Download Regulation of Action-Potential Firing in Spiny Neurons of the Rat

Regulation of Action-Potential Firing in Spiny Neurons of the Rat
Neostriatum In Vivo
J. R. WICKENS 1 AND C. J. WILSON 2
1
Department of Anatomy and Structural Biology, School of Medical Sciences, University of Otago, Dunedin, New
Zealand; and 2 Department of Anatomy and Neurobiology, University of Tennessee, Memphis, Tennessee 38163
INTRODUCTION
Action-potential firing of neostriatal spiny neurons in awake
animals typically occurs in brief episodes separated by longer
periods of relative quiescence (Kimura et al. 1990; Schultz and
Romo 1988). Such episodes of firing are often associated with
initiation, execution, or termination of particular movements
on the part of the animal (Alexander 1987; Kimura 1990;
Schultz and Romo 1988). These patterns of firing were also
demonstrated in intracellular records made from neostriatal
neurons in immobilized, locally anesthetized rats (Wilson and
Groves 1981) and in urethan-anesthetized rats (Wilson 1993).
In addition, it has long been known that under most experimental conditions a proportion of the neostriatal neurons do not
2358
spontaneously fire action potentials at all (Calabresi et al.
1987b; Wilson 1993; Wilson and Groves 1981). Because these
silent spiny neurons are not observed to fire in extracellular
records made before penetration, their silence is not thought to
be from the effects of impalement (Wilson and Groves 1981).
Extracellular recording combined with iontophoretic application of excitatory neurotransmitters has also revealed a large
population of silent spiny neurons in awake behaving animals
(Kiyatkin and Rebec 1996).
Membrane potential shifts from a hyperpolarized DOWN
state to a depolarized UP state appear to be necessary for
action-potential firing in striatal neurons (Wilson and Groves
1981; Wilson and Kawaguchi 1996). Several pieces of evidence suggest that these UP state transitions are brought
about by synaptic input from the cerebral cortex and the
thalamus. UP state transitions do not occur following removal
or deactivation of the cortex (Wilson et al. 1983) or in brain
slices in which most cortical inputs have been disconnected
(Arbuthnott et al. 1985; Kawaguchi et al. 1989). On the
other hand, cortical stimulation in the intact animal can
evoke depolarizing events very similar to the UP state transitions that occur spontaneously (Wilson 1995; Wilson and
Kawaguchi 1996). Thus corticostriatal inputs are necessary
and sufficient for UP state transitions. UP state transitions,
however, do not necessarily lead to action-potential firing
and occur in silent as well as spontaneously firing cells (Wilson and Groves 1981).
In addition to the large amplitude shifts in membrane
potential that occur with UP state transitions, numerous small
amplitude noiselike fluctuations in membrane potential appear superimposed on the UP and DOWN states. In the spontaneously firing neurons these noiselike fluctuations in membrane potential trigger action potential generation. Similar
fluctuations are also observed in the silent spiny neurons but
they do not reach threshold for action potential firing, although this can occur if the membrane potential is brought
closer to threshold by injection of depolarizing current (Wilson and Kawaguchi 1996).
Previous work has shown that dopamine, acetylcholine,
and possibly other neurotransmitters act in part to alter the
threshold for action potential generation in striatal neurons
(Calabresi et al. 1987a; Rutherford et al. 1988) or the sensitivity of their threshold to the recent history of membrane
potential changes (Kitai and Surmeier 1993; Surmeier et al.
1988). They may also modulate the efficacy of corticostriatal
afferents (Calabresi et al. 1992; Wickens et al. 1996). Thus,
whereas both active and silent neurons exhibit qualitatively
0022-3077/98 $5.00 Copyright q 1998 The American Physiological Society
/ 9k28$$my09 J804-7
04-09-98 08:42:27
neupa
LP-Neurophys
Downloaded from http://jn.physiology.org/ by 10.220.33.4 on June 16, 2017
Wickens, J. R. and C. J. Wilson. Regulation of action-potential
firing in spiny neurons of the rat neostriatum in vivo. J. Neurophysiol. 79: 2358–2364, 1998. Both silent and spontaneously firing
spiny projection neurons have been described in the neostriatum,
but the reason for their differences in firing activity are unknown.
We compared properties of spontaneously firing and silent spiny
neurons in urethan-anesthetized rats. Neurons were identified as
spiny projection neurons after labeling by intracellular injection of
biocytin. The threshold for action-potential firing was measured
under three different conditions: 1) electrical stimulation of the
contralateral cerebral cortex, 2) brief directly applied current
pulses, and 3) spontaneous action-potentials occurring during
spontaneous episodes of depolarization ( UP state). The average
membrane potential and the amplitude of noiselike fluctuations of
membrane potential in the UP state were determined by fitting a
Gaussian curve to the membrane-potential distribution. All neurons
in the sample exhibited spontaneous membrane potential shifts
between a hyperpolarized DOWN state and a depolarized UP state,
but not all fired action potentials while in the UP state. The difference between the spontaneously firing and the silent spiny neurons
was in the average membrane potential in the UP state, which was
significantly more depolarized in the spontaneously firing than in
the silent spiny neurons. There were no significant differences in
the threshold, the amplitude of the noiselike fluctuations of membrane potential in the UP state, or in the proportion of time that the
membrane potential was in the UP state. In both spontaneously
firing and silent neurons, the threshold for action potentials evoked
by current pulses was significantly higher than for those evoked
by cortical stimulation. Application of more intense current pulses
that reproduced the excitatory postsynaptic potential rate of rise
produced firing at correspondingly lower thresholds. Because the
membrane potential in the UP state is mainly determined by the
balance between the synaptic drive and the outward potassium
conductances activated in the subthreshold range of membrane
potentials, either or both of these factors may determine whether
firing occurs in response to spontaneous afferent activity.
ACTION-POTENTIAL FIRING IN SPINY STRIATAL NEURONS
similar membrane-potential shifts, the difference between
spontaneously active and silent spiny neurons may be attributable to a difference in either 1) the mean depolarization
during the UP state, 2) the amplitude of the membrane-potential fluctuations while in the UP state, or 3) the action-potential threshold, or some combination of these.
In the experiments described here, we compared the action-potential firing threshold, the average membrane potentials in the UP and DOWN states, and the amplitude of the
noiselike fluctuations in the UP state of the silent and spontaneously firing neurons.
METHODS
Intracellular records were made from striatal neurons in male
Sprague-Dawley or Long-Evans rats (210–400 g) anesthetized
with urethan (1.25 g kg 01 ). Hourly doses of ketamine (35 mg
kg 01 ) and xylazine (7 mg kg 01 ) were given by intramuscular injection throughout the experiment to supplement anesthesia and reduce the blood pulsations of the brain. The animals were supported
in a stereotaxic unit and suspended by a tail clamp to reduce
breathing movements. The animal’s temperature was maintained
at 37 { 0.57C with a feedback-controlled heating pad. Bipolar
stimulating electrodes were fabricated from 000 stainless steel insect pins, insulated except for within 0.5 mm of the tips, separated
by 0.7 mm. Burr holes were drilled above stimulation sites and
stimulating electrodes were implanted in the contralateral cortex
(interaural coordinates AP 12.2, ML 02.0, and DV 7.4) and substantia nigra (coordinates AP 3.6, ML 1.6, and DV 1.6) and fixed
in place with dental cement. A flap of bone (from 8.5–12.5 mm
anterior to the interaural line and 1.0–4.5 mm lateral to the midline) was removed to expose the dura, which was then excised.
The cisterna magna was opened to drain the cerebrospinal fluid.
During penetrations the brain surface was covered with paraffin
wax to reduce brain pulsations.
Recording microelectrodes were pulled from 3.0-mm-diam glass
and their tips were broken back under microscopic control to 0.1to 0.5-mm diam (as judged from interference colors under epiillumination). Electrodes were filled with 4% biocytin in 1 M
potassium acetate and had resistances ranging from 27 to 54 MV.
Recording electrodes were advanced into the striatum from initial
penetrations at the level of bregma and 3.0–3.5 mm lateral to the
midline. Cells were penetrated by passing brief pulses of current
through the recording electrode. After waiting for the cell membrane potentials to stabilize, action-potential firing was evoked by
depolarizing current injection and cortical stimulation. Episodes of
spontaneous activity lasting 90 s were recorded after the initial
penetration and at 20-min intervals thereafter for as long as the
cell remained stable. After recording intracellular data, the electrode was withdrawn from the cell and extracellular control records
were taken.
At the end of the experiments, animals were deeply anesthetized
with an additional injection of urethan (2 g kg 01 ) and perfused
intracardially with a solution of 4% formaldehyde in 0.15 M phosphate buffer (pH 7.4). The brain was then removed and stored
overnight. Sections were cut with a vibratome and stained with
FIG . 2. Intracellular records from 2 different neurons.
A: silent spiny neuron. B: spontaneously firing neuron.
Both neurons displayed subthreshold membrane potential
fluctuations between UP and DOWN states, but only one
fired action potentials while in the UP state.
/ 9k28$$my09 J804-7
04-09-98 08:42:27
neupa
LP-Neurophys
Downloaded from http://jn.physiology.org/ by 10.220.33.4 on June 16, 2017
FIG . 1. Photomontage of one of the intracellularly filled spiny projection
neurons used in the study.
2359
2360
TABLE
J. R. WICKENS AND C. J. WILSON
1.
Firing properties of spiny projection neurons
Spontaneously
Firing
(n Å 17)
Silent
(n Å 6)
040.0 { 3.3
043.8 { 4.1
043.2
047.6
046.0
045.5
{
{
{
{
4.7
4.7
6.0
6.0
NS
NS
061.6
4.2
073.4
1.8
051.1
3.6
069.2
3.1
{
{
{
{
7.1
1.4
9.4
1.1
P õ 0.005
NS
NS
NS
{
{
{
{
4.6
1.4
7.1
0.5
0.5 { 0.1
0.4 { 0.1
NS
0.86 { 0.21
26.3 { 10.6
0.70 { 0.19
23.0 { 8.2
NS
NS
56.4 { 8.4
0.8 { 0.1
56.8 { 7.9
0.9 { 0.1
NS
NS
9.8 { 3.1
6.7 { 4.1
NS
Data are means { SD. NS, not significant. a Firing threshold was significantly more hyperpolarized for action potentials evoked by cortical stimulation than for those evoked by current pulses (P õ 0.05, paired t-test).
b
Average membrane potential in the UP state was more depolarized in the
spontaneously firing than in the silent spiny neurons (P õ 0.005, t-test on
time-matched samples of n Å 5). c Membrane resistance was determined
from membrane potential 40 ms after onset of subthreshold depolarizing
current pulses. d Action-potential duration was measured at half maximal
amplitude. e AHP amplitude was the difference between threshold potential
and minimum value of the AHP.
the avidin-biotin-horseradish peroxidase method as described by
Horikawa and Armstrong (1988).
Electrophysiological data traces were digitized and recorded to
disk. Individual waveforms were analyzed using custom software
to measure threshold and action potential parameters. Threshold
was defined as the voltage at which the rate of depolarization
exceeded 4 V s 01 . The threshold defined in this way agreed with
that judged by inspection of the traces, in which the abrupt increase
in the rate of depolarization was indicated by the separation of
individual sampling points. Action potential amplitude was defined
as the potential difference between threshold and the peak of the
action potential waveform. Afterhyperpolarization (AHP) was de-
RESULTS
Intracellular records were obtained from 23 striatal cells
that were identified as spiny projection neurons by histological examination after the experiment (Fig. 1). Five cells
in the sample were identified as striatonigral neurons by
antidromic activation from the substantia nigra. All neurons
in the sample displayed subthreshold membrane-potential
fluctuations between UP and DOWN states (Fig. 2). Cells that
were not observed to fire action potentials before penetration
and that did not fire at least once during 90-s periods recorded after the cell had stabilized were classified as ‘‘silent’’ spiny cells (Wilson and Groves 1981). Neurons that
fired once or more during this period were classified as
‘‘spontaneously firing’’ cells. Of the sample, 17 were spontaneously firing and 6 were silent spiny cells. Three of the
spontaneously firing cells and two of the silent cells were
able to be antidromically activated by substantia nigra stimulation, suggesting that there is no relationship between the
occurrence of spontaneous firing activity in a cell and
whether it projects to the substantia nigra.
In all neurons, silent as well as spontaneously firing, action
potentials could be evoked by electrical stimulation of the
contralateral cortex and also by application of depolarizing
FIG . 3. Intracellular records showing action potential firing in response to the different methods of excitation employed in the study. A and B: cortical stimulation. C and D: current pulse. E and F: spontaneous
activity. All traces (A–F) are from same neuron. Note
that in this cell, action potential threshold in response
to current injection is about 2.6 mV more depolarized
than threshold in response to cortical stimulation. x,
points at which the rate of rise of voltage trajectory
exceeded 4 mV ms 01 .
/ 9k28$$my09 J804-7
04-09-98 08:42:27
neupa
LP-Neurophys
Downloaded from http://jn.physiology.org/ by 10.220.33.4 on June 16, 2017
Firing threshold, mV
Current pulsea
Cortical stimulationa
Initial UP state
Final UP state
Membrane potential, mV
b
UP state average (m2)
UP state variance (d2)
DOWN state average (m1)
DOWN state variance (d1)
Ratio (DOWN:UP time)
(a)
Rate of rise, mV/ms
DOWN to UP state
Membrane resistance,c MV
Action potential
Amplitude (mV)
Duration (ms)d
Afterhyperpolarization
Amplitude (mV)e
fined as the potential difference between threshold and the minimum of the AHP waveform that immediately followed each action
potential.
The average membrane potential in the UP and DOWN states and
the amplitude of the fluctuations in membrane potential in each
state were measured from the all-amplitudes distribution of the
membrane potential. A binwidth of 1 ms over a 10-s period of
continuous recording was used. The best fit of the sum of two
Gaussian distributions to the all-amplitudes distribution was found
with the use of the Mathematica procedure NonLinearFit, which
employs the Levenberg-Marquardt method. The membrane potential rate of rise during the transition from the DOWN state to the UP
state was defined as the slope of the tangent to the membranepotential trajectory at the point midway between the average membrane potential in the UP and DOWN states. Measurements of all
DOWN to UP transitions were averaged over the same 10-s period
of continuous recording used to determine the average membrane
potential in the UP and DOWN states.
All group comparisons were made with t-tests for independent
samples, and within group comparisons used paired t-tests.
ACTION-POTENTIAL FIRING IN SPINY STRIATAL NEURONS
the spontaneously active neurons the threshold for action
potentials arising from spontaneous fluctuations in membrane potential was intermediate between that for current
pulses and that for cortical stimulation.
Comparison of traces showing firing in response to cortical stimulation and firing in response to current injection,
such as those shown in Fig. 3, B and D , indicated that
the differences in threshold were related to the voltage
trajectory immediately before action-potential firing. The
voltage trajectory produced by cortical stimulation reflects
the synchronous activation of many afferents and has a
faster rate of rise than that produced by the just suprathreshold current pulses or the less synchronous spontaneous synaptic input activity from corticostriatal neurons.
To investigate the role of the subthreshold voltage trajectory more directly, the intensity of the current pulses was
increased until the voltage trajectory matched the excitatory postsynaptic potential ( EPSP ) rate of rise. A faster
rate of rise resulted in action potential firing at a correspondingly lower threshold ( Fig. 4 A ) .
Figure 4, B and C, shows that the effect of increasing the
FIG . 4. Comparison of action potential thresholds
when evoked by long pulse, an excitatory postsynaptic potential (EPSP), or current injection adjusted to
match EPSP trajectory. A: when voltage trajectory
evoked by current injection is made to match the
EPSP rate of rise, firing occurs at a correspondingly
lower threshold. Two traces from the same cell are
superimposed. When action potential firing is evoked
by a current pulse that produces a gradual depolarization, the threshold ( c ) is higher than when an action
potential is evoked by cortical stimulation (right).
Firing occurs at a lower threshold in response to a
more intense current pulse that reproduces the EPSP
membrane potential trajectory (left). B: when action
potential firing is evoked by current pulses of different intensity, the effect of voltage trajectory is most
marked in the initial 5–10 ms. Note that the threshold
( c ) is lowest for the action potential evoked at the
shortest latency, but there is little change at latencies
longer than 5 ms. C: threshold for action potential
firing evoked by EPSPs increases when the voltage
trajectory is more slowly depolarizing, with a time
course in the order of 5–10 ms. Note increase in
threshold ( c ) between the shortest latency action potential and the longer latency action potentials. A, B,
and C: records from different neurons. F, cortical
stimulus.
/ 9k28$$my09 J804-7
04-09-98 08:42:27
neupa
LP-Neurophys
Downloaded from http://jn.physiology.org/ by 10.220.33.4 on June 16, 2017
direct current pulses via the recording electrode. Thus the
lack of firing activity in silent spiny cells was not due to
any lack of ability to fire action potentials. Their lack of
firing must, therefore, be because of a higher threshold, a
less depolarized membrane potential in the UP state, or a
lower amplitude of noiselike fluctuations of membrane potential while in the UP state. Each of these possibilities was
investigated.
Threshold was determined by measuring the membranepotential trajectory before action-potential firing under three
different stimulation conditions: current pulse injection, cortical stimulation, and spontaneous firing in the case of spontaneously active cells. An example of action potentials
evoked by these three different methods in the same cell is
shown in Fig. 3. The group averages are shown in Table 1.
There was no significant difference in threshold between
spontaneously firing and silent spiny neurons, regardless of
whether action potentials were evoked by directly applied
current pulses or synaptic input. Threshold was, however,
higher for action potentials evoked by current pulses than
for those evoked by cortical stimulation (P õ 0.01). In
2361
2362
J. R. WICKENS AND C. J. WILSON
q
The resulting parameters of the fitted equation were thus
estimates of the average membrane potential in the DOWN
( m1 ) or UP state ( m2 ) and the amplitude of the noiselike
fluctuations in the corresponding state ( d1 , d2 ), whereas the
weighting factor ( a ) gave an index of the time the neuron
spent in each state. These parameters were determined for
all neurons in the sample. The amplitude distributions and
fitted curves for representative spontaneously firing and silent spiny neurons are presented in Fig. 5.
Table 1 shows the group averages for m1 , m2 , d1 , d2 , and
a. The average membrane potential in the UP state ( m2 ) was
significantly higher in the spontaneously firing neurons than
in the silent spiny neurons (P õ 0.005). The injection of
ketamine supplements had no effect on the average membrane potential in the UP state or DOWN state. There was no
significant difference between spontaneously firing and silent spiny cells in the average membrane potential in the
DOWN state ( m1 ), the amplitude of the noiselike fluctuations
in either the UP or DOWN state ( d1 , d2 ), the proportion of
time spent in the DOWN state ( a ), or the membrane-potential
rate of rise during the transition from the DOWN to the UP
state. There was also no significant difference between spontaneously firing and silent spiny cells in their action-potential
amplitude or duration, AHP amplitude, or membrane resistance as determined from subthreshold depolarizing current
pulses.
Pr( n ) Å a exp[0( n 0 m1 ) 2 /2s 21 ]/ 2p s1
q
/ (1 0 a ) exp[ 0( n 0 m2 ) 2 /2s 22 ]/ 2p s2
(1)
FIG . 5. Amplitude distributions of membrane potentials over a 10-s period of continuous recording, based on data from 2 neurons presented in
Fig. 2. A: silent spiny neuron. B: spontaneously firing neuron. The curves
are best fits obtained for Eq. 1.
/ 9k28$$my09 J804-7
DISCUSSION
The present study measured spontaneous membrane potential fluctuations and responses to cortical stimulation or
direct current injection in silent and spontaneously firing
striatal neurons. The silent and spontaneous firing neurons
probably represent different points along a continuum in
several different dimensions, including differences in synaptic input, membrane responsiveness, or threshold for action
potential firing. Silent and spontaneously active neurons do
not represent different subtypes of spiny neurons. Direct and
indirect pathway neurons (identified by antidromic stimulation) belonged to both groups, and there were no morphological differences between the silent and spontaneously active
cells. It is most likely that the silent and spontaneously active
cells represent differences in the functional state of the spiny
neurons and not any permanent difference in excitability.
There was no significant threshold difference between the
spontaneously firing and silent spiny neurons, regardless of
which measure of threshold was used. The use of two different methods to determine the voltage threshold (synaptic
input and current pulse input) provided a cross-check on the
values obtained, and it is unlikely that a threshold difference
of sufficient magnitude to account for the different firing
properties was overlooked.
The difference between the threshold for action potentials
arising from the depolarizations evoked by current pulses
and those arising from cortically evoked EPSPs confirms
previous work showing that spike thresholds in striatal neurons are higher for direct than for synaptic activation (Sugimori et al. 1976). This difference in thresholds was attributed to nonisopotentiality of recording and spike-initiation
areas by several authors in relation to striatal (Sugimori et al.
1976), spinal (Frank and Fuortes 1956), and hippocampal
04-09-98 08:42:27
neupa
LP-Neurophys
Downloaded from http://jn.physiology.org/ by 10.220.33.4 on June 16, 2017
rate of rise on threshold was only seen in the initial few
milliseconds of the voltage trajectory. The threshold of action potentials evoked at longer latencies showed no change
between latencies of 20–100 ms. By repeatedly eliciting
firing over a range of different latencies, it was possible to
obtain an estimate of the time course of this effect. A single
exponential equation produced a good fit to the relation between latency and threshold. The time constants of the fitted
equations were typically õ10 ms. The effect of latency on
threshold was observed in synaptically evoked firing as well
as firing in response to current pulses in the majority of cells
tested, suggesting that the membrane-voltage trajectory is a
stronger determinant of threshold than whether excitation is
synaptic or direct.
If the firing threshold is not the difference between the
spontaneously active and silent spiny neurons then the difference must be either that the average membrane potential in
the UP state of the spontaneously firing cells is higher or
that the amplitude of the noiselike fluctuations in membrane
potential is greater. Estimates of the average membrane potential in the UP and DOWN state and the amplitude of the
fluctuations in membrane potential in each state were obtained as outlined in METHODS . A curve-fitting procedure
was used to find the parameters of Eq. 1 (the weighted sum
of 2 Gaussians) that gave the best fit to the distribution of
the membrane potentials ( n )
ACTION-POTENTIAL FIRING IN SPINY STRIATAL NEURONS
/ 9k28$$my09 J804-7
A comparison of the amplitudes of the rapid, noiselike
fluctuations in membrane potential showed there was no
significant difference between the spontaneously firing and
silent neurons on this measure. These smaller amplitude
fluctuations are also believed to be a reflection of the synaptic inputs to spiny striatal neurons, because they are produced
by a membrane conductance with the same reversal potential
as the EPSPs evoked by cortical stimulation (Wilson and
Kawaguchi 1996). They probably represent the fine structure of the synaptic barrages that produce the UP state transitions and maintain the neurons in the UP state. It is interesting
that the amplitude of these fluctuations is not the difference
between the spontaneously firing and silent spiny cells, even
though spontaneously occurring action potentials are seen
to arise from them. This finding is further evidence that
synaptic input is necessary but not sufficient for action potential firing in these neurons and that some other factor governs
whether firing occurs.
The difference between the spontaneously firing and the
silent spiny neurons was in the average membrane potential
of the UP state, with the spontaneously firing neurons being
significantly more depolarized than the spiny neurons. The
membrane potential in the UP state is mainly determined
by the balance between the synaptic drive and the outward
potassium conductances activated in the subthreshold range
of membrane potentials. In the absence of these potassium
conductances, membrane potential in the UP state closely
approaches the reversal potential for the corticostriatal synapses (Wilson and Kawaguchi 1996). The voltage dependence of these conductances, which would determine their
strength during synaptic activation, is subject to modulation
by dopamine, acetylcholine, and perhaps a variety of other
neuromodulators (Akins et al. 1990; Surmeier and Kitai
1993). Thus the difference between the spontaneously firing
and the silent spiny neurons may be in the strength of these
potassium conductances and, indirectly, their modulation
state or in the strength and total number of the synaptic
inputs active at any given time.
We thank B. Ross for histological work.
This research was supported by National Institute of Neurological Disorders and Stroke Grant NS-20743.
Address for reprint requests: J. Wickens, Dept. of Anatomy and Structural
Biology, University of Otago, PO Box 913, Dunedin, New Zealand.
Received 2 October 1997; accepted in final form 20 January 1998.
REFERENCES
AKINS, P. T., SURMEIER, D. J., AND KITAI, S. T. Muscarinic modulation of
the transient potassium current in rat neostriatal neurons. Nature 344:
240–242, 1990.
ALEXANDER, G. E. Selective neuronal discharge in monkey putamen reflects
intended direction of planned limb movements. Exp. Brain Res. 67: 623–
634, 1987.
ARBUTHNOTT, G. W., MACLEOD, N., AND RUTHERFORD, A. The rat corticostriatal pathway in vitro (Abstract). J. Physiol. (Lond.) 367: 102P, 1985.
CALABRESI, P., MAJ, R., MERCURI, N. B., AND BERNARDI, G. Coactivation
of D1 and D2 dopamine receptors is required for long-term synaptic
depression in the striatum. Neurosci. Lett. 142: 95–99, 1992.
CALABRESI, P., MERCURI, N., STANZIONE, P., STEFANI, A., AND BERNARDI,
G. Intracellular studies on the dopamine-induced firing inhibition of neostriatal neurons in vitro: evidence for D1 receptor involvement. Neuroscience 20: 757–771, 1987a.
CALABRESI, P., MISGELD, U., AND DODT, H. U. Intrinsic membrane proper-
04-09-98 08:42:27
neupa
LP-Neurophys
Downloaded from http://jn.physiology.org/ by 10.220.33.4 on June 16, 2017
neurons (Spencer and Kandel 1961). These differences in
threshold were taken to indicate a remote site for action
potential generation. The present data showed that firing
occurred at a lower threshold when the intensity of the current pulses was increased so that the voltage trajectory produced by current pulses matched the EPSP rate of rise. This
evidence does not support the existence of a remote site for
action potential initiation because such an explanation would
predict a greater difference in threshold when more intense
current pulses are applied. In principle, however, this observation is consistent with the effects of rapidly inactivating
channels in the spiny striatal cell membrane.
In biophysical models that assume a uniform membrane
potential, threshold is the point above the resting membrane
potential at which the net current flow across the membrane
is zero (Fitzhugh 1960; Noble 1966; Noble and Stein 1966).
Above this point, inward currents predominate and regenerative excitation occurs. However, the voltage at which this
occurs depends on the effect of the preceding membranepotential trajectory on the availability of sodium and potassium channels involved in action-potential firing. The rapid
inactivation kinetics of sodium channels means that their
availability is reduced by slow depolarizations, and the availability of these channels is a key determinant of threshold
(Holden and Yoda 1981). The potassium currents that are
activated as the membrane potential approaches threshold
are also time dependent in both their activation and inactivation, and thus may also modify the point at which net current
flow crosses zero or act indirectly to modify the availability
of sodium channels by slowing the rate of rise of the membrane-potential trajectory.
All the neurons in the sample exhibited spontaneous UP
state transitions, indicating that the silent spiny neurons do
receive synaptic input from the cortex and that their inputs
are sufficient to produce UP state transitions. Furthermore,
in all neurons in the sample action potentials could be evoked
by stimulation of the contralateral cerebral cortex during
the DOWN state. Thus the silent spiny neurons also receive
sufficient corticostriatal inputs to fire them, at least in response to the synchronous activation produced by electrical
stimulation.
The silent spiny neurons in the sample also spent as much
time in the UP state as the spontaneously firing neurons. The
probability of action-potential firing was not related to the
amount of time spent in the UP state. This is important because spiny striatal neurons possess slowly inactivating voltage-dependent potassium currents that delay their firing in
response to constant current pulses in the absence of synaptic
input (Nisenbaum and Wilson 1994; 1995). The action of
these currents in slices suggests that the likelihood of firing
during an UP state might increase with time, but that suggestion is not supported by the present findings. These results
suggest that the probability of firing in the UP state is controlled by different mechanisms from the ones that control
the timing of UP state transitions. Although cortical stimulation can apparently override these mechanisms, whether firing actually occurs in the UP state under more natural conditions must be determined by other factors such as the amplitude of the noiselike fluctuations in membrane potential, the
threshold for action-potential firing, or the average membrane potential in the UP state.
2363
2364
J. R. WICKENS AND C. J. WILSON
/ 9k28$$my09 J804-7
RUTHERFORD, A., GARCIA-MUNOZ, M., AND ARBUTHNOTT, G. An afterhyperpolarization recorded in striatal cells ‘‘in vitro’’: effect of dopamine
administration. Exp. Brain Res. 71: 399–406, 1988.
SCHULTZ, W. AND ROMO, R. Neuronal activity in the monkey neostriatum
during the initiation of movements. Exp. Brain Res. 71: 431–436, 1988.
SPENCER, W. A. AND KANDEL, E. R. Electrophysiology of hippocampal neurons. III. Firing level and time constant. J. Neurophysiol. 24: 260–271,
1961.
SUGIMORI, M., PRESTON, R. J., AND KITAI, S. T. Response properties and
electrical constants of caudate nucleus neurons in the cat. J. Neurophysiol.
41: 1662–1676, 1976.
SURMEIER, D. J., BARGAS, J., AND KITAI, S. T. Voltage-clamp analysis of a
transient potassium current in rat neostriatal neurons. Brain Res. 473:
187–192, 1988.
SURMEIER, D. J. AND KITAI, S. T. D1 and D2 dopamine receptor modulation
of sodium and potassium currents in rat neostriatal neurons. Prog. Brain
Res. 99: 277–297, 1993.
WICKENS, J. R., BEGG, A. J., AND ARBUTHNOTT, G. W. Dopamine reverses
the depression of rat cortico-striatal synapses which normally follows
high frequency stimulation of cortex in vitro. Neuroscience 70: 1–5,
1996.
WILSON, C. J. The generation of natural firing patterns in neostriatal neurons. Prog. Brain Res. 99: 277–297, 1993.
WILSON, C. J. The contribution of cortical neurons to the firing pattern of
striatal spiny neurons. In: Models of Information Processing in the Basal
Ganglia, edited by J. C. Houk, J. L. Davis, and D. G. Beiser. Cambridge,
MA: MIT Press, 1995, p. 187–214.
WILSON, C. J., CHANG, H. T., AND KITAI, S. T. Disfacilitation and longlasting inhibition of neostriatal neurons in the rat. Exp. Brain Res. 51:
227–235, 1983.
WILSON, C. J. AND GROVES, P. M. Spontaneous firing patterns of identified
spiny neurons in the rat neostriatum. Brain Res. 220: 67–80, 1981.
WILSON, C. J. AND KAWAGUCHI, Y. The origins of two-state spontaneous
membrane potential fluctuations of neostriatal spiny neurons. J. Neuroscience 16: 2397–2410, 1996.
04-09-98 08:42:27
neupa
LP-Neurophys
Downloaded from http://jn.physiology.org/ by 10.220.33.4 on June 16, 2017
ties of neostriatal neurons can account for their low level of spontaneous
activity. Neuroscience 20: 293–303, 1987b.
FITZHUGH, R. Threshold and plateaus in the Hodgkin-Huxley nerve equations. J. Gen. Physiol. 43: 867–896, 1960.
FRANK, K. AND FUORTES, M.G.F. Stimulation of spinal motoneurons with
intracellular electrodes. J. Physiol. (Lond.) 134: 451–470, 1956.
HOLDEN, A. V. AND YODA, M. The effects of ionic channel density on
neuronal function. J. Theor. Neurobiol. 1: 60–81, 1981.
HORIK AWA, K. AND ARMSTRONG, W. E. A versatile means of intracellular
labelling: injection of biocytin and its detection with avidin conjugates.
J. Neurosci. Methods 25: 1–11, 1988.
KAWAGUCHI, Y., WILSON, C. J., AND EMSON, P. C. Intracellular recording
of identified neostriatal patch and matrix spiny cells in a slice preparation
preserving cortical inputs. J. Neurophysiol. 62: 1052–1068, 1989.
KIMURA, M. Behaviorally contingent property of movement-related activity
of the primate putamen. J. Neurophysiol. 63: 1277–1296, 1990.
KIMURA, M., KATO, M., AND SHIMAZAKI, H. Physiological properties of
projection neurons in the monkey striatum to the globus pallidus. Exp.
Brain Res. 82: 672–676, 1990.
KITAI, S. T. AND SURMEIER, D. J. Cholinergic and dopaminergic modulation
of potassium conductances in neostriatal neurons. Adv. Neurol. 60: 40–
52, 1993.
KIYATKIN, E. A. AND REBEC, G. V. Dopaminergic modulation of glutamateinduced excitations of neurons in the neostriatum and nucleus accumbens
of awake, unrestrained rats. J. Neurophysiol. 75: 142–153, 1996.
NISENBAUM, E. S. AND WILSON, C. J. Potassium currents responsible for
inward and outward rectification in rat neostriatal spiny projection neurons. J. Neuroscience 15: 4449–4463, 1995.
NISENBAUM, E. S., XU, Z. C., AND WILSON, C. J. Contribution of a slowly
inactivating potassium current to the transition to firing of neostriatal
spiny projection neurons. J. Neurophysiol. 71: 1174–1189, 1994.
NOBLE, D. Applications of Hodgkin-Huxley equations to excitable tissues.
Physiol. Rev. 46: 1–50, 1966.
NOBLE, D. AND STEIN, R. B. The threshold conditions for initiation of action
potentials by excitable cells. J. Physiol. (Lond.) 187: 129–162, 1966.