The Journal of Neurophysiology Vol. 79 No. 5 May 1998, pp. 2358-2364
Copyright ©1998 by the American Physiological Society

Regulation of Action-Potential Firing in Spiny Neurons of the Rat Neostriatum In Vivo

J. R. Wickens¹ and C. J. Wilson²

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

	ABSTRACT

Abstract Introduction Methods Results Discussion References

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.

	INTRODUCTION

Abstract Introduction Methods Results Discussion References

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 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 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.

View larger version (127K): [in this window] [in a new window]   FIG. 1. Photomontage of one of the intracellularly filled spiny projection neurons used in the study.

View larger version (27K): [in this window] [in a new window]   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.

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

Abstract Introduction Methods Results Discussion References

Intracellular records were made from striatal neurons in male Sprague-Dawley or Long-Evans rats (210-400 g) anesthetized with urethan (1.25 g kg¹). Hourly doses of ketamine (35 mg kg¹) and xylazine (7 mg kg¹) 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 ± 0.5°C 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 2.0, 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 0.1- to 0.5-µm diam (as judged from interference colors under epi-illumination). Electrodes were filled with 4% biocytin in 1 M potassium acetate and had resistances ranging from 27 to 54 M. 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 kg¹) 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 the avidin-biotin-horseradish peroxidase method as described by Horikawa and Armstrong (1988).

View larger version (11K): [in this window] [in a new window]   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. , points at which the rate of rise of voltage trajectory exceeded 4 mV ms1.

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 s¹. 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 defined 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 membrane-potential 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.

	RESULTS

Abstract Introduction Methods Results Discussion References

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 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.

View larger version (20K): [in this window] [in a new window]   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 () 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 () 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 () between the shortest latency action potential and the longer latency action potentials. A, B, and C: records from different neurons. , cortical stimulus.

Threshold was determined by measuring the membrane-potential 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 < 0.01). In 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. 4A).

Figure 4, B and C, shows that the effect of increasing the 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 <10 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.

View larger version (36K): [in this window] [in a new window]   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.

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 ()

(1)

The resulting parameters of the fitted equation were thus estimates of the average membrane potential in the DOWN (µ₁) or UP state (µ₂) and the amplitude of the noiselike fluctuations in the corresponding state (₁, ₂), whereas the weighting factor () 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 µ₁, µ₂, ₁, ₂, and . The average membrane potential in the UP state (µ₂) was significantly higher in the spontaneously firing neurons than in the silent spiny neurons (P < 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 (µ₁), the amplitude of the noiselike fluctuations in either the UP or DOWN state (₁, ₂), the proportion of time spent in the DOWN state (), 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.

	DISCUSSION

Abstract Introduction Methods Results Discussion References

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 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 membrane-potential 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.

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.

	ACKNOWLEDGEMENTS

  We thank B. Ross for histological work.

  This research was supported by National Institute of Neurological Disorders and Stroke Grant NS-20743.

	FOOTNOTES

  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.

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