions the
current inactivation could be fit by a single exponential
(dotted line) with a time constant of 21.5 msec.
[View Larger Version of this Image (11K GIF file)]
Fig. 2.
Activation and inactivation properties of CA1
pyramidal neuron transient currents in outside-out patches.
A, Transient currents were activated at test potentials
positive to 60 mV and up to +70 mV (10 mV increments). Interleaved
with each cycle to activate the transient current (prepulse to 110
mV) was a test pulse cycle including a prepulse to 30 mV (see
inset). Inclusion of alternating prepulses to 110 and
30 mV allowed the isolation of the transient current from the total
current for each test potential as described in Figure 1. A plot of the
current-voltage relationship of the isolated transient current reveals
that transient currents were a steep function of the test potential.
B, Steady state inactivation of the transient current
was determined by the use of a test pulse to +40 mV preceded by a
series of prepulse conditioning potentials ranging from 120 to 10
mV. The transient current was completely inactivated at potentials
positive to 40 mV. The relative amplitudes of the transient current
were plotted as a function of the prepotential and fit with a Boltzmann
equation to generate the steady-state inactivation curve (right
panel). Half-inactivation of the transient current
occurred at a voltage of 75.2 mV.
[View Larger Version of this Image (29K GIF file)]
The transient current is blocked by arachidonic acid
The observation that recombinant channels formed by the
Shaker subfamily member Kv4.2 were blocked by low
concentrations of AA (Villaroel and Schwarz, 1996) and that
Kv4.2 was strongly expressed in the hippocampal CA1 subfield
(Maletic-Savatic et al., 1995) prompted us to determine whether
transient currents expressed in CA1 pyramidal neurons were sensitive to
modulation by AA. Application of AA dose dependently
attenuated the transient current in outside-out patches obtained from
CA1 pyramidal neurons (Fig. 3). In the presence of
AA both the peak amplitude and the time constant of inactivation were affected. The effects of AA on the current amplitude varied from patch to patch (range, 7-60% block by 1 µM
AA). To obtain a more accurate estimate of the effects of
arachidonic acid, we measured changes in the charge transfer associated
with the transient current. The transient current charge transfer was
obtained by the cumulative integration of the transient current with
respect to time (Fig. 3B). Figure 3D shows the
dose-response relationship for AA effects. The maximal
reduction in the charge transfer was 87.0 ± 0.4% (n = 7) at a concentration of 10 µM arachidonic acid. The
IC50 for the AA effect was 0.97 ± 0.03 µM (Fig. 3D). The block of the transient
current occurred slowly over 2-3 min and reached steady state by ~5
min. On removal of AA the current rapidly returned to near
control values and did not require bovine serum albumin to facilitate
the washout, as was reported for AA block of Kv4.2 expressed in
oocytes (Villaroel and Schwarz, 1996). The reasons for the highly
variable effect of AA on the current amplitude are at present
unclear; it should be pointed out, however, that there was no
correlation between the magnitude of current amplitude block and the
reduction in the charge transfer.
Fig. 3.
Arachidonic acid dose dependently blocks the
transient current in CA1 pyramidal neurons. A, Both the
amplitude and time course of the transient current were attenuated by
AA (3 µM). The effects of AA were readily
reversible on washing. B, Plot of the cumulative charge
transfer associated with the transient current. Integration of the
transient current with respect to time allowed the calculation of the
charge transfer. The transient current charge transfer was markedly
attenuated in the presence of AA. The effect of AA was
partially reversed on washing. C, AA dose
dependently increased the rate of transient current inactivation.
Normalization of the transient currents obtained in the control and in
the presence of AA demonstrates an increase in the rate of
steady-state inactivation in the presence of AA. The rate of
current inactivation in both the control and in the presence of
AA were fit by a single exponential function. In the presence of
AA, the rate of current inactivation was 2.6 msec compared with
35 msec in the control (dotted line). D,
Dose-response relationship of the effect of AA on the transient current charge transfer reveals an IC50 of ~1
µM. The numbers indicated above each data
point reflect the numbers of patches used to construct the
points.
[View Larger Version of this Image (24K GIF file)]
The effect of arachidonic acid on the pyramidal neuron transient
current was associated with a marked increase in the rate of current
inactivation occurring during a prolonged test pulse. Figure
3C shows that when the transient current recorded in 3 µM arachidonic acid was scaled to the peak control
current, currents in the presence of arachidonic acid inactivated more
rapidly than those seen in the control. At concentrations of 1 and 10 µM arachidonic acid, the time constants of current
inactivation were 12.0 ± 1.2 (n = 16) and
10.0 ± 1.8 (n = 8) msec, respectively, compared
with 23.3 ± 1.2 msec (n = 47) in the control
(Vtest = +40 mV). These data contrast with the
effects of arachidonic acid on channels formed by recombinant Kv4.2
subunits, in which the effect of arachidonic acid on current amplitude
was not associated with an alteration of the inactivation kinetics.
Arachidonic acid has been shown previously to accelerate the kinetics
of inactivation of currents through channels formed by the
Shaker subunit; however, these effects of AA were
also associated with an enhancement of the peak amplitude (Villaroel
and Schwarz, 1996). Arachidonic acid was without effect on the voltage
dependence of inactivation. Figure 4 demonstrates that
despite a large reduction in the charge transfer associated with the
transient current, arachidonic acid did not shift the voltage
dependence of inactivation. The mean half-inactivation voltage of
transient currents in 10 µM arachidonic acid was
76.6 ± 2.8 (k, 10.7; n = 7) compared
with 72.1 ± 1.8 mV (k, 8.8; n = 8)
in the control. The effects of arachidonic acid on the voltage
dependence of activation could not be studied in detail, because at
test potentials of up to +70 mV the transient current did not reach
maximal conductance (data not shown) in the majority of cells. In only
two patches in which the maximal conductance was observed to saturate
were we able to study the effects of AA on the voltage
dependence of activation. In these patches the voltage dependence of
the transient current was not altered in the presence of AA (1 µM; half-activation voltage, 2.1 mV; k,
19.3; compared with 5.5 mV; k, 19.3 in control) (data not
shown).
Fig. 4.
AA does not alter the voltage dependence of
inactivation. Despite increasing the rate of transient current
inactivation, AA does not alter the voltage dependence of
inactivation. AII, BII, The relative amplitudes of the
transient current were plotted as a function of the prepotential and
fit with a Boltzmann equation to generate the steady-state inactivation
curve (see Fig. 2). In the presence of 10 µM AA,
the half-inactivation voltage (75.8 mV) is similar to that observed
in the control (77.7 mV). All currents were obtained from the same
patch.
[View Larger Version of this Image (25K GIF file)]
AA decreases the rate of recovery from inactivation
In striatal neurons, the block of voltage-dependent
Na+ currents by AA is associated with a slowing of
the rate of recovery from inactivation (Fraser et al., 1993). In the
present experiments AA also delayed the rate of recovery of the
transient current from inactivation (n = 5). Figure
5 demonstrates that in the control, the rate of recovery
from inactivation at 110 mV was best fit by a single exponential with
a time constant of 13 msec. In the presence of 1 µM
AA, the time constant of recovery was 24 msec. In all cells
tested, 1 µM AA increased the time constant of the rate of recovery from inactivation at 110 mV by 170 ± 13%
(n = 5) over control.
Fig. 5.
AA decreases the rate of recovery from
inactivation. Outside-out patches were voltage clamped at 30 mV to
fully inactivate the transient current. A prepulse to 110 mV of
increasing duration preceded the test pulse (10 msec increments up to
the 100 msec prepulse duration, then 50 msec increments up to 550 msec;
the inset shows only 50 msec increments for clarity). A
test pulse to +40 mV (200 msec duration) was then made to activate the
transient current. A plot of the transient current peak amplitude
against the prepulse duration allowed the determination of the rate of recovery from current inactivation. Under control conditions the rate
of recovery from steady-state inactivation proceeded with a single
exponential of 12.8 msec. In the presence of AA (1 µM) the time constant of the rate of recovery from
inactivation increased by 88% to 24 msec.
[View Larger Version of this Image (41K GIF file)]
ETYA mimics the effects of AA
The arachidonic acid-mediated inhibition of transient currents
through recombinant Kv4.2 channels (Villaroel and Schwarz, 1996) and
transient currents in sympathetic neurons (Villaroel, 1993, 1994) was
mimicked by the nonhydrolyzable arachidonic acid analog ETYA. Because
ETYA is not a substrate for metabolism by the cyclooxygenase,
lipoxygenase, or cytochrome P450 (epoxygenase) pathways associated with
arachidonic acid, these data suggested that arachidonic acid interacted
directly with Kv4.2 channels without requiring the formation of a
metabolic end product. In agreement with the previous data, ETYA had an
effect on pyramidal neuron transient currents identical to that of
arachidonic acid. ETYA maximally attenuated the transient current
charge transfer by 63 ± 9% (n = 7) at a
concentration of 10 µM (Fig. 6). ETYA was
also without effect on the voltage dependence of inactivation but did
increase the rate of steady state inactivation (Fig. 6). In the
presence of 10 µM ETYA, the transient current
inactivation time constant was 12.1 ± 1.5 msec compared with
21.4 ± 2.7 in the control (n = 7). The effects of
ETYA did not require an elevation in [Ca2+]i,
because recordings made with pipettes containing the calcium chelator
BAPTA (10 mM) did not alter the magnitude of the block observed in the presence of ETYA (data not shown). The similarity of
the effects of arachidonic acid and ETYA suggests that the two agents
act via an identical mechanism. Furthermore, these data suggest that
arachidonic acid has a direct effect on transient channels and does not
act by being converted to prostaglandins or by the formation of the
metabolites hydroxyeicosatetraenoic acids, epoxyeicosatrienoic acids,
or hydroperoxyeicosatetraenoic acids.
Fig. 6.
ETYA mimics the effects of AA on the
transient current. The nonmetabolizable analog of AA, ETYA,
mimicked the effects of AA on transient current charge transfer.
In the presence of 10 µM ETYA both the amplitude
(A) and the charge transfer (B) of the transient current were inhibited. The effects of ETYA were partially reversed on return to control. C, Normalization of the
transient current obtained in both the control and 10 µM
ETYA reveal that the rate of steady-state inactivation is increased in
the presence of ETYA, similar to the effects of AA (Fig. 3).
Single exponentials adequately described the current inactivation in
both the control and 10 µM ETYA (dotted
line). The time constants of inactivation in control and ETYA
were 16.0 and 7.0 msec, respectively.
[View Larger Version of this Image (13K GIF file)]
AA blocks the transient current in st. oriens-alveus
interneurons but not st. pyramidale basket cells
The subpopulation of inhibitory interneurons which reside in the
st. oriens-alveus have been well characterized with respect to their
morphology (McBain et al., 1994), voltage-dependent K+
current properties (Zhang and McBain, 1995a,b), and lack of synaptic plasticity (Maccaferri and McBain, 1995, 1996). Previously we have
demonstrated that transient currents recorded from st. oriens-alveus interneurons possess biophysical and pharmacological properties similar
to those of CA1 pyramidal neurons, suggesting that similar or related
channel subunits may underlie both transient currents (Zhang and
McBain, 1995a,b). In support of this hypothesis, AA had an
identical effect on the transient current in macropatches excised from
the somata of visually identified st. oriens-alveus inhibitory neurons
(n = 7; Fig. 7). At a concentration of 1 µM, AA blocked the st. oriens-alveus inhibitory
interneuron transient current charge transfer by 47 ± 9.0%
(n = 4). Similar to pyramidal neurons, AA had a
maximal effect at 10 µM, reducing the charge transfer by
57 ± 1% (n = 4). In all st. oriens-alveus
interneurons, AA also increased the rate of current inactivation
(Fig. 7). The time constant for current inactivation in the presence of
AA (1 µM) was 22.7 ± 2.4 msec
(n = 4) compared with to 34.8 + 6.2 msec seen in the
control. Where possible, post hoc morphological
identification of these cells revealed them to be horizontally oriented
interneurons, the axons of which ramify in the strata lacunosum and
moleculare (McBain et al., 1994; Maccaferri and McBain, 1995).
Fig. 7.
The transient current in CA1 st. oriens-alveus
interneurons but not basket cell interneurons is blocked by AA.
A, An outside-out macropatch excised from a
morphologically confirmed interneuron of the stratum oriens-alveus
possesses a transient current similarly modulated by AA. At a
concentration of 1 µM AA, the charge transfer of
the transient current is blocked by 41% (B). In
contrast, an outside-out patch excised from the soma of a confirmed CA1
pyramidal cell layer inhibitory interneuron possessed a transient
current insensitive to AA (1 µM).
[View Larger Version of this Image (23K GIF file)]
In contrast, a population of morphologically distinct inhibitory
interneurons located at the border between the CA1 pyramidal subfield and the st. oriens, the so-called basket cells, were relatively insensitive to AA (n = 9).
Figure 7 shows data obtained from one basket cell in which 1 µM AA did not block the transient. At a
concentration of 10 µM, the mean block by AA was
17 ± 7% (n = 8) of the transient current charge
transfer. Where possible, post hoc morphological
identification of these cells confirmed them as typical basket cells
with axons that ramified throughout the pyramidal cell layer (Buhl et
al., 1994; Du et al., 1996).
AA does not alter the time course of single
action potentials
The transient potassium current has been suggested to
possess a variety of roles in CNS neurons, including setting the
frequency of neuronal discharge by influencing the interspike interval, influencing the threshold for action potential initiation, and contributing to the spike repolarization and afterhyperpolarization (AHP) (for review, see Rogawski, 1985; Halliwell, 1990). Because the
transient current is thought to have a role in action potential repolarization in central neurons (Storm, 1987), we next performed whole-cell recordings from CA1 pyramidal neurons under current clamp
conditions to determine whether AA block of the transient current influenced the properties of the evoked action potential waveform. Figure 8A demonstrates that
although the threshold for action potential initiation was raised 1-2
mV in the presence of both 1 and 10 µM AA, neither
concentration of AA altered the action potential waveform. In
these experiments, because CA1 pyramidal neurons do not fire
spontaneous action potentials, action potentials were initiated by
holding the cell at 60 mV, and depolarizing current pulses of
sufficient amplitude to trigger action potential activity were
delivered through the electrode. AA (10 µM), at a
concentration that blocked >80% of the transient current charge transfer in outside-out patches, was without effect on action potential
activity recorded in six neurons (Fig. 8). The waveforms of action
potentials occurring late in the train similarly were not affected by
AA. In addition, AA did not alter the cell membrane potential or input resistance of hippocampal neurons (data not shown).
Similar data were obtained using ETYA (10 µM; data not shown). Despite the lack of effect of AA on single spike
activity, AA did reduce the frequency of action potential firing
in response to a depolarizing current pulse (data not shown). This
effect on spike frequency is unlikely to result from a blockade of the transient current, because any reduction of the transient current would
be expected to increase the spike discharge frequency. These latter
effects and the effects on spike threshold are more probably attributable to an effect of AA on voltage-dependent
Na+ channels, similar to that described for striatal
neurons (Fraser et al., 1993), or alternatively by activation of the M
current (Schweitzer et al., 1990).
Fig. 8.
AA does not alter the time course of single
action potentials but broadens spikes during electrographic interictal
events. A, Under control physiological recording
conditions, whole-cell current-clamp recordings were made from CA1
pyramidal neurons. AA (1 and 10 µM) raised the
threshold for action potential firing (A) without
altering the time course of single action potentials (B). Action potentials were activated by depolarizing
pulses delivered from a holding potential of 60 mV. Typically, the
action potential threshold occurred close to 45 mV in the control.
B, Alignment of the action potential waveforms shown in
A clearly shows that AA at concentrations that
block 50 and 80% of the transient current in outside-out patches fail
to modify the action potential waveform. C, When
extracellular K+ was elevated to 8.5 mM,
electrographic interictal bursts of action potentials were observed
(insets). These action potentials were of a longer
duration than seen under control physiological conditions (>10 msec)
because of the reduced driving force for K+ current
repolarization. Spike duration was prolonged and the amplitude was
reduced in the presence of 3 µM AA.
D, Normalization of the two action potentials shown in
C shows that despite a similar time to peak, the entire
repolarization phase of the action potential was prolonged. In the
presence of AA, interictal events of similar durations were
observed. The number of spikes usually contained in these episodes was
reduced (inset). These data suggest that action
potentials occurring during electrographic interictal events possess an
increased fraction of transient current, which is a target for
AA modulation.
[View Larger Version of this Image (18K GIF file)]
The lack of effect of AA on the action potential waveform
suggested that either the transient current does not play a role in
action potential repolarization or, alternatively, that the duration of
a single action potential is insufficient to activate a large enough
fraction of transient current to be a target for AA modulation.
To determine the transient current component elicited by a single
action potential, we used a test pulse waveform designed to mimic the
average parameters of single action potentials recorded during
current-clamp experiments to activate transient currents in outside-out
macropatches (see Fig. 9, inset). The
"action potential" test pulse comprised a 1.2 msec depolarizing
ramp with a "spike" amplitude of 85 mV
(Vhold = Vthreshold = 45 mV; test pulse, +40 mV); the repolarization phase was a 3.8 msec
ramp back to 45 mV. The "spike waveform" had an overall duration
of 5 msec. Because the inactivation of the transient current is almost
complete at resting membrane potentials (Figs. 2 and 4), the test pulse
was preceded by a waveform designed to mimic the spike
afterhyperpolarization. This waveform comprised a test pulse to 90 mV
(Vhold, 60 mV) followed by a ramp to 45 mV
(spike initiation threshold) of a duration of 150 msec (see Fig. 9,
inset). The inclusion of this waveform permitted the partial
removal of transient current inactivation, by an amount equivalent to
that removed during an AHP immediately preceding the action potential
of interest. Figure 9 demonstrates that in a macropatch containing a
transient current of greater than 1 nA in amplitude
(Vtest = +40 mV) when the test pulse duration was 200 msec (associated charge transfer of 40 pC; Fig.
9AI), the action potential pulse paradigm activated
only ~1% of the total transient current charge transfer available
during a single spike of 5 msec duration (Fig.
9AII,AIII). Increasing the spike duration by 1 msec
increments increased the transient current component (Fig.
9AII). A "spike duration" of 10 msec activated 2.5 pC of transient current charge transfer, which corresponded to
~6.5% of the maximum charge transfer available in this patch. These
data suggest that only a modest transient current component is
activated during a single action potential waveform (5 msec duration)
in CA1 pyramidal neurons.
Fig. 9.
AA does not block the fraction of transient
current underlying short duration "single action potentials" but
does inhibit transient currents activated by longer duration spikes.
The lack of an effect of AA on action potentials evoked in
physiological conditions suggests that the transient current associated
with a single spike may deactivate too rapidly for AA
modulation. To determine the contribution of the transient current
during a single spike, a test pulse paradigm designed to simulate the
time course of pyramidal neuron action potentials
(inset; see text for details) was used to activate
transient currents in an outside-out patch containing a transient
current >1 nA in amplitude during a 200 msec duration test pulse
(Vtest = +40 mV). A, Current
inactivation in the control was fit by a single exponential with a time
constant of 23 msec (dotted line). AII,
Increasing the duration of the spike test potential from 5 to 10 msec
(1 msec increments) recruited an increasing fraction of the transient
current (AII). The data shown in
AII represent only the transient current component
activated during the test pulse to +40 mV
(Vhold = 45 mV).
AIII, Plots of the charge transfer associated
with each transient current activated by increasing action potentials
reveals that doubling the duration of the action potential yields a
fivefold increase in the transient current component obtained in the
patch. Note that even when the duration of the action potential was 10 msec, the transient current activated was <5% of the total current
activated by a 200 msec duration test pulse. B, In the
same patch, AA (1 µM) blocked 50% of the
transient current activated by a 200 msec test pulse to +40 mV and
increased the rate of current inactivation ( = 11 msec;
dotted line). BII, BIII, In the presence
of AA, short duration action potentials (5-7 msec) activated a
similar fraction of transient current charge transfer to that seen in control. In contrast, transient currents activated by longer duration action potentials were subject to modulation by AA. The
transient current charge transfer associated with a 10 msec action
potential was reduced by 24% compared with control. These data are
consistent with the data illustrated in Figure 8, which showed that
AA was without effect during short duration action potentials
but increased the duration of the broader action potentials recorded
during electrographic interictal events.
[View Larger Version of this Image (31K GIF file)]
Addition of AA (1 µM) to this macropatch reduced
the transient current amplitude activated during a 200 msec duration
test pulse (Vtest = +40 mV) and blocked the
associated charge transfer by 50% (Fig. 9BI). In the
presence of AA, however, a similar fraction of the transient
current charge transfer was activated during a 5 msec action potential
to that seen in the control, i.e., 0.4 pC (Fig. 9BII,BIII).
Only when spike waveforms of greater durations (>8 msec) were
delivered was an effect of AA observed. Figure 9BIII
shows that when the spike duration was increased to 10 msec, AA
reduced the associated charge transfer by 24%. Similar results were
observed in patches excised from five other CA1 pyramidal neurons. The
apparent lack of an effect of AA on shorter duration action
potentials results presumably because the transient current is forced
to deactivate soon after the depolarizing test pulse. This rapid
deactivation of the channel will prevent the occurrence of significant
steady state inactivation, one of the processes that would seem to be a
major target of the effects of AA. The lack of effect of
AA on transient currents activated during shorter duration
simulated action potentials is consistent with the lack of effect of
AA on action potentials recorded during current-clamp experiments described above (Fig. 8).
The results shown in Figure 9 suggest that AA will only affect
action potentials when the spike duration is long enough to activate an
appreciable fraction of the transient current charge transfer. Action
potentials of >10 msec duration are not normally observed under
physiological conditions but readily occur during electrographic
interictal events observed in the
"high-[K+]o" model of epilepsy (for
review, see McBain et al., 1993). In this model extracellular
K+ is elevated to 8.5 mM (from 3.5 mM), a manipulation that reliably induces stereotypical
electrographic seizure activity in CA1 pyramidal neurons, attributable
in part to the reduction in the K+-driving force, impaired
GABA-mediated inhibition, enhanced NMDA receptor-mediated activation,
and glial swelling (see McBain et al., 1993, for a more detailed
description of the elevated [K+]o model).
Interictal activity in CA1 pyramidal neurons comprises a short
paroxysmal depolarizing shift superimposed on which is a brief
discharge of three to five action potentials (see Fig. 8B,
inset). Action potential durations recorded during these events are significantly longer than those seen under control conditions of
3.5 mM [K+]o (Fig.
8B) (see also McBain, 1994). The voltage-clamp data
shown in Figure 9 predict that the longer duration action potentials (10-15 msec) routinely observed during interictal electrographic events (see Fig. 8B, inset) would possess an
appreciable transient current component for AA modulation.
Figure 8B demonstrates that in the presence of 8.5 mM K+ and 3 µM AA,
spontaneous action potential duration was increased 148% over the
control (mean duration, 23.5 ± 0.8 vs 15.9 ± 1.5 msec seen
in 8.5 mM [K+]o only;
n = 4). Likewise, the time to 50% repolarization was increased by 125% in all neurons tested (5.6 ± 0.2 vs 4.5 ± 0.3 msec in control; n = 4). In the presence of
AA (3 µM) the spike amplitude was also attenuated
(50.3 ± 4.9 vs 69.0 ± 1.6 mV in control); however, the
action potential time to peak remained unchanged. In the continued
presence of AA, action potential and interictal activity
increased in frequency and then abruptly ceased after 10-15 min. This
cessation of action potential activity was not associated with a change
in the membrane potential or input resistance. Action potentials could
be induced by direct depolarization through the electrode only if a
large hyperpolarization of the membrane potential preceded the
depolarizing stimuli (data not shown). These effects were only
partially reversible on washing. These data confirm the prediction that
action potentials of longer duration would be a target for AA
modulation and suggest that AA released during pathological but
not physiological conditions will strongly influence action potential
activity.
DISCUSSION
The principal findings of this study are: (1) arachidonic acid
inhibited the transient current in hippocampal CA1 pyramidal neurons
and st. oriens-alveus inhibitory interneurons; (2) the block of the
transient current by AA was associated with an increased rate of
current inactivation and prolongation of the rate of recovery from
inactivation. AA did not, however, affect the voltage dependence of inactivation. (3) The effects of AA were mimicked by the
nonmetabolizable analog ETYA and suggest that the effect of AA
on transient current channels is direct and does not involve
arachidonate metabolism; and (4) AA was without an effect on
action potentials recorded under physiological conditions but did
prolong action potentials recorded during electrographic interictal
episodes. Consistent with this observation was the finding that
transient currents activated by test pulses designed to simulate single
action potential waveforms were not a target for AA modulation
until the action potential waveform was of a sufficient duration to
activate a larger transient current component.
The block of the hippocampal transient current by AA extends the
already considerable list of voltage- and ligand-gated ion channels
that are targets for AA or AA metabolite modulation (for review, see Meves, 1994). In the present experiments, several lines of
evidence suggest that the effects of AA on the hippocampal transient currents were direct: (1) The use of outside-out patches excised from the somata of pyramidal neurons will dialyze out any
cytoplasmic constituents rapidly, minimizing the production of
metabolic end products of AA. (2) The similar effect of the nonmetabolizable analog ETYA supports the hypothesis of a direct effect. ETYA is not a substrate for metabolic pathways involving cyclooxygenase, lipoxygenase, and epoxygenase and inhibits many of
these enzymes. We cannot, however, unequivocally rule out the possibility that both ETYA and AA are metabolized into more
potent metabolites. (3) The effects of AA were readily
reversible on washout of AA, arguing against the participation
of a phosphorylation (or dephosphorylation) process, because reversal
of the AA effect would require the action of a phosphatase (or a
kinase). (4) Finally, the lack of action of intracellularly applied
BAPTA rules out a requirement for an elevation of intracellular
Ca2+ for the effects of AA.
The similarity between the effects of AA described here and
those of AA on channels formed from recombinant Kv4.2 (Villaroel and Schwarz, 1996) suggest that the major transient current component present on cell bodies of pyramidal neurons occurs through channels comprising Kv4.2 subunits. Consistent with this hypothesis is the
strong expression of the Kv4.2 subunit protein in CA1 pyramidal neuron
somata and dendrites (Sheng et al., 1992; Maletic-Savatic et al.,
1995). In the present experiments, the reduction of the charge transfer
by AA was associated with a increase in the rate of current
inactivation and a slowing of the recovery from inactivation. In
contrast, AA did not alter the rate of current inactivation in
recombinant Kv4.2 channels. This suggests that channels responsible for
transient currents in hippocampal neurons may comprise additional subunits that possess additional sites for AA modulation. In
support of this hypothesis, a recent study by Serodio et al. (1994)
suggested that native channels responsible for the transient current
are probably assembled from Kv4.2 subunits and an as yet unidentified low molecular weight accessory protein (Serodio et al., 1994).
The precise mechanism for the effects of AA on the transient
current is at present unknown. The faster rate of current inactivation observed in AA suggests, however, an action on the inactivation process. Mutagenesis experiments on Kv4.2 channels have shown that the
intracellular S4-S5 linker, which has been proposed to act as the
receptor site for the N-terminal inactivation ball peptide,
participates in AA inhibition (Villaroel and Schwarz, 1996).
Access to an intracellular binding site limited by diffusion across the
lipid bilayer would explain the time required for AA effects to
reach steady state.
The present study demonstrated that currents through channels excised
from st. oriens-alveus interneurons were also targets for modulation
by AA. Although the Kv4.2 protein is strongly expressed in
principal neurons of the CA1 hippocampus, it is largely absent from
inhibitory interneurons in the st. oriens-alveus (Maletic-Savatic et
al., 1995). It would seem unlikely, therefore, that modulation of Kv4.2
channels underlies the effects seen in st. oriens-alveus interneurons.
Consistent with this observation was the finding that transient
currents in st. oriens-alveus interneurons had a time course of steady
state inactivation slower than pyramidal neurons and were significantly
less sensitive to AA than those of pyramidal neurons (57 vs 87%
maximal block). It is possible that other members of the Kv4 subfamily
(Kv4.1 and Kv4.3) are expressed in these cells, although Kv4.1
expression is low in the hippocampus. Recently, a new member of this
subfamily was cloned, Kv4.3, which is strongly expressed in the
hippocampus (Serodio et al., 1996). Expression of this subunit is
highest in interneurons of the CA1 st. oriens-alveus (P. Serodio and
B. Rudy, unpublished observation) and is largely absent from CA1 pyramidal neurons. Expression of recombinant Kv4.3 subunits, such as
Kv4.1 and Kv4.2, also results in the formation of channels carrying a
transient current phenotype (Serodio et al., 1996). Recovery from
steady state inactivation occurs at a slower rate in Kv4.3 than in
Kv4.2 channels (Serodio et al., 1996), consistent with the slower rate
of recovery seen in st. oriens-alveus-lacunosum-moleculare interneurons (Zhang and McBain, 1995a) compared with pyramidal neurons
(Fig. 5). Whether channels formed by these subunits underlie the
transient current seen in st. oriens-alveus interneurons or whether
currents through homomeric Kv4.3 channels are subject to modulation by
AA remains to be tested.
The concentrations of AA used in the present experiments are
within the physiological range for modulation by AA (Anderson and Welsh, 1990; Meves, 1994). Concentrations of exogenous AA in
excess of 10 µM are generally required to mimic the
actions of neurotransmitter-induced AA effects. In addition, the
Km values of cyclooxygenase and 12-lipoxygenase
for AA are both 5 µM (Needleman et al., 1986). In
CNS neurons, various neurotransmitters act to release AA by a
mechanism involving phospholipase A2 or through the combined action of
phospholipase C and diacylglycerol lipase (Axelrod, 1990). How might
AA be released in the hippocampal formation? In the hippocampus,
a variety of principal neurotransmitters are candidates for activation
of the AA induction cascade. Muscarinic receptor activation has
been shown to induce release of AA (Kanterman, 1990) and
muscarinic agonists block transient potassium currents (Nakajima et
al., 1986). Activation of hippocampal somatostatin receptors has been
shown to liberate AA (Bito et al., 1993), although at present it
is unknown whether somatostatin modulates transient potassium currents.
Both metabotropic glutamate receptors (mGluR) and NMDA-preferring
glutamate receptor activation induce the AA cascade system
(Dumuis et al., 1990a,b), and NMDA receptor currents have also been
shown to be potentiated by AA (Miller et al., 1992). A role for
AA in the induction phase of hippocampal long-term potentiation
(LTP) has been demonstrated (Williams et al., 1989; Drapeau et al.,
1990), suggesting that AA may be liberated during the
high-frequency tetanic stimulation used to induce LTP. AA production has been associated with ischemic cell damage in CNS neurons
(Madden et al., 1986) and seizure generation (for review see Bazan et
al., 1986), conditions associated with increased neuronal activity.
Both NMDA receptor and mGluR activation are intimately associated with
the generation of electrographic seizures in a variety of epilepsy
models (for review, see Schwartzkroin, 1993), including the
High-K+ model used in the present experiments (Traynelis
and Dingledine, 1988; McBain et al., 1993; McBain, 1994). It is
entirely plausible, therefore, that AA may be liberated during
electrographic seizure activity as a consequence of either mGluR or
NMDA receptor activation. Because action potential durations are
prolonged during electrographic interictal activity, AA may act
on transient current channels to broaden the action potential waveform
further, consequently enhancing Ca2+ influx into synaptic
terminals, resulting in a greater release of neurotransmitter.
Consistent with this hypothesis, glutamate release from hippocampal
mossy fiber terminals has been demonstrated to be facilitated by
AA (Freeman et al., 1990). Synaptically released glutamate may
then activate an increased number of mGluR or NMDA receptors, leading
to a self-sustaining cycle. In the present experiments, however, the
continued presence of AA led to the cessation of all
electrographic activity and the termination of action potential firing,
suggesting that prolonged AA exposure ultimately prevents action
potential activity presumably by altering the activity of a variety of
ion channels in hippocampal neurons. These effects may arise in part
from the action of AA on both voltage-dependent Na+
channels (Fraser et al., 1993) and/or activation of the M current (Schweitzer et al., 1990). An understanding of the modulation of the
currents responsible for these combined cellular mechanisms, together
with the action of AA on the transient current, will ultimately
provide insight into the total functional significance of AA
modulation of hippocampal neurons.
In conclusion, these data suggest that arachidonic acid modulates the
transient potassium current in both CA1 pyramidal neurons and st.
oriens interneurons by a mechanism involving an increase in the
inactivation rate and a slowing of the recovery from inactivation. Current-clamp experiments suggest that the transient current normally associated with single action potentials in normal physiological conditions would not be a target for AA modulation. In contrast, the longer duration action potentials occurring during electrographic seizure activity are strongly modulated by AA, suggesting that AA liberated during intense neuronal activity may act to
exacerbate pathological conditions such as seizure and ischemic cell
damage.
FOOTNOTES
Received Jan. 13, 1997; revised Feb. 25, 1997; accepted March 3, 1997.
S.K. was a National Institute of Child Health and Human Development
pre-Intramural Research Training Award (IRTA) fellow. We thank Drs.
Mark Mayer, Gianmaria Maccaferri, and Vittorio Gallo for their
constructive criticism of this manuscript.
Correspondence should be addressed to Chris J. McBain, Laboratory of
Cellular and Molecular Neurophysiology, Room 5A72, Building 49, National Institute of Child Health and Human Development, National
Institutes of Health, 49 Convent Drive, Bethesda, MD 20892-4495.
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