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Brain Research Reviews 40 (2002) 223–229
www.elsevier.com / locate / brainresrev
Review
Spinal plasticity mediated by postsynaptic L-type Ca 21 channels
Jean-Franc¸ois Perrier, Aidas Alaburda, Jørn Hounsgaard*
Department of Medical Physiology, Panum Institute, University of Copenhagen, Blegdamsvej 3, DK 2200 Copenhagen N, Denmark
Abstract
In the spinal cord, motoneurons and specific subgroups of interneurons express L-type Ca 21 channels. As elsewhere, these
dihydropyridine-sensitive channels mediate a slowly activating inward current in response to depolarisation and show little or no
inactivation. The slow kinetics for activation and deactivation provide voltage-sensitive properties in a time range from hundreds of
milliseconds to tens of seconds and lead to plateau potentials, bistability and wind-up in neurons in both sensory and motor networks. This
slow dynamics is in part due to facilitation of L-type Ca 21 channels by depolarisation. The voltage sensitivity of L-type Ca 21 channels is
also regulated by a range of metabotropic transmitter receptors. Up-regulation is mediated by receptors for glutamate, acetylcholine,
noradrenaline and serotonin in motoneurons and by receptors for glutamate and substance P in plateau-generating dorsal horn
interneurons. In both cell types, L-type Ca 21 channels are down-regulated by activation of GABA B receptors. In this way, metabotropic
regulation in cells expressing L-type Ca 21 channels provides mechanisms for flexible adjustment of excitability and of the contribution of
plateau currents to the intrinsic properties. This type of regulation also steers the magnitude and compartmental distribution of Ca 21 influx
during depolarisation, thus providing a signal for local synaptic plasticity.
 2002 Elsevier Science B.V. All rights reserved.
Keywords: L-type Ca 21 channels; Plateau potential; Spinal cord; Motoneuron; Interneuron; Modulation
Contents
1. Introduction ............................................................................................................................................................................................
2. L-type Ca 21 channels...............................................................................................................................................................................
2.1. Molecular structure .........................................................................................................................................................................
2.2. Voltage sensitivity ...........................................................................................................................................................................
2.3. Activation / deactivation kinetics .......................................................................................................................................................
3. Postsynaptic L-type Ca 21 channels in spinal cord neurons ..........................................................................................................................
4. Non-linear electrophysiological properties of spinal cord neurons mediated by L-type Ca 21 channels ............................................................
4.1. Boosting of remote dendritic synapses ..............................................................................................................................................
4.2. Plateau potentials and bistability.......................................................................................................................................................
4.3. Depolarisation-induced facilitation of L-channels: wind-up, warm-up, delayed activation and hysteresis................................................
4.4. Modulation .....................................................................................................................................................................................
5. L-type Ca 21 channels and spinal plasticity ................................................................................................................................................
Acknowledgements ......................................................................................................................................................................................
References...................................................................................................................................................................................................
1. Introduction
A careful balance between stability and flexibility is the
hallmark of spinal function. It seems likely that most
neurons in the spinal cord are part of networks for final
processing of motor commands or for early sensory
*Corresponding author. Tel.: 145-35-327-559; fax: 145-35-327-555.
E-mail address: j.hounsgaard@mfi.ku.dk (J. Hounsgaard).
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processing of somatosensory information, or both. The
faithful sensory representation of the external world and
reliable execution of motor behaviour are fundamental
features of spinal function, conserved over long periods of
time. This suggests a high degree of constancy in crucial
signalling properties in most spinal neurons. At the same
time, spinal networks meet rapidly changing functional
needs with remarkable flexibility and continuously adapt
and adjust signalling properties over a wide functional
0165-0173 / 02 / $ – see front matter  2002 Elsevier Science B.V. All rights reserved.
PII: S0165-0173( 02 )00204-7
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range. A way to achieve stability and flexibility would be
regulation by transient changes from a preserved ground
state. Here, we review data suggesting that postsynaptic
L-type Ca 21 channels mediating plateau potentials provide
a mechanism for regulation of this kind.
Plateau potentials have been described in spinal
motoneurons from adult terrestrial vertebrates in all species
tested, including turtle [20], cat [2,7,14,24], mouse [4] and
frog [28]. Their presence has also been suggested in human
motoneurons [6,12,21]. In addition, plateau potentials are
found in certain classes of spinal interneurons, including
ventral horn interneurons [19] and deep dorsal horn
interneurons in the turtle [34,35] and deep dorsal horn
interneurons in the rat [27]. For technical reasons, the
involvement of L-type Ca 21 channels has only been
demonstrated in in vitro preparations. In motoneurons and
interneurons in the adult spinal cord, plateau potentials are
blocked by dihydropyridine antagonists of L-type Ca 21
channels [4,19,20,27,34,35,39].
2. L-type Ca 21 channels
2.1. Molecular structure
L-type Ca 21 channels belong to the voltage-gated Ca 21
channel family. Like other voltage-gated Ca 21 channels,
the L-type Ca 21 channel is a hetero-oligomeric complex of
a pore forming a1 subunit, which can be of type S, C, D or
F (a1S, a1C, a1D or a1F), associated with four accessory
subunits (a2, b, g, d) [11]. Only the C and the D type of
a1 subunits are expressed in the central nervous system
[5]. The channels formed by these subunits were recently
renamed Ca V 1.2 and Ca V 1.3 [11]. Pharmacologically, the
L-type Ca 21 channels are separated from the other Ca 21
channels by their sensitivity to dihydropyridines, Ca V 1.2
being approximately 10 times more sensitive than Ca V 1.3
[23].
2.2. Voltage sensitivity
Classically, L-type Ca 21 channels are classified among
the high voltage-gated Ca 21 channels, i.e. channels open at
voltages positive to 210 mV [13]. It was recently shown,
however, that the L-type Ca 21 channel, formed with the
a1D subunit (Ca V 1.3), activates at negative potentials
(around 245 mV), while the channel formed with the a1C
subunit (Ca V 1.2) activates at positive potentials [23].
rather than brief depolarisations such as a single action
potential in a neuron. L-type Ca 21 channels are also
distinguished by the slow rate of inactivation. This property makes them good candidates for a persistent inward
current.
3. Postsynaptic L-type Ca 21 channels in spinal cord
neurons
Motoneurons and interneurons in the spinal cord express
both C- and D-type L-channels [4,41]. Two noticeable
general characteristics for plateau potentials in spinal
neurons have helped to assess the relative importance of
these channel subtypes. While L-type Ca 21 channels are
classified as high threshold, it was immediately noted that
dihydropyridine-sensitive plateau potentials in spinal neurons were activated by moderate depolarisations from the
resting membrane potential [20,34,35] as was the underlying persistent inward current [39]. This suggested that
plateau potentials were generated by low-threshold L-type
Ca 21 channels [35]. Secondly, as originally reported by
Hounsgaard and Mintz [20], although the selectivity of
dihydropyridines is high, the sensitivity is relatively low.
These observations, which have been confirmed by subsequent studies in mammals [4,27], are in remarkably good
agreement with the properties of cloned human Ca V 1.3
channels (L-channels expressing the a1D subunit) expressed in tsA-201 cells [23]. For plateau potentials in
spinal neurons [35,39] and for expressed Ca V 1.3 channels
[23] the threshold for activation was 245 mV and the
sensitivity to dihydropyridines was in the micromolar
rather than the submicromolar range that characterises
Ca V 1.2.
The idea that the persistent inward current and plateau
potentials are generated by Ca V 1.3 is supported by the
differential immunohistochemical localisation of a1C and
a1D subunits in motoneurons. While the a1C subunit is
expressed in cell bodies and proximal dendrites, a1D
subunits are also expressed in dendrites, as shown in the
mouse [4] and subsequently confirmed in the turtle (Simon
et al., unpublished; see Fig. 1). This is in agreement with
the finding that plateau potentials in turtle motoneurons
can be evoked by selective depolarisation of distal dendrites [9,17]. The spatial distribution of the persistent
inward current generator is important because it strongly
influences its functional manifestation [1].
2.3. Activation /deactivation kinetics
The activation kinetics of L-type Ca 21 channels recorded in dissociated neurons is relatively slow. The
macroscopic L-current needs more than 7 ms to reach 90%
of its maximal value, which is more than twice as long as
for non-L-type channels [26]. For this reason, L-type Ca 21
channels respond to sustained or repeated depolarisation
4. Non-linear electrophysiological properties of spinal
cord neurons mediated by L-type Ca 21 channels
4.1. Boosting of remote dendritic synapses
The voltage-dependent contribution of L-type Ca 21
channels to the postsynaptic response is illustrated by
J.-F. Perrier et al. / Brain Research Reviews 40 (2002) 223–229
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Fig. 1. Distribution of the a1D subunit of L-type Ca 21 channels in the ventral horn of the spinal cord of the turtle. The a1D subunit was labelled by a
specific antibody (Alomone, Israel) revealed by a secondary antibody coupled to FITC. The membranes of large cells of the ventral horn from the spinal
cord of the turtle (i.e. presumed motoneurons) are fluorescent. The labelling is present both on the soma and the dendrites (Den). Picture provided by
Simon, Perrier and Hounsgaard (article in preparation).
recordings from plateau-generating interneurons in the
dorsal horn [34,35]. In the experiment illustrated in Fig. 2,
a single stimulus applied to the ipsilateral segmental dorsal
root evoked a long lasting burst of spikes at rest. This
response was reduced in vigour and duration when evoked
at more hyperpolarized holding potentials in the postsynaptic cell or after application of nifedipine. In functional
terms, this conditional, voltage-sensitive contribution of
plateau potentials to the postsynaptic response can regulate
the threshold, sensitivity and receptive field size dynamically with the level of L-channel activation [36]. In the
spinal motor system the issue of synaptic amplification by
a persistent inward current has received particular attention
in experiments on cat motoneurons [3,25,32].
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Fig. 2. Examples of responses involving L-type Ca 21 channels. (A) Stimulation of the ipsilateral dorsal root elicited a plateau potential in a dorsal horn
interneuron of the spinal cord of the adult turtle. Hyperpolarization gradually shortened the synaptically induced response (recording adapted from Ref.
[35], Fig. 3C). (B) Repetitive depolarising current pulses of constant amplitude induced a warm-up / wind-up of the response. (C) Plateau potential induced
by a depolarising current pulse. (D) In another motoneuron, a current pulse induced bistability that could be turned off by a negative current pulse.
Recordings (B), (C) and (D) obtained from different motoneurons, after blocking of fast synaptic transmission with CNQX, AP5 and Strychnine.
4.2. Plateau potentials and bistability
In analogy with the crucial role of plateau potentials in
rhythm generation in the stomatogastric ganglion of the
lobster [33], it was shown that plateau potentials mediated
by calcium channels could act as a mechanism for bistability in spinal motoneurons [15,20]. Because of their
slow kinetics and lack of inactivation, L-type Ca 21 channels generate a steady, voltage-activated persistent inward
current during a maintained depolarisation. In spinal cord
neurons expressing L-type Ca 21 channels, the persistent
inward current is often, once activated, of sufficient
amplitude to support plateau potentials that outlast the
stimulus for seconds (Fig. 2C) and may reach the level of
stable depolarisation, from which resetting requires an
active hyperpolarization (Fig. 2D). This means that
plateau-generating neurons can be in two stable, but
functionally different, states. The activation threshold for
plateau potentials may be lower than the threshold for
action potentials and therefore contribute to the depolarising envelope that underlies neuronal firing, or higher than
the threshold for action potentials, in which case it
contributes to the modulation of discharge frequency (for
review, see Ref. [22]).
4.3. Depolarisation-induced facilitation of L-channels:
wind-up, warm-up, delayed activation and hysteresis
It was originally thought that delayed activation, late
acceleration in firing frequency during long lasting depolarisations and hysteresis of firing during ramp depolarisations were due to slow activation of the channel underlying
the persistent inward current. It was obvious, however, that
the kinetics was unusually slow and complex. More
detailed analysis of plateau-generating dorsal horn neurons
revealed a mechanism involving a slow, depolarisationinduced facilitation of L-type Ca 21 channels [34,35]. In
these experiments, it was first noted that classical wind-up
was not only observed for the response to repeated primary
afferent synaptic input, but also for the response to a
repeated depolarising current pulse injected through the
recording electrode. Both types of wind-up were voltage
dependent and dihydropyridine sensitive, implicating Ltype Ca 21 channels. Interestingly, the gradual increase in
the response to repeated depolarising current pulses did not
depend on cumulative depolarisation of the membrane
potential during the interval between stimuli. For this
reason we suggested that the underlying mechanism, which
we termed warm-up, was due to depolarisation-induced
facilitation of L-type Ca 21 channels [34]. The simplest
scheme to explain the warm-up phenomenon is a voltagedependent transition between two closed states of the
L-type Ca 21 channels, an unwilling state with a high
activation threshold and a willing state with a low activation threshold [8]. Depolarisation-induced facilitation of
L-type Ca 21 channels is also the cause of the wind-up and
warm-up phenomena expressed by spinal motoneurons
[39]. These experiments revealed that the L-type Ca 21
J.-F. Perrier et al. / Brain Research Reviews 40 (2002) 223–229
current, during repeated depolarising commands in voltage
clamp, winds up at the same rate as activation of the
L-type Ca 21 current during a maintained depolarising
command. This result is important because it suggests that
warm-up is not only mediating wind-up, but is also
responsible for the delayed activation of plateau potentials
and therefore the mechanism for the characteristic hysteresis in firing frequency during ramp depolarisations in
neurons expressing plateau potentials [16,18]. This interpretation is confirmed by the finding that the I–V relation
during a triangular depolarising command ramp shows a
parallel hysteresis with an identical time course [39]. Both
the hysteresis in the I–V relation in current clamp and the
I–V relation in voltage clamp is mediated by low-threshold
L-type Ca 21 channels [16,39].
4.4. Modulation
In spinal motoneurons of the turtle, acetylcholine,
glutamate and serotonin all promote plateau potentials by
directly facilitating L-type Ca 21 channels [16,40]. Pharmacological analyses have shown that group I metabotropic
glutamate receptors mediate the effect of glutamate [10,40]
and 5-HT 2 receptors the facilitation by serotonin [29,30].
Interestingly, these receptor types, as well as subclasses of
muscarinic receptors, exert their action via the phospholipase C (PLC), diacylglycerol, inositol trisphosphate (IP3 )
pathway, which leads to the release of calcium from
intracellular stores. The fact that a transient increase in the
intracellular calcium concentration facilitates plateau potentials and that this effect disappears when intracellular
Ca 21 is chelated with BAPTA [31] suggests that the
different modulators facilitating L-type Ca 21 channels all
converge on the IP3 pathway. Blockade of calmodulin
227
(CaM) also prevents the facilitation of the calcium current
by intracellular calcium [31]. This result is compatible
with the recent finding that Ca 21 / CaM facilitates the
L-type Ca 21 channels expressing the a1C subunit [42,43].
It is possible, but not yet shown, that Ca 21 / CaM also
regulates Ca V 1.3. Our current hypothesis for the modulation of L-type Ca 21 channels is summarized in Fig. 3. This
hypothetical pathway is interesting, because it suggests
that, if intracellular calcium mediates the metabotropic
facilitation of the L-channels, then it also provides a
mechanism for wind-up. During a depolarisation that
reaches the threshold for the L-type Ca 21 channels, Ca 21
influx through a few open channels may facilitate Lchannels in the region, which would increase their probability of opening during continued or renewed depolarisation. This positive feedback mechanism is suggested to
gradually propagate facilitation throughout the dendritic
tree. The immediate buffering of free Ca 21 may explain
the slow rate of spread. This scenario also explains why
the time constant for delayed activation and wind-up (1–5
s) is much slower than the time constant for activation of
expressed Ca V 1.3 (in the range of ms [23,26]). These
possibilities need experimental evaluation.
The postsynaptic properties mediated by L-type Ca 21
channels in motoneurons are depressed by activation of
GABA B receptors [40]. Neither the postsynaptic pathways
nor the identity of the presynaptic GABAergic neurons
have been identified.
In dorsal horn neurons expressing L-type Ca 21 channels,
metabotropic facilitation is mediated by group I metabotropic glutamate receptors and NK-1 tachykinin receptors,
both glutamate and substance P being released from
primary afferents [37].
As in motoneurons, metabotropic facilitation of L-type
Fig. 3. Hypothetical intracellular pathways modulating L-type Ca 21 channels in motoneurons. Glutamate, serotonin and muscarine up-regulate L-type Ca 21
channels by activating the phospholipase C (PLC), diacylglycerol, inositol trisphosphate (IP3 ) pathway, which leads to the release of calcium from
intracellular stores. GABA B receptor activation down-regulates L-type Ca 21 channels via an unknown pathway.
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Ca 21 channels is counteracted by activation of GABA B
receptors. Neither the presynaptic origin nor the intracellular pathway postsynaptically of down-regulation of Lchannels by GABA is known [38].
Metabotropic facilitation of Ca V 1.3 can be induced by
synaptically released transmitters [10,37].
5. L-type Ca 21 channels and spinal plasticity
In adult terrestrial vertebrates, mammalian and nonmammalian, L-type Ca 21 channels are expressed by
particular cell types in the spinal sensori-motor network.
They provide distinct non-linear conversions of synaptic
input to axonal output. Several features suggest a major
role in spinal motor function. The unusually slow kinetics
is well adapted to provide the driving potential for the
firing patterns that regulate the muscle activity of posture
and locomotion. This arguably reduces the computational
load on the premotor network [8]. Motor behaviour is the
concerted action of hundreds of muscles. The relative
contribution of any particular muscle to different motor
behaviours varies over the full scale from none to maximal
involvement. The metabotropic synaptic regulation of Ltype Ca 21 channels [10] provides a mechanism for changing the excitability of motoneurons so that the recruitment
order among functional pools of motoneurons can be
adjusted to match their relative involvement in particular
motor acts. The fact that both the spinal [10] and supraspinal [14] pathways converge on the metabotropic regulation
of L-type Ca 21 channels in motoneurons provides a
mechanism for conditioning the final motor output by a
wide variety of signals from multiple independent origins.
It is conceivable that this type of short-term functional
plasticity also plays a role during ongoing motor behaviour. Recent experiments in humans [6] show that
sustained activation of primary afferents from a muscle
leads to a dramatic recruitment of force over a timescale of
tens of seconds. The origin has been attributed to increased
activity in the motoneurons supplying the muscle due to
induction of plateau potentials. This is compatible with
metabotropic facilitation of L-type Ca 21 channels in
motoneurons [10]. If so, the most likely pathway is
activation of mGluRI receptors on motoneurons by glutamate released from the stimulated primary afferents. These
findings pose the intriguing possibility that primary afferents provide ionotropic and metabotropic synaptic input in
parallel to motoneurons, a mechanism already demonstrated for the regulation of L-type Ca 21 channels in deep
dorsal horn neurons [37].
Arguments for the involvement of L-type Ca 21 channels
in early sensory processing are less compelling. The
interneurons in the deep dorsal horn expressing L-type
Ca 21 channels are monosynaptically innervated by myelinated and unmyelinated dorsal root afferents [34,35].
Based on the finding that wind-up is an intrinsic property
of these cells they have been suggested to be ‘‘wide
dynamic range neurons’’ [27,35]. The possible function of
L-type Ca 21 channels and their metabotropic regulation in
these cells has been discussed elsewhere [36].
The study of postsynaptic properties mediated by L-type
Ca 21 channels in spinal neurons has revealed mechanisms
that may provide functional plasticity on a time scale from
hundreds of milliseconds to tens of seconds.
It remains to be seen if this plasticity also involves
mechanisms activated by focal Ca 21 influx in dendrites
controlled by metabotropically regulated L-channels [9]. It
is also an open question if the expression of L-type Ca 21
channels is regulated and a contributing factor to functional plasticity in the spinal cord.
Acknowledgements
This work was kindly funded by the European Union,
the Danish MRC, The Lundbeck Foundation, The NovoNordisk Foundation and The Foundation Agnes and Poul
Friis. J.-F. Perrier is supported by a grant from the Danish
MRC.
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