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Centre for Neuroscience, University of Alberta, Edmonton, Alberta T6G 2S2, Canada
Submitted 11 March 2003; accepted in final form 21 April 2003
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ABSTRACT |
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,b).
The present study examined the voltage-gated persistent inward currents (PICs)
underlying these plateaus. Adult rats were spinalized at the S2
sacral spinal level and after 2 mo, when spasticity developed, intracellular
recordings were made from motoneurons below the injury. For recording, the
whole sacrocaudal spinal cord was removed and maintained in vitro in normal
artificial cerebral spinal fluid (nACSF), without application of
neuromodulators. During a slow triangular voltage-clamp command (ramp) a PIC
was activated with a threshold of –54.2 ± 4.8 mV (similar to
plateau threshold), with a peak current of 2.88 ± 0.95 nA and produced
a pronounced negative-slope region in the V–I relation. This
PIC was in part mediated by Cav1.3 L-type calcium channels because it was low
threshold and significantly reduced by 10 to 20 µM nimodipine or 400 µM
Cd2+. The PIC that remained during a calcium channel
blockade (in Cd2+) was completely and rapidly blocked by
tetrodotoxin (TTX; 0.5 to 2 µM), and thus was a TTX-sensitive persistent
sodium current. This persistent sodium current was activated rapidly about 7
mV below the spike threshold (spike threshold –46.1 ± 4.5 mV),
contributed approximately 1/2 of the initial peak of the total PIC,
inactivated partly to contribute only approximately 1/3 of the sustained PIC
(at 5 to 10 s), and deactivated rapidly with hyperpolarization (<50 ms).
When TTX was added to the bath first, the nimodipine-sensitive persistent
calcium current (L-type) was seen in isolation; it was slowly activated
(>250 ms), had a low but variable threshold (either slightly above or below
the spike threshold), contributed the other approximately 1/2 of the initial
peak of the total PIC (before TTX), did not usually inactivate with time
(contributed approximately two-thirds of the sustained PIC), and deactivated
slowly with hyperpolarization to rest (in >300 ms). In summary,
low-threshold persistent calcium (Cav1.3) and sodium currents spontaneously
develop in motoneurons of chronic spinal rats and these enable large, rapidly
activated plateaus that ultimately lead to spasticity. |
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INTRODUCTION |
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,b;
Hounsgaard and Kiehn 1989;
Hultborn 2002;
Kiehn and Eken 1997;
Lee and Heckman 1998b;
Schwindt and Crill 1982). That
is, in motoneurons there are voltage-dependent persistent inward currents
(PICs) that are regeneratively activated once the membrane is depolarized
beyond a critical threshold (about –45 to –55 mV) by a brief
stimulus (<1 s). These currents can remain active for many seconds
afterward, and produce a sustained depolarization (plateau) and
after-discharge (self-sustained firing). In motoneurons these PICs underlying
the plateau are mainly mediated by calcium currents from low-threshold L-type
calcium channels (Cav1.3 type) (Carlin et
al. 2000b; Hounsgaard and Kiehn
1985,
1993), although persistent
sodium currents may also play a role
(Hsiao et al. 1998;
Lee and Heckman 2001), and
outward voltage- and calcium-dependent K+ currents can oppose the
inward calcium current (Hounsgaard and
Kiehn 1989). Thus the PIC is considered to be the net persistent
current from the combined inward and outward current sources.
The ability to activate plateaus in normal motoneurons relies on the
facilitation of PICs by neuromodulators such as 5-HT
(Hounsgaard and Kiehn 1989;
Hsiao et al. 1998), NE
(Foehring et al. 1989), or glutamate (through mGluR1 receptors;
Svirskis and Hounsgaard 1998),
and this occurs both by a direct facilitation of L-type calcium channels
(Hounsgaard and Kiehn 1989) or
by reduction of opposing outward K+ currents
(Hounsgaard and Kiehn 1989;
Hultborn and Kiehn 1992).
Evidence from awake humans (Gorassini et
al. 1998; Kiehn and Eken
1997) and animals (Gorassini
et al. 1999), and brain stem–intact decerebrate cats
(Hounsgaard et al. 1984)
indicates that there is normally an adequate supply of neuromodulators to
enable plateaus and associated self-sustained firing in motoneurons. After an
acute spinal cord transection, these brain stem–derived neuromodulors
are lost, and motoneurons caudal to the injury lose their ability to produce
plateaus. However, these motoneurons regain their ability to produce plateaus
with externally applied neuromodulators, such as 5-HT2, NE
1, mGluR1 and muscarine receptor agonists
(Conway et al. 1988;
Hounsgaard and Kiehn 1985,
1989;
Svirskis and Hounsgaard 1998),
or with stimulation activating neuromodulator release
(Delgado-Lezama et al.
1999).
Although acute spinal cord transection can eliminate plateaus in
motoneurons, recent evidence indicates that these motoneurons somehow regain
their ability to produce plateaus over the months that follow the injury
(Bennett et al.
2001a,b;
Eken et al. 1989). For
example, after chronic sacral spinal transection, the motoneurons below the
injury spontaneously exhibit plateaus, even though they were completely
isolated from the brain stem and there was no externally applied
neuromodulators or facilitated neuromodulator release (Bennett et al.
2001a,b).
Ultimately, these plateaus cause an enhanced intrinsic excitability that leads
to spasms in affected muscles (Bennett et
al. 2001a) and thus are of major clinical significance.
The purpose of the present study was to examine the ionic mechanisms
underlying these spontaneous plateaus that emerge in chronic spinal rats
despite the lack of brain stem control or externally applied neuromodulators.
Considering the involvement of the L-type calcium channels in generation of
plateaus in other preparations, we first examined whether blocking calcium
currents could eliminate the plateaus. Surprisingly, the PIC and plateaus
could be reduced to only about half their initial values with a calcium
channel blockade. The remaining PIC was found to be mediated by tetrodotoxin
(TTX)-sensitive persistent sodium currents. Part of this work was previously
published in abstract form (Li et al.
2001).
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METHODS |
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,
2001a,b).
Usually within 30 days dramatic spasticity developed in the tail muscles,
which are innervated by motoneurons below the level of the injury. Only rats
more than 50 days postinjury with clear spasticity were included in the
present study (see Bennett et al.
1999 for details of the animal model). All experimental procedures
were approved by the University of Alberta animal welfare committee
(HSAPWC). In vitro preparation
The detailed in vitro procedures were described previously
(Bennett et al. 2001b).
Briefly, normal and chronic spinal rats were anesthetized with urethan (0.18
g/100 g), and the whole cord caudal to the L12 vertebrate (which is
above the S2 injury level in chronic spinal rats) was exposed and
wetted with modified artificial cerebral spinal fluid (mACSF). The rat was
then given pure oxygen with a mask until the dorsal vein turned bright red and
then the cord was quickly removed to the dissection chamber, and immersed in
mACSF. In contrast to the previous study, the dorsal roots attached to the
cord were cut off (except the Ca1 caudal dorsal roots, which were
kept together with the caudal equina), and the cord was glued (super glue, RP
1500; Adhesive Systems) onto a small piece of nappy paper (with the ventral
side facing up) to increase stability. After an hour's rest in the dissection
chamber maintained at room temperature (20°C), the cord was transferred to
the recording chamber, where it was immersed in continuously flowing (at a
rate of 5 ml/min) normal ACSF (nACSF), which was maintained at 25°C. The
cord was then secured at the bottom of the recording chamber by pinning the
nappy paper onto the Sylgard base of the chamber.
Intracellular recording
The long ventral roots (usually sacral S4 and caudal
Ca1) and caudal equina were mounted on silver chloride wires
supported above the recording chamber fluid and covered with high vacuum
grease. Sharp intracellular recording electrodes were made from thick wall
glass capillaries (1.5 mm OD; Warner GC 150F-10) with a micropipette puller
(Sutter P-87 puller), filled with a 1:1 mixture of 2 M potassium acetate and 2
M KCl to give an initial impedance of 40 to 60 M
, and beveled down to
20 to 30 M on a rotary grinder (Sutter BV-10, fine 006 beveling stone).
Electrodes had a short bee-stinger shape for maximum current-passing
capability to enable good voltage clamp. Electrodes were advanced
perpendicularly into the ventral surface of the cord with a stepper-motor
micromanipulator (660, Kopf), initially with fast 30-µm steps to pass the
pia and white matter, and then with 2-µm steps. Ventral roots were
stimulated with 0.1 ms, 0.015 mA (2xT) pulses at 1 Hz to evoke an antidromic
field during the search for motoneurons. Brief capacitance over compensation
was applied to produce a high-frequency current to break the cell membrane.
Motoneurons were identified by antidromic spikes from ventral root
stimulation. Only motoneurons with a stable penetration, resting potential
< –60 mV, spike amplitude >60 mV, and reliable repetitive firing
were included in the study. An Axoclamp2b intracellular amplifier (Axon
Instruments, Burlingame, CA) running in either discontinuous current-clamp
modes (DCC, switching rate 7 to 10 kHz, output bandwidth 3.0 kHz) or
discontinuous voltage-clamp modes (gain 1 to 2.5 nA/mV) was used to collect
the data.
Drugs and solution
Two kinds of ACSF were used in the experiments: nACSF in the recording
chamber and mACSF in the dissection chamber before recording. The composition
of nACSF was (in mM): 122 NaCl, 24 NaHCO3, 2.5 CaCl2, 3
KCl, 1 MgSO4, and 12 D-glucose. The composition of mACSF
was (in mM): 118 NaCl, 24 NaHCO3, 1.5 CaCl2, 3 KCl, 5
MgCl2, 1.4 NaH2PO4, 1.3 MgSO4, 25
D-glucose, and 1 µM kynurenic acid; the latter is a nonspecific
blocker of glutamate transmission (Kekesi
et al. 2002). Both kinds of ACSF were saturated with 95%
O2-5% CO2, and maintained at pH 7.4. Drugs added to the
nACSF in the experiments included: 0.5 to 2 µM TTX (RBI), 3 to 20 µM
nimodipine (Sigma, St. Louis, MO), 400 µM Cd2+
(Sigma), and 2 µM conotoxin GVIA (RBI) and 1 µM conotoxin MVIIC (RBI).
TTX and Cd2+ were dissolved in high concentrations
(x100) as stocks; nimodipine was dissolved in DMSO before each
experiment (100–200 mM). These drugs were then diluted to the desired
concentration in nACSF. The DMSO concentration was <0.02% in the final
nASCF solution (DMSO had no effect on plateaus, n = 5). The
conotoxins were directly dissolved in the nACSF before each experiment.
Persistent inward current in current and voltage clamp recording
Slow triangular current ramps (ramp speed 0.4 nA/s) and voltage ramps
(standard ramp speed 3.5 mV/s, varied from 2 to 5 mV/s) were applied to the
motoneurons to evoke the plateaus and the associated PIC. During the current
ramps (in current-clamp), the PIC that contributed to the plateau and
sustained firing was estimated from the difference in injected current
required to terminate a plateau (Iend), compared with the
current required to start the plateau (
I =
Iend – Istart; see Fig.
2A or
3A and
Bennett et al. 2001b for
detail). During voltage ramps (in voltage-clamp), the amplitude of PIC was
measured directly, as shown in Fig.
1. That is, when the voltage was increased in a slow ramp the
measured current initially increased proportionally because of linear
subthreshold leak currents. However, above the PIC threshold the current
deviated negatively from following the applied current (at
Ion in Fig.
1), and ultimately decreased dramatically despite the continued
increase in voltage, and thus formed a negative-slope region in the
current–voltage relation (N-shaped V–I relation). When
the voltage ramp turned downward, the inward current continued, but was
ultimately deactivated (at Ioff in
Fig. 1) and thus produced
another negative-slope region in the V–I relation. To obtain an
estimation of the passive leak currents that sum with the PIC to give the
recorded current, a linear relation was fit to the subthreshold current
response in the linear region 10 mV below the PIC threshold (to give a leak
conductance) and extrapolated to more positive voltages (leak current, thin
triangular line overlaying current; Fig.
1). The PIC amplitude was then estimated by subtracting this leak
current from the recorded current. The PIC revealed after leak subtraction
demonstrated a clear initial peak and sustained peak
(Fig. 1, bottom
trace). There was at times an error in the voltage-clamp when the PIC was
activated (deviation from triangular shape), and this was compensated for by
scaling the actual voltage recorded by the leak conductance and using this as
the leak current.
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), the first zero slope
point on the up ramp in the recorded current was defined as the onset current
(Ion) of the PIC, and the corresponding voltage was
defined as the onset voltage (Von); the second zero slope
point of the recorded current in the up ramp was defined as the initial peak
current (Ii) of the PIC; the first zero slope point on the
down ramp of the recorded current was defined as the sustained peak current
(Is) of the PIC; the second zero slope point on the down
ramp of the recorded current was defined as the offset current
(Ioff) of the PIC and the corresponding voltage was
defined as the offset voltage (Voff). Because the recorded
current went down at the negative slope region, and then went up again during
the upward ramp, it always passed the onset current level line twice (the
onset current point itself and the later one); the voltage corresponding to
this latter point was defined as the jump-voltage (Vj; see
RESULTS associated with Fig.
9, below). In some of the motoneurons, the offset of the inward
current was very gradual, so it was hard to choose the sustained peak; in
these cases, the point on the down ramp corresponding to the same voltage,
given that the onset voltage was defined as the sustained peak. Initial and
sustained peak amplitudes after leak subtraction in voltage clamped ramps were
measured to quantify the size of the persistent inward currents (as shown in
Fig. 1).
The basic properties of the motoneurons, such as cell resistance, firing
threshold, and firing level, were measured during current ramps in DCC mode.
The resistance of the motoneurons was obtained by measuring the slope of the
V–I plot at the subthreshold region during a current-clamp
ramp. The spike threshold for each cell was measured from the first spike
elicited by the current ramp, at the potential where there first began a rapid
acceleration in the rate of depolarization to >10 V/s
(Brownstone et al. 1992;
Krawitz et al. 2001).
To better understand the dynamics of the inward currents, a series of voltage steps/pulses were also applied to some of the motoneurons. Each series consisted of 10 consecutive pulses (2.5 mV increases between each pulse), lasting 4.5 s.
Data analysis
To avoid warm-up or inactivation between ramps (Bennett et al.
1998a,
2001a), only ramp responses
measured >10 s after a previous ramp were included in the analysis. Data
were analyzed in Clampfit 8.0 (Axon Instruments). Data are shown as averages
± SD. A Student's t-test was used to test for statistical
differences, with a significance level of P < 0.05.
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RESULTS |
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, resting membrane potential of –66.2
± 8.5 mV, firing threshold of 1.78 ± 1.51 nA, firing level of
–46.1 ± 4.5 mV, and spike height of 82.5 ± 10.6 mV. Plateaus were caused by L-type calcium and TTX-sensitive persistent sodium currents
As we found previously (Bennett et al.
2001b), all motoneurons of chronic spinal rats were able to
spontaneously exhibit plateaus (onset at arrow in
Fig. 2A) and
self-sustained firing (that continued at currents below the recruitment
current) in response to slow triangular current ramps (Fig.
2A and
3A). The maintained
depolarizations (plateaus) underlying the self-sustained firing were clearly
revealed in the presence of TTX (0.5 to 2 µM, n = 16,
Fig. 2B), where the
potential deviated markedly from a linear increase with the current ramp (at
arrow), and continued for many seconds as the current was reduced. Either
Cd2+ (400 µM, n = 4), a nonspecific calcium
channel blocker, or nimodipine (10 to 20 µM, n = 8), a specific
L-type calcium channel blocker, completely abolished this TTX-resistant
plateau (Fig. 2C),
indicating that it was mediated by L-type calcium channels. However, when
nimodipine (20 µM, n = 9) was added into the nACSF first, although
the self-sustained firing was shortened
(Fig. 3, A and
B), it was not completely eliminated. After nimodipine,
the application of 2 µM TTX (n = 7,
Fig. 3C) completely
blocked the remaining plateaus. This result suggested that part of the PIC
underlying the plateau was sensitive to TTX, probably attributable to a
TTX-sensitive persistent sodium current
(Hsiao et al. 1998), as shown
below. Thus we estimated the effects of TTX on the PIC itself, as follows.
Previously we showed that the amplitude of the PIC that produces the
plateau and self-sustained firing can be indirectly estimated during current
ramps from the reduction in injected current required to terminate the plateau
(and self-sustained firing), compared with the current required to initiate
the plateau (i.e., PIC 
I = Iend
– Istart, Figs.
2A and
3A; also see Fig.
2B in Bennett et al.
2001b for detail). Oddly enough, when we compare
Fig. 2A with
Fig. 2B, the PIC
estimated from I increased when TTX was added, as it did for
most other motoneurons when TTX was added (8/10, with an average increase from
0.67 to 1.41 nA; see later section). This occurred because TTX has two major
effects: it blocks any TTX-sensitive persistent sodium current and it also
blocks the spikes; the latter eliminates a substantial outward current caused
by the spike afterhyperpolarization (AHP), and thus on balance the estimated
PIC increased with TTX. Thus to study the persistent sodium current directly
without the effect of spiking and AHPs, we voltage-clamped the motoneurons to
eliminate fast sodium spikes, and this gave a direct measurement of the slow
PIC before and after TTX, as follows.
When a slow depolarizing voltage ramp was applied under voltage-clamp conditions, the measured current initially increased linearly (left of Fig. 2D, bottom trace), but deviated from linear about 10 mV below the spike threshold (dotted line) as the PIC was activated. For these slow ramps the spikes were usually blocked by the voltage-clamp as in Fig. 2D (n = 30/35 cells; the remaining 5 cells had one or two unblocked spikes), and the spike threshold was measured separately during the current clamp, as in Fig. 2A. Eventually the current decreased, even though the voltage continued to increase (at arrow in Fig. 2D). This formed a characteristic negative-slope region in the current response (N-shaped V–I relation; see Fig. 1 in METHODS for detail), with a drop in current of 1.5 nA in Fig. 2D (initial depth of negative-slope region). However, this depth of the negative-slope region is less than the total PIC because the membrane potential was being ramped up continuously, which caused a proportional increase in current that is estimated by the leak current drawn as a thin line overlaying the current in Fig. 2D (see METHODS). The difference between the measured current and the leak current represents the total PIC (length of arrow in Fig. 2D; 3.25 nA). After TTX the PIC was smaller (arrow in Fig. 2E, 1.73 nA) compared with before TTX (Fig. 2D). Also, after TTX the negative-slope region occurred at a higher threshold (above the spike threshold; dotted line). Together, these results indicate that part of the PIC was caused by a TTX-sensitive persistent inward current. The remaining PIC and negative-slope region after TTX (Fig. 2E) was completely eliminated by nimodipine (Fig. 2F), indicating that it was mediated by L-type calcium channels, in this case (Fig. 2) with a slightly higher threshold than the TTX-sensitive portion of the PIC (near spike threshold).
When nimodipine was applied by itself, the PIC and associated negative-slope region was reduced (Fig. 3, D and E, Table 1), as was the plateau, further confirming the role of L-type calcium channels in plateau production. The remaining PIC after nimodipine was completely eliminated by TTX (Fig. 3, E and F), again indicating that part of the PIC was sensitive to TTX.
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Because TTX blocked not only the postsynaptic sodium channels, but also the
presynaptic spike-mediated neurotransmitter release, there remained a question
of whether the TTX-sensitive PIC was mediated by this synaptic activity,
rather than by a TTX-sensitive persistent sodium current. For example, basal
levels of synaptic activity could release glutamate that could induce a PIC
either directly (by NMDA receptors) or indirectly (by metabotropic glutamate
receptor facilitation of L-type calcium channels;
Delgado-Lezama et al. 1999).
To answer this question, 400 µM Cd2+ was added into
the nACSF (n = 5; compare PIC and plateaus before and after
Cd2+ in Fig. 4,
A and D and B and E).
Cd2+ at this concentration completely blocks preand
postsynaptic calcium currents, including the L-type calcium currents (as shown
above; see also Chow 1991). Thus Cd2+ blocks normal
presynaptic transmitter release, and indeed we found that
Cd2+ rapidly eliminated both spontaneous and reflex
evoked postsynaptic potentials (EPSPs, not shown). After
Cd2+ blocked the calcium channels, there was still a
substantial PIC (and plateau) that remained
(Fig. 4, B and
E), which was completely eliminated by TTX
(Fig. 4, C and
F; n = 4). This result proves that the
TTX-sensitive PIC was indeed mediated by a TTX-sensitive persistent sodium
current because, with Cd2+ present, TTX can have no
effects other than on postsynaptic sodium channels, with all the synaptic
activity already blocked and only sodium inward currents remaining. Taken
together, our results demonstrate that the plateaus and self-sustained firing
in motoneurons after chronic spinal cord transection were mediated by both an
L-type calcium current (calcium PIC) and a persistent sodium current (sodium
PIC).
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Characteristics of the sodium and calcium PIC
AMPLITUDE OF THE SODIUM AND CALCIUM PIC. The amplitude of the PIC in voltage-clamp recordings was quantified by measuring the initial and sustained peak amplitudes of the PIC after subtraction of the leak current (see METHODS and Fig. 1 for detail). On average the initial peak was 2.88 ± 0.95 nA, and the sustained peak was 1.64 ± 0.52 nA (n = 23). These large PICs occurred in all cells, with no correlation to the leak conductance (r < 0.5). When TTX was added into the nACSF (n = 12, Fig. 5A), the amplitude of the initial and sustained peak of PIC decreased by 57.6 ± 22.2% (from 2.95 ± 0.83 nA to 1.21 ± 0.60 nA) and 36.8 ± 28.7% (from 1.54 ± 0.50 nA to 1.03 ± 0.55 nA), respectively, and thus the TTX-sensitive PIC contributed these proportions to the total PIC. The PIC that remained after TTX (white bars in Fig. 5A) represented the calcium PIC by itself because this current was completely eliminated by nimodipine or Cd2+ (not significantly different from zero; gray bars in Fig. 5, A and B). Thus the calcium PIC contributed 42.4% (1.21 ± 0.60 nA) of the initial peak and 63.2% (1.03 ± 0.56 nA) of the sustained peak of the total PIC.
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When Cd2+ was added into the nACSF first (n = 4, Fig. 5B), the amplitude of the initial and sustained peak decreased by 61.4 ± 8.0% (from 2.31 ± 0.65 nA to 0.89 ± 0.31 nA) and 63.0 ± 19.4% (from 1.64 ± 0.46 nA to 0.57 ± 0.30 nA), respectively. The PIC that remained after Cd2+ (white bars in Fig. 5B) represented the sodium PIC by itself because this current was completely eliminated by TTX (not significantly different from zero; gray bars in Fig. 5B). This sodium PIC measured this way (as opposed to with direct application of TTX) contributed 38.6% (0.89 ± 0.31 nA) of the initial peak and 37.0% (0.57 ± 0.30 nA) of the sustained peak of the total PIC. When nimodipine was added into the nACSF (n = 7, Fig. 5C), the amplitude of the initial and sustained peak of PIC deceased by 45.2 ± 22.6% (from 3.10 ± 1.25 nA to 1.75 ± 0.99 nA) and 45.7 ± 23.3% (from 1.83 ± 0.60 nA to 1.01 ± 0.58 nA), respectively. Nimodipine did not block the synaptic transmission in our preparation (data not shown); thus these numbers represent the amplitude of calcium PIC and are similar to the numbers obtained from the experiments adding TTX first, just described. In summary, these results indicate that, although sodium and calcium PIC contributed almost equally in generating the initial part of the total PIC, sodium PIC contributed to only approximately 1/3 of the sustained peak and calcium PIC contributed to approximately two-thirds of the sustained peak of the total PIC. The small discrepancies in sodium and calcium PIC estimates with different drug combinations may represent a portion of the PIC that is blocked by the presynaptic actions of TTX or Cd2+, as quantified further in the DISCUSSION.
VOLTAGE THRESHOLD OF THE SODIUM AND CALCIUM PIC. In all the motoneurons (20/20 in Fig. 6), the voltage threshold of the PIC (–54.2 ± 4.76 mV) was lower than the firing threshold (–46.1 ± 4.5 mV). Because the voltage threshold of the total PIC is determined by the current with lower voltage threshold, we blocked one of the inward currents to reveal the threshold of the other current. When TTX was added into the nACSF (n = 10, Fig. 6A), the voltage threshold of the remaining current (calcium PIC) was on average –48.7 ± 6.42 mV, significantly higher than before. With TTX the threshold increased in 7/10 motoneurons (by >2.5 mV), suggesting that in these cells the calcium PIC had a clearly higher voltage threshold than the sodium PIC. In the remainder (3/10), there was only a small change in threshold, suggesting that in these cells calcium PIC either had a lower or similar threshold compared with the sodium PIC. In addition, of the 10 cells studied, 2 cells had a calcium PIC threshold (after TTX) higher than the voltage threshold of the spike (before TTX), and the remainder had a calcium PIC threshold below the spike threshold. Thus the voltage threshold of calcium PIC could be either below or above the firing threshold or the sodium PIC threshold.
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When Cd2+ (n = 3) or nimodipine (n
= 7, Fig. 6B) was
added into the nACSF first, the threshold of the remaining current
(TTX-sensitive sodium PIC) was –52.8 ± 3.95 mV, not significantly
different from before (–54.1 ± 4.48 mV). In most of the cells
(8/10) the PIC threshold did not increase (<2.5 mV change), suggesting that
the sodium PIC had a voltage threshold lower or similar to the calcium PIC in
these cells. In the other cells (2/10) there was an increase in threshold
>2.5 mV with calcium blockade, suggesting that the calcium PIC had a lower
threshold than that of sodium PIC. However, no matter how the threshold
changed with calcium blockade, it never exceeded the firing threshold of these
cells, suggesting that sodium PIC was always activated subthreshold to the
spike. In conclusion, our results indicate that 1) the sodium PIC was
activated about 7 mV subthreshold to the spike, whereas the calcium PIC was
activated either lower, or higher (by 5 mV), than the spike threshold, and
2) in most of the motoneurons, the calcium PIC had a higher voltage
threshold than that of the sodium PIC, whereas in a few of them, calcium PIC
had a similar or lower threshold than that of the sodium PIC. The activation
voltages of these PICs were measured at the electrode, which may be different
from the actual gating voltages for the channels mediating these currents,
considering that these channels may be on distal dendrites
(Bennett et al. 1998b;
Powers and Binder 2003).
KINETICS OF THE SODIUM AND CALCIUM PIC. As shown above, the sodium PIC decreased significantly during the approximately 8-s-long standard voltage ramp (from an average of 0.82 nA initial peak to 0.39 nA sustained peak); in contrast, most of the calcium PIC persisted during the same ramp (from an average of 1.19 nA initial peak to 1.01 nA sustained peak, not a significant reduction). These results indicate that the sodium PIC inactivated significantly, whereas calcium PIC did not. To further study the kinetics of these two different PICs, a series of 4.5-s voltage steps/pulses of increasing size were applied to the motoneurons (n = 7). With small voltage steps (subthreshold to the PIC), the current responded simply in proportion to the voltage step, with a steplike shape and amplitude that increased with applied voltage (leak current). When the threshold of the PIC was reached, instead of increasing, the amplitude of the recorded current decreased with increasing pulse size (PIC activated, thick lines in Fig. 7A). When the negative peak of the recorded current was plotted against the voltage applied (Fig. 7B), an N-shaped V–I relation was formed, with a negative-slope region corresponding to the PIC activation (just as for the slow ramps described in Figs. 1, 2, 3, 4). This series of voltage steps were applied before (squares in Fig. 7B) and after each drug application, and the PIC components were eliminated in succession as expected of blocking the sodium PIC (with TTX, circles) and calcium PIC (with Cd2+ and TTX, triangles), leaving a linear V–I relation.
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Currents recorded from the same suprathreshold depolarizing step/pulse with different drugs applied are overlaid in Fig. 7C. With a blockade of the PICs with TTX and Cd2+ the current response was steplike, and represented the passive leak current (Fig. 7C, trace c). With just TTX present (trace b, sodium blocked) the current response to the step was initially the same as in trace c, but after about 1 s the current dropped, as the calcium PIC was activated. The actual calcium PIC was estimated from subtracting trace b from trace c (lower part of Fig. 7C). Likewise, the sodium PIC was estimated from subtracting trace a in normal ACSF from trace b in TTX. The calcium PIC had a slow onset (approximately 1 s in Fig. 7C) that was highly voltage dependent. That is, the time to activate half of the PIC (T1/2) was 250 to 500 ms with high-voltage steps, whereas the T1/2 was more than 1 s with voltage steps just above threshold (Fig. 7D). The slow onset of the calcium PIC is also seen in the raw data in Fig. 7A (at vertical lines for traces 5–7) recorded in TTX when only the calcium PIC remained. Interestingly, the lowest voltage step (trace 5) evoked a calcium PIC that took more than 2 s to start and was activated in 2 discrete steps. Once activated, the calcium PIC usually did not inactivate with time (Fig. 7, A and C). Finally, corresponding to its slow activation, the calcium PIC also turned off slowly after the depolarizing step (deactivated slowly). That is, there was usually a tail current following the pulse (5/7, Fig. 7A, arrow), which was on average about 1 nA and lasted for about 500 ms. The tail current was not significantly affected by TTX, and completely blocked by nimodipine or Cd2+, which indicated that it was mediated by an L-type calcium current; and thus it serves as a useful positive indicator of the presence of a calcium PIC in normal CSF (Fig. 7C, trace a).
The activation of the sodium PIC (Fig. 7C) was in general much more rapid than the calcium activation. However, it was more difficult to study because in normal ACSF there was usually an unclamped sodium spike at the start of the voltage step (not shown), followed by a voltage-clamped outward current corresponding to the AHP currents and lasting approximately 80 ms (brief outward current at onset of step in trace a of Fig. 7C). Nevertheless, following this brief unclamped behavior the sodium PIC was immediately visible, as the current crossed below the dotted zero-line in the lower part of Fig. 7C (at 80 ms), and thus the sodium PIC was likely activated in <80 ms. The sodium PIC reached its peak rapidly (at arrow in Fig. 7C), partly inactivated over about 1 s, and there was usually a steady sodium current that persisted throughout the voltage step. Sometimes, at voltages just below the spike threshold of the cell, we saw a slow onset of sodium PIC (approximately 1 s; data not shown), indicating that just at threshold the sodium PIC could come on slowly. This was a threshold phenomenon, unlike the slow onset of calcium PIC over a wide voltage range (Fig. 7D), and it was difficult to study because of the unclamped spikes at higher voltages, as mentioned. The deactivation of the sodium current was rapid (<50 ms), like its onset, and produced no tail current after the pulse.
Involvement of N- and P-type calcium currents?
Plateaus and the associated PICs were usually completely blocked by
nimodipine and TTX, and thus it was unlikely that other types of calcium
currents could play a major role in plateau activation. However, in a few
cells with nimodipine and TTX added (2/15), there was a low-threshold transit
inward current that remained, which produced a brief depolarization during the
current ramps, and was sensitive to Cd2+, suggesting
that significant low-voltage activated T-type calcium current might exist in
these cells (Russo and Hounsgaard
1996), although this needs further investigation. The
nimodipine-sensitive persistent calcium current in our preparation was
low-voltage activated (
–50 mV), and was probably associated with
the Cav1.3 Ca channel with low voltage behavior (see DISCUSSION).
This current was usually fully activated at < –40 mV, and indeed we
usually did not voltage-clamp our cells above this –40 mV level,
suggesting that high-voltage–activated calcium channels do not play a
major role. However, to directly rule out the involvement of
high-voltage–activated calcium channels (i.e., N-, P-, Q-type, etc.) in
the activation of the PIC, conotoxin GVIA, and MVIIC,
high-voltage–activated calcium channel blockers were added into the
nACSF. Conotoxin GVIA and MVIIC partially blocked the EPSPs and the AHP, but
did not block the plateau or the associated PIC (n = 3, data
not shown). Thus these high-voltage–activated calcium currents were not
involved in the low threshold PIC studied here.
Sensitivity of the PIC to TTX and nimodipine
In the preceding results we used standard doses of TTX, Cd2+, and nimodipine that produced a complete block in about 10 min (steady-state effect). We also tested lower doses to determine these standard doses and judge the sensitivity of the PIC to these drugs. When TTX was applied at the standard dose of 2 µM, it usually blocked the fast sodium spikes in 3 to 5 min, and at this time the TTX-sensitive portion of the PIC was also nearly completely blocked. Lower doses of TTX (0.5 to 1 µM) gave longer times to block the spike (6 to 14 min), but the TTX-sensitive portion of the PIC was again blocked at the same time as the spikes. These results suggest that, at least in the 0.5- to 2-µM range, the fast spike and the PIC have a similar sensitivity to TTX.
When nimodipine was applied at the standard 20-µM dose there was a steady-state reduction in the PIC in 8 to 15 min. This moderately high dose had no effect on the sodium spike, and thus was unlikely to affect the sodium channels. A 10-µM dose took 20 to 30 min to take effect. Nimodipine doses as low as 3 µM only partly blocked the calcium portion of the PIC (with TTX present), and a further full block required 10 to 20 µM.
Acute spinal rats motoneurons have a small PIC
Consist with previous studies, motoneurons from acute spinal rats did not produce plateaus in current-clamp recording (Fig. 8A), and corresponding to this, they usually (4/5) did not produce a negative-slope region during voltage-clamped ramps (Fig. 8B). However, during these voltage ramps there was a small PIC (seen with leak subtraction, arrows in Fig. 8B), and this produced an inflection (left arrow) in the current response. The mean initial and sustained peaks of the PIC are 0.59 ± 0.44 and 0.54 ± 0.32 nA, respectively, significantly smaller than the PIC in chronic spinal rats (Fig. 8D). This PIC is TTX and Cd2+ sensitive, although we have not quantified the respective sodium and calcium PICs.
|
Role of PICs in activation of plateaus
In the present section we examine how the PICs measured from voltage-clamp
experiments are involved in producing plateaus, similar to the analysis of
Booth et al. (1997) and Lee
and Heckman (1998a), but
specifically examining the separate roles of the sodium and calcium PICs. This
issue is initially addressed in cells with spikes blocked with TTX
(Fig. 9B), by
replotting the data recorded in current-clamp (plateau;
Fig. 9B) and
voltage-clamp (PIC; Fig.
9C) in a voltage–current format (V–I
plot; Fig. 9E upward
ramp and Fig. 9F
downward ramp). In current-clamp (thick line in
Fig. 9E; first half of
9B), when the current was increased between the levels labeled 1 and
2 (horizontal lines in Fig.
9E) the voltage increased and followed closely to the
V–I plot of the voltage-clamp data (thin line in
Fig. 9E; first half of
Fig. 9C), as expected
of this region subthreshold to the plateau activation. However, when the
current was increased further (in current-clamp) from level 2 to level 3, the
membrane potential response (thick line) could no longer continuously follow
the V–I plot of the voltage-clamp current response (thin line),
but instead the voltage jumped rapidly across the negative-slope region to
rejoin the voltage-clamp V–I plot at a current corresponding to
the current level 3 (bistable point; Vj). This jump
corresponds to the onset of the plateau, and thus, the width of the
valley formed by the negative-slope region in the V–I plot
corresponds to the amplitude of the plateau that would be produced by the PICs
alone, without spikes present (width: Vj –
Von, thick arrow in
Fig. 9E).
Interestingly, this width measured in TTX
(Table 1) is not significantly
different from the corresponding width measured in nimodipine; and thus the
respective calcium and sodium PICs must contribute equally to the onset of a
plateau (before drug applications). Also, either TTX or nimodipine reduced the
width of the negative-slope region only marginally from control conditions
(only significant reduction in nimodipine;
Table 1), and thus either
current is sufficient to activate a large plateau. The primary requirement for
a plateau is a negative-slope region of adequate width.
Role of PICs in current-clamp hysteresis, I
During a triangular ramp under current-clamp, when the current was
decreased after the PIC activation, the voltage response (thick line in
Fig. 9F; downward
ramp) initially followed closely to the associated downward voltage-clamp
V–I plot (thin line, covered by thick line from current-clamp;
upper right corner of Fig.
9F; level 4 to level 1). However, when the current was
decreased further in current-clamp (to level 0 in
Fig. 9F), the PIC was
deactivated, and the potential (thick line) jumped from the bottom of the
negative-slope region to the lower-left branch of the voltage-clamp
V–I plot (at level 0; bottom left of
Fig. 9F), as the
plateau was terminated. Thus the relative depth of the negative-slope region
on the downward ramp (sustained depth) compared with the onset of the
PIC (Ion – Is, sustained depth
shown as thick arrow in Fig.
9C; 1.8 nA) corresponds to the current-clamp hysteresis
I (Fig.
9B; 2 nA). In fact, the mean I
from all cells measured in current-clamp after TTX (1.41 ± 1.13 nA;
e.g., 2 nA in Fig. 9B)
was indeed close to the sustained depth (Ion –
Is in Fig.
9C) of the negative-slope region after TTX (mean 1.12
± 0.66 nA; see Table 1).
In voltage-clamp, the sustained depth measured in normal ACSF was
significantly reduced by nimodipine, but not TTX, indicating that the calcium
PIC plays a primary role in the current-clamp hysteresis and self-sustained
firing during long slow ramps (unpublished data). However, the initial depth
of the negative slope region (Ion –
Ii) was significantly reduced by TTX
(Table 1), indicating that the
sodium PIC should play a role in the self-sustained firing during short ramps
that turn around just after activating the PIC (e.g.,
Fig. 3).
Voltage-clamp hysteresis
Hysteresis in voltage-clamp PIC response was associated with additionally
prolonged plateaus and sustained firing, and we demonstrate next that this PIC
hysteresis was mainly caused by the calcium PIC. The voltage-clamp hysteresis
is in general seen as a clockwise loop in the V–I plot
(Fig. 9D). The size of
this loop was quantified as the difference between the current or voltage at
the onset of the PIC (Ion or Von) and
offset of the PIC (Ioff or Voff). This
hysterisis (Ion – Ioff or
Von – Voff) was significantly
reduced by the application of nimodipine
(Table 1), as was the
I. In contrast, when the TTX was added the hysteresis
(Ion – Ioff or
Von – Voff) was not
significantly reduced (Table
1), and the I was also not reduced. Thus most of
the voltage-clamp hysteresis was mediated by the calcium PIC (seen with TTX in
Fig. 9D), whereas the
sodium PIC produced little voltage-clamp hysteresis. Indeed the sodium PIC,
seen directly in Cd2+ or nimodipine, was usually not
hysteretic (see symmetric response in Fig.
4E).
|
|
DISCUSSION |
|---|
|
,b).
The PICs occur spontaneously, that is, without the application of
neuromodulators or facilitation of neurotransmitter release, and remain even
after possible spike-mediated transmitter/neuromodulator release is completely
blocked by TTX or Cd2+. Acute spinal transection is
associated only with small PICs, consistent with the lack of plateaus or
spastic behavior (Bennett et al.
2001a,b).
The large PIC in chronic spinal rats is mediated by both persistent sodium and
calcium currents. The sodium PIC is activated subthreshold, inactivates
partly, and deactivates rapidly, and thus contributes to almost half of the
initial part of the PIC, but only a third of the sustained part. In contrast,
the calcium PIC (L-type) can be activated above or below the firing threshold
of the motoneurons, does not show much inactivation, and deactivates slowly,
and thus contributes to about half of the initial part of the PIC and two
thirds of the sustained PIC. The calcium PIC is clearly hysteretic, even
during slow voltage ramps (Fig.
9D), suggesting that these calcium currents are of
dendritic origin, and thus not fully voltage-clamped
(Lee and Heckman 1998a). In
contrast, the sodium PIC is not hysteretic, likely because of its partial
inactivation with time. Role of voltage-clamp recordings
The present experiments examined the persistent inward currents underlying
plateaus, using voltage-clamp methods. The main objective of the voltage-clamp
was to clamp the membrane potential of the soma, and thus stop the spikes (and
the associated AHPs) to make it possible to quantify the effect of TTX on the
PICs underlying the plateaus. As mentioned in the RESULTS, when
spiking occurs during current-clamp experiments the outward potassium current
during AHP reduces the net PIC, and thus when TTX is applied it is difficult
to infer whether it blocks the persistent sodium current because it also
blocks the AHP current, with often a net increase, rather than decrease, in
inferred PIC (I). This difficulty indeed might explain why a prominent
role of TTX-sensitive persistent sodium currents has not been previously
described in motoneurons (Hounsgaard and
Kiehn 1985), although see Hsiao et al.
(1998). Thus the main
objective of the voltage-clamp experiments was to block the spikes and the
associated AHPs, without blocking the TTX-sensitive persistent sodium current,
so that this persistent sodium current could be measured before TTX
application. A good voltage-clamp of the soma was sufficient for this purpose
and a clamp of the dendrites was neither necessary nor possible because of the
large dendritic trees of motoneurons (Ritz
et al. 1992). In fact, it is probable that unclamped channels on
the dendrites produced most of the hysteresis of the PIC in voltage-clamp
recording (Bennett et al.
1998a; Hounsgaard and Kiehn
1993; Lee and Heckman
1996).
Ionic mechanisms underlying the persistent inward current
An important finding of the present study is that a major part of the
plateau is mediated by a TTX-sensitive persistent sodium current. Although
TTX-sensitive persistent sodium currents mediating plateaus in motoneurons
have not been extensively studied, persistent sodium currents have been
proposed to exist in normal spinal motoneurons
(Lee and Heckman 2001), and
they have been suggested to play a role in plateau activation in hamster
trigeminal motoneurons (Hsiao et al.
1998) and many other neurons
(Angstadt and Choo 1996;
Elson and Selverston 1997;
Rekling and Laursen 1989;
Sandler et al. 1998;
Schwindt and Crill 1995;
Stafstrom et al. 1982,
1985). According to these
studies, the persistent sodium currents are sensitive to TTX, have a voltage
threshold a few millivolts below the spike threshold, activate and deactivate
rapidly, and demonstrate considerable inactivation after activation. In our
experiments, Cd2+ was used to block calcium channels and
thus reveal the persistent sodium current in isolation. This PIC that remained
after Cd2+ was completely eliminated by TTX, and its
characteristics (low threshold, fast kinetics, inactivation) closely resemble
the persistent sodium current seen in other preparations, and thus it is
mediated by a similar TTX-sensitive persistent sodium current (see review,
Crill 1996).
The other major part of the PIC in chronic spinal rats was found to be
mediated by L-type calcium channels, consist with data shown in many other
preparations (Hounsgaard and Kiehn
1989; Hsiao et al.
1998; Mills and Pitman
1997; Morisset and Nagy
1999). Although L-type calcium channels are conventionally
considered as high-voltage gated channels, activated at above –30 mV
(Fox et al. 1987;
Tsien et al. 1988), our
results demonstrate that the threshold of L-type calcium channels is around
the firing threshold of the motoneurons, which is similar to the low threshold
obtained in other studies of plateaus in neurons (i.e., –45 to
–55mV; Hounsgaard and Kiehn
1989; Mills and Pitman
1997; Morisset and Nagy
1999; Voisin and Nagy
2001; Zhang and Harris-Warrick
1995). In addition, these L-type calcium channels involved in
plateau activation require a higher concentration of dihydropyridines (10
µM nimodipine in our experiments, 15 µM nifedipine in
Hounsgaard and Kiehn 1989; 10
µM nifedipine in Voisin and Nagy
2001; and 50 µM nifedipine in
Mills and Pitman 1997) to be
completely blocked than do conventional L-type calcium channels (<1 µM)
(Fanelli et al. 1994;
McCarthy and TanPiengco 1992).
Two subtypes of L-type calcium channels, Cav1.3 and Cav1.4, have recently been
found. The Cav1.3 subtype has a lower activation threshold and a much lower
sensitivity to the dihydropyridines
(Koschak et al. 2001;
Xu and Lipscombe 2001); thus
it is very likely that the plateaus found in ours and others' preparations are
mediated by the Cav1.3 subtype L-type calcium channels. Although higher
threshold calcium channels (N- and P-type) are not involved in plateaus under
physiological conditions (nimodipine blocks plateaus,
Carlin et al. 2000b;
Hounsgaard and Kiehn 1989),
they can produce large plateaus and PICs (above –30 mV) when
K+ currents and intracellular Ca2+ are
artificially reduced (our unpublished data and
Carlin et al. 2000a;
Powers and Binder 2003).
Although our results demonstrate that part of the PIC in chronic spinal
rats is mediated by L-type calcium channels (nimodipine-sensitive), it does
not mean that this calcium current acts simply by directly depolarizing the
cell membrane and producing the plateaus. Calcium from the L-type calcium
channels may trigger many intracellular cascades and affect the activity of
other channels and receptors that ultimately contribute to the PIC and
plateau. For example, in rat deep dorsal horn interneurons, after L-type
calcium currents initiate plateaus, these plateaus are further prolonged by a
calcium-activated nonselective cation current (ICAN)
(Morisset and Nagy 1999;
Zhang et al. 1995); however,
see Perrier and Hounsgaard
(1999). Also, in turtle
motoneurons, calcium facilitates plateaus by activating a calmodulin pathway,
which may ultimately facilitate the L-type calcium channel itself
(Perrier et al. 2000). Recent
experiments have shown that the calmodulin levels in motoneurons of chronic
spinal rats are increased compared with that in normal rats
(Anelli et al. 2001); therefore
it is possible that calmodulin is also involved in the large PICs and plateaus
seen after injury. Finally, the inflow of calcium can activate
Ca2+-dependent K+ currents, which oppose the
inward current; thus the amplitude of inward current recorded in the present
experiments may be underestimated. However, it is unlikely that the emergence
of large inward currents in chronic spinal rats is simply caused by a
reduction in the AHP-related K+ currents because the AHP itself is
not reduced in chronic spinal rats (Bennett
et al. 2001b).
Possible origin of persistent inward currents after chronic injury
There may be several reasons why after chronic spinal cord injury
motoneurons are spontaneously able to produce such large persistent inward
currents and plateaus. First, after spinal cord injury, synaptic transmission
below the level of injury is no longer controlled by descending inhibitory
tracts (Baldissera et al. 1981;
Jankowska 1992), and thus
there might be more neurotransmitter released from certain afferent terminals
or interneurons (Thor et al.
1994). However, although this may be important, its actions are
clearly relevant only in the long-term, given that large PICs and plateaus are
not present immediately after acute spinal cord transection, presumably
because of the acute loss of brain stem–derived transmitters such as
5-HT or NE (Conway et al.
1988; Hounsgaard et al.
1988). With long-term injury additional changes may occur that
make the residual transmitters more effective in facilitating PICs. For
example, metabotropic receptors that facilitate PICs may become supersensitive
to the released neurotransmitters (Hains
et al. 2002) or the receptors may be upregulated after chronic
spinal cord injury (Mills and Hulsebosch
2002). If a supersensitivity does occur, then even lower than
normal levels of transmitters might be important; for example, 
12% of
normal 5-HT remains chronically below a complete spinal transection
(Newton and Hamill 1988;
Shapiro 1997). Thus enhanced
metabotropic receptor action (by glutamate, 5-HT, etc.) might contribute to
the exaggerated PICs and associated plateaus after chronic injury. It is
noteworthy that sodium currents should be modulated by metabotropic receptor
actions (by cyclic AMP and protein kinase C pathways;
Li et al. 1992;
Crill 1996;
Astman et al. 1998;
Mittmann and Alzheimer 1998),
just as persistent calcium currents are (Russo and Hounsgaard 1999).
This possible involvement of metabotropic receptor action may appear to be
at odds with our present finding that calcium or sodium PICs survive synaptic
blockade with TTX or Cd2+, respectively. However, in our
studies we measured the calcium PIC (or sodium PIC) within 10 to 15 min after
TTX (or Cd2+) application, a time that may not be long
enough for the long-lasting intracellular actions of metabotropic receptors to
be reversed. For example, 5-HT2c receptor activation can have
effects that last for 1 h after 5-HT agonist has been removed
(Machacek et al. 2001; see
also Miller et al. 1996). In
contrast, metabotropic glutamate receptor facilitation of PICs has a shorter
lasting action, and is reversed within a few minutes of removal of receptor
activation (Delgado-Lezama et al.
1999). Thus part but not all of the PIC might be reduced by the
10- to 15-min synaptic blockade in our experiments, and this might explain why
about 15% of the total PIC is unaccounted for by the sum of the individual
sodium and calcium PICs that remain after either Cd2+ or
TTX (see RESULTS).
The exaggerated PICs after chronic injury might also be related to an
upregulation in the number of L-type calcium channels. Expression of more
calcium channels has been shown after peripheral nerve trauma in dorsal root
ganglion cells (Kim et al.
2001; Luo et al.
2001). At the present time, there is no evidence of increase
expression of calcium channels after CNS trauma. However, increased expression
of calcium channels does occur after ischemia or hypoxia
(Chung et al. 2001;
Duffy and MacVicar 1996;
Westenbroek et al. 1998).
In summary, large persistent inward currents can be activated in
motoneurons of chronically transected rat spinal cord, without the application
of neuromodulators, or stimulated neuromodulator release. These PICs are
mediated by low-threshold persistent sodium (TTX-sensitive) and calcium
(L-type) currents. Ultimately, these PICs cause the large plateaus that have
been shown to underlie muscle spasms after injury
(Bennett et al. 2001b). The
detailed involvement of persistent sodium and calcium inward currents in
abnormal firing and spasticity after spinal cord injury is addressed in a
companion paper (unpublished data).
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DISCLOSURES |
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Address for reprint requests: D. Bennett, Centre for Neuroscience, 513 Heritage Medical Research Centre, University of Alberta, Edmonton, Alberta T6G 2S2, Canada (E-mail: bennettd{at}ualberta.ca).
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REFERENCES |
|---|
|
Angstadt JD and
Choo JJ. Sodium-dependent plateau potentials in cultured Retzius cells of
the medicinal leech. J Neurophysiol
76: 1491–1502,
1996.
Astman N,
Gutnick MJ, and Fleidervish IA. Activation of protein kinase C increases
neuronal excitability by regulating persistent Na+ current in mouse
neocortical slices. J Neurophysiol
80: 1547–1551,
1998.
Baldissera F, Hultborn H, and Illert M. Integration in spinal neuronal systems. In: Handbook of Physiology. The Nervous System. Motor Control. Bethesda, MD: Am. Physiol. Soc., 1981, sect. 1, vol. II, parts 1 and 2, p. 509–595.
Bennett DJ, Gorassini M, Fouad K, Sanelli L, Han Y, and Cheng J. Spasticity in rats with sacral spinal cord injury. J Neurotrauma 16: 69–84, 1999.[Web of Science][Medline]
Bennett DJ,
Hultborn H, Fedirchuk B, and Gorassini M. Short-term plasticity in
hindlimb motoneurons of decerebrate cats. J
Neurophysiol 80:
2038–2045, 1998a.
Bennett DJ,
Hultborn H, Fedirchuk B, and Gorassini M. Synaptic activation of plateaus
in hindlimb motoneurons of decerebrate cats. J
Neurophysiol 80:
2023–2037, 1998b.
Bennett DJ, Li
Y, Harvey PJ, and Gorassini M. Evidence for plateau potentials in tail
motoneurons of awake chronic spinal rats with spasticity. J
Neurophysiol 86:
1972–1982, 2001a.
Bennett DJ, Li
Y, and Siu M. Plateau potentials in sacrocaudal motoneurons of chronic
spinal rats, recorded in vitro. J Neurophysiol
86: 1955–1971,
2001b.
Booth V, Rinzel
J, and Kiehn O. Compartmental model of vertebrate motoneurons for
Ca2+-dependent spiking and plateau potentials under
pharmacological treatment. J Neurophysiol
78: 3371–3385,
1997.
Brownstone RM, Jordan LM, Kriellaars DJ, Noga BR, and Shefchyk SJ. On the regulation of repetitive firing in lumbar motoneurones during fictive locomotion in the cat. Exp Brain Res 90: 441–455, 1992.[Web of Science][Medline]
Carlin KP, Jiang Z, and Brownstone RM. Characterization of calcium currents in functionally mature mouse spinal motoneurons. Eur J Neurosci 12: 1624–1634, 2000a.[Web of Science][Medline]
Carlin KP, Jones KE, Jiang Z, Jordan LM, and Brownstone RM. Dendritic L-type calcium currents in mouse spinal motoneurons: implications for bistability. Eur J Neurosci 12: 1635–1646, 2000b.[Web of Science][Medline]
Chung YH, Shin CM, Kim MJ, and Cha CI. Enhanced expression of L-type Ca2+ channels in reactive astrocytes after ischemic injury in rats. Neurosci Lett 302: 93–96, 2001.[Web of Science][Medline]
Conway BA,
Hultborn H, Kiehn O, and Mintz I. Plateau potentials in alpha-motoneurones
induced by intravenous injection of L-dopa and clonidine in the spinal cat.
J Physiol 405:
369–384, 1988.
Crill WE. Persistent sodium current in mammalian central neurons. Annu Rev Physiol 58: 349–362, 1996.[Web of Science][Medline]
Delgado-Lezama R, Perrier JF, and Hounsgaard J. Local
facilitation of plateau potentials in dendrites of turtle motoneurones by
synaptic activation of metabotropic receptors. J
Physiol 515:
203–207, 1999.
Duffy S and
MacVicar BA. In vitro ischemia promotes calcium influx and intracellular
calcium release in hippocampal astrocytes. J Neurosci
16: 71–81,
1996.
Eken T, Hultborn H, and Kiehn O. Possible functions of transmitter-controlled plateau potentials in alpha motoneurones. Prog Brain Res 80: 257–267; discussion 239–242, 1989.[Web of Science][Medline]
Elson RC and Selverston AI. Evidence for a persistent Na+ conductance in neurons of the gastric mill rhythm generator of spiny lobsters. J Exp Biol 200: 1795–1807, 1997.[Abstract]
Fanelli RJ, McCarthy RT, and Chisholm J. Neuropharmacology of nimodipine: from single channels to behavior. Ann NY Acad Sci 747: 336–350, 1994.[Web of Science][Medline]
Fox AP, Nowycky
MC, and Tsien RW. Kinetic and pharmacological properties distinguishing
three types of calcium currents in chick sensory neurones. J
Physiol 394:
149–172, 1987.
Gorassini M,
Bennett DJ, Kiehn O, Eken T, and Hultborn H. Activation patterns of
hindlimb motor units in the awake rat and their relation to motoneuron
intrinsic properties. J Neurophysiol
82: 709–717,
1999.
Gorassini MA, Bennett DJ, and Yang JF. Self-sustained firing of human motor units. Neurosci Lett 247: 13–16, 1998.[Web of Science][Medline]
Hains BC, Everhart AW, Fullwood SD, and Hulsebosch CE. Changes in serotonin, serotonin transporter expression and serotonin denervation super-sensitivity: involvement in chronic central pain after spinal hemisection in the rat. Exp Neurol 175: 347–362, 2002.[Web of Science][Medline]
Hounsgaard J, Hultborn H, Jespersen B, and Kiehn O. Intrinsic membrane properties causing a bistable behaviour of alpha-motoneurones. Exp Brain Res 55: 391–394, 1984.[Web of Science][Medline]
Hounsgaard J,
Hultborn H, Jespersen B, and Kiehn O. Bistability of alpha-motoneurones in
the decerebrate cat and in the acute spinal cat after intravenous
5-hydroxytryptophan. J Physiol
405: 345–367,
1988.
Hounsgaard J and Kiehn O. Ca++ dependent bistability induced by serotonin in spinal motoneurons. Exp Brain Res 57: 422–425, 1985.[Web of Science][Medline]
Hounsgaard J and Kiehn O. Serotonin-induced bistability of turtle motoneurones caused
by a nifedipine-sensitive calcium plateau potential. J
Physiol 414:
265–282, 1989.
Hounsgaard J and Kiehn O. Calcium spikes and calcium plateaux evoked by differential
polarization in dendrites of turtle motoneurones in vitro. J
Physiol 468:
245–259, 1993.
Hsiao CF, Del
Negro CA, Trueblood PR, and Chandler SH. Ionic basis for serotonin-induced
bistable membrane properties in guinea pig trigeminal motoneurons.
J Neurophysiol 79:
2847–2856, 1998.
Hultborn H. Plateau potentials and their role in regulating motoneuronal firing. Adv Exp Med Biol 508: 213–218, 2002.[Web of Science][Medline]
Hultborn H and Kiehn O. Neuromodulation of vertebrate motor neuron membrane properties. Curr Opin Neurobiol 2: 770–775, 1992.[Medline]
Jankowska E. Interneuronal relay in spinal pathways from proprioceptors. Prog Neurobiol 38: 335–378, 1992.[Web of Science][Medline]
Kekesi G, Joo G, Csullog E, Dobos I, Klimscha W, Toth K, Benedek G, and Horvath G. The antinociceptive effect of intrathecal kynurenic acid and its interaction with endomorphin-1 in rats. Eur J Pharmacol 445: 93–96, 2002.[Web of Science][Medline]
Kiehn O and
Eken T. Prolonged firing in motor units: evidence of plateau potentials in
human motoneurons? J Neurophysiol
78: 3061–3068,
1997.
Kim DS, Yoon CH, Lee SJ, Park SY, Yoo HJ, and Cho HJ. Changes in voltage-gated calcium channel alpha(1) gene expression in rat dorsal root ganglia following peripheral nerve injury. Brain Res Mol Brain Res 96: 151–156, 2001.[Medline]
Koschak A,
Reimer D, Huber I, Grabner M, Glossmann H, Engel J, and Striessnig
J. alpha 1D (Cav1.3) subunits can form l-type Ca2+
channels activating at negative voltages. J Biol Chem
276: 22100–22106,
2001.
Krawitz S,
Fedirchuk B, Dai Y, Jordan LM, and McCrea DA. State-dependent
hyperpolarization of voltage threshold enhances motoneurone excitability
during fictive locomotion in the cat. J Physiol
532: 271–281,
2001.
Lee RH and
Heckman CJ. Influence of voltage-sensitive dendritic conductances on
bistable firing and effective synaptic current in cat spinal motoneurons in
vivo. J Neurophysiol 76:
2107–2110, 1996.
Lee RH and
Heckman CJ. Bistability in spinal motoneurons in vivo: systematic
variations in persistent inward currents. J
Neurophysiol 80:
583–593, 1998a.
Lee RH and
Heckman CJ. Bistability in spinal motoneurons in vivo: systematic
variations in rhythmic firing patterns. J Neurophysiol
80: 572–582,
1998b.
Lee RH and
Heckman CJ. Essential role of a fast persistent inward current in action
potential initiation and control of rhythmic firing. J
Neurophysiol 85:
472–475, 2001.
Li M, West JW, Lai Y, Scheuer T, and Catterall WA. Functional modulation of brain sodium channels by cAMP-dependent phosphorylation. Neuron 8: 1151–1159, 1992.[Web of Science][Medline]
Li Y, Sanelli L, and Bennett DJ. Ionic mechanisms for plateau potentials in motoneurons of chronic spinal spastic rats. Soc Neurosci Abstr 31: 933.10, 2001.
Luo ZD, Chaplan
SR, Higuera ES, Sorkin LS, Stauderman KA, Williams ME, and Yaksh
TL. Upregulation of dorsal root ganglion (alpha)2(delta) calcium channel
subunit and its correlation with allodynia in spinal nerve-injured rats.
J Neurosci 21:
1868–1875, 2001.
Machacek DW,
Garraway SM, Shay BL, and Hochman S. Serotonin 5-HT(2) receptor activation
induces a long-lasting amplification of spinal reflex actions in the rat.
J Physiol 537:
201–207, 2001.
McCarthy RT and TanPiengco PE. Multiple types of high-threshold calcium channels in rabbit sensory neurons: high-affinity block of neuronal L-type by nimodipine. J Neurosci 12: 2225–2234, 1992.[Abstract]
Miller JF, Paul
KD, Lee RH, Rymer WZ, and Heckman CJ. Restoration of extensor excitability
in the acute spinal cat by the 5-HT2 agonist DOI. J
Neurophysiol 75:
620–628, 1996.
Mills CD and Hulsebosch CE. Increased expression of metabotropic glutamate receptor subtype 1 on spinothalamic tract neurons following spinal cord injury in the rat. Neurosci Lett 319: 59–62, 2002.[Web of Science][Medline]
Mills JD and
Pitman RM. Electrical properties of a cockroach motor neuron soma depend
on different characteristics of individual Ca components. J
Neurophysiol 78:
2455–2466, 1997.
Mittmann T and
Alzheimer C. Muscarinic inhibition of persistent Na+ current in
rat neocortical pyramidal neurons. J Neurophysiol
79: 1579–1582,
1998.
Morisset V and
Nagy F. Ionic basis for plateau potentials in deep dorsal horn neurons of
the rat spinal cord. J Neurosci
19: 7309–7316,
1999.
Newton BW and Hamill RW. The morphology and distribution of rat serotoninergic intraspinal neurons: an immunohistochemical study. Brain Res Bull 20: 349–360, 1988.[Web of Science][Medline]
Perrier JF and
Hounsgaard J. Ca(2+)-activated
nonselective cationic current [I(CAN)] in turtle motoneurons. J
Neurophysiol 82:
730–735, 1999.
Perrier JF,
Mejia-Gervacio S, and Hounsgaard J. Facilitation of plateau potentials in
turtle motoneurones by a pathway dependent on calcium and calmodulin.
J Physiol 528:
107–113, 2000.
Powers RK and
Binder MD. Persistent sodium and calcium currents in rat hypoglossal
motoneurons. J Neurophysiol 89:
615–624, 2003.
Rekling JC and Laursen AM. Evidence for a persistent sodium conductance in neurons from the nucleus prepositus hypoglossi. Brain Res 500: 276–286, 1989.[Web of Science][Medline]
Ritz LA, Bailey SM, Murray CR, and Sparkes ML. Organizational and morphological features of cat sacrocaudal motoneurons. J Comp Neurol 318: 209–221, 1992.[Web of Science][Medline]
Russo RE and
Hounsgaard J. Burst-generating neurones in the dorsal horn in an in vitro
preparation of the turtle spinal cord. J Physiol
493: 55–66,
1996.
Sandler VM, Puil E, and Schwarz DW. Intrinsic response properties of bursting neurons in the nucleus principalis trigemini of the gerbil. Neuroscience 83: 891–904, 1998.[Web of Science][Medline]
Schwindt PC and
Crill WE. Factors influencing motoneuron rhythmic firing: results from a
voltage-clamp study. J Neurophysiol
48: 875–890,
1982.
Schwindt PC and
Crill WE. Amplification of synaptic current by persistent sodium
conductance in apical dendrite of neocortical neurons. J
Neurophysiol 74:
2220–2224, 1995.
Shapiro S. Neurotransmission by neurons that use serotonin, noradrenaline, glutamate, glycine, and gamma-aminobutyric acid in the normal and injured spinal cord. Neurosurgery 40: 168–176; discussion 177, 1997.[Web of Science][Medline]
Stafstrom CE,
Schwindt PC, Chubb MC, and Crill WE. Properties of persistent sodium
conductance and calcium conductance of layer V neurons from cat sensorimotor
cortex in vitro. J Neurophysiol
53: 153–170,
1985.
Stafstrom CE, Schwindt PC, and Crill WE. Negative slope conductance due to a persistent subthreshold sodium current in cat neocortical neurons in vitro. Brain Res 236: 221–226, 1982.[Web of Science][Medline]
Svirskis G and
Hounsgaard J. Transmitter regulation of plateau properties in turtle
motoneurons. J Neurophysiol 79:
45–50, 1998.
Thor KB, Roppolo JR, Kawatani M, Erdman S, and deGroat WC. Plasticity in spinal opioid control of lower urinary tract function in paraplegic cats. Neuroreport 5: 1673–1678, 1994.[Web of Science][Medline]
Tsien RW, Lipscombe D, Madison DV, Bley KR, and Fox AP. Multiple types of neuronal calcium channels and their selective modulation. Trends Neurosci 11: 431–438, 1988.[Web of Science][Medline]
Voisin DL and Nagy F. Sustained L-type calcium currents in dissociated deep dorsal horn neurons of the rat: characteristics and modulation. Neuroscience 102: 461–472, 2001.[Web of Science][Medline]
Westenbroek RE,
Bausch SB, Lin RC, Franck JE, Noebels JL, and Catterall WA.
Upregulation of L-type Ca2+ channels in reactive
astrocytes after brain injury, hypomyelination, and ischemia. J
Neurosci 18:
2321–2334, 1998.
Xu W and
Lipscombe D. Neuronal Ca(V)1.3alpha(1) L-type channels activate at
relatively hyperpolarized membrane potentials and are incompletely inhibited
by dihydropyridines. J Neurosci
21: 5944–5951,
2001.
Zhang B and
Harris-Warrick RM. Calcium-dependent plateau potentials in a crab
stomatogastric ganglion motor neuron. I. Calcium current and its modulation by
serotonin. J Neurophysiol 74:
1929–1937, 1995.
Zhang B,
Wootton JF, and Harris-Warrick RM. Calcium-dependent plateau potentials in
a crab stomatogastric ganglion motor neuron. II. Calcium-activated slow inward
current. J Neurophysiol 74:
1938–1946, 1995.
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ABSTRACT
INTRODUCTION
