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NEUROSCIENCE
Silent plateau potentials, rhythmic bursts, and pacemaker firing: Three patterns of activity that coexist in quadristable subthalamic neurons

Jason I. Kass ^*, , and Isabelle M. Mintz ^*, 

^*Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611; and Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, MA 02118

Edited by Charles F. Stevens, The Salk Institute for Biological Studies, La Jolla, CA, and approved October 27, 2005 (received for review August 5, 2005)

	Abstract

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Subthalamic neurons display uncommon intrinsic behaviors that are likely to contribute to the motor and cognitive functions of the basal ganglia and to many of its disorders. Here, we report silent plateau potentials in these cells. These plateau responses start with a transient burst of action potentials that quickly diminish in amplitude because of spike inactivation and current shunt. The resulting interruption of spiking reveals a stable depolarization (up state) that clamps the cell membrane potential near –40 mV for several seconds. These plateau potentials coexist in single subthalamic neurons with more familiar patterns of burst and pacemaker firing. Within a narrow range of baseline membrane potentials (–67 to –60 mV), depolarization abruptly switches single cells from bistable to rhythmic bursts or tonic firing modes, thus selecting entirely distinct algorithms for integrating cortical and pallidal synaptic inputs.

basal ganglia | bistability | cortex

At rest, subthalamic neurons display a regular pacemaker activity maintained by sustained (7, 8) and resurgent (9) voltage-gated Na currents. However, there is little consensus on their firing patterns when they are hyperpolarized.

Studies in whole-cell or perforated-patch configurations have reported a quasilinear modulation of cell firing by current injection, excitatory postsynaptic potentials (EPSPs), or inhibitory postsynaptic potentials (IPSPs) (8, 10–12), with nonlinearities limited to small rebound bursts after IPSPs (13). Consistent with these findings, the in vivo subthalamic responses to cortical stimulation (14–17), their synchronization to cortical slow oscillations (18), and spike-wave discharges (19) are readily explained by the summating contributions of direct cortical inputs and indirect pathways (18, 20, 21).

Studies in whole-cell or cell-attached configurations have revealed more complex bursts of action potentials or spike-generating plateau potentials that switch to pacemaker firing with membrane depolarization (22–26). These bursts may occur spontaneously (23, 24), generating rhythms strikingly similar to the multisecond-long oscillations reported in subthalamic neurons of locally anesthetized rats (27) and awake monkeys (28).

In this study, we investigated the intrinsic behaviors of subthalamic neurons challenged with a wide range of synaptic and current stimuli, during whole-cell, perforated-patch, or cell-attached recordings. We found an unexpected homogeneity and complexity in their firing patterns. Independent of the recording conditions, subthalamic neurons display the following four self-sustaining regimes: a resting down state, a quiescent plateau depolarization (or silent up state), a rhythmic bursting mode, and a steady tonic firing mode.

	Methods

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Slice Preparation. Parasagittal brain slices (300 µm) were prepared from 11- to 16-day-old Sprague–Dawley rats, which were anesthetized with isofluorane. Slices were cut in ice-cold artificial cerebrospinal fluid solution (125 mM NaCl/2.5 mM KCl/2 mM CaCl₂/1 mM MgCl₂/1.75 mM NaH₂PO₄/25 mM NaHCO₃/25 mM glucose) and oxygenated with 95% O₂/5% CO₂. They were then incubated in the same artificial cerebrospinal fluid solution for 40 min at 34°C and stored at room temperature (20–22°C). Most experiments were performed at 20–22°C. At 35°C, spontaneous synaptic activity triggered frequent, reversible transitions between the down and up states of plateau potentials, compromising their experimental control by evoked EPSPs or IPSPs. Thus, experiments at elevated temperature (performed with a 37–32°C gradient between the inlet and outlet of the recording chamber) were all carried out in the presence of synaptic blockers (n = 13; see Fig. 3D).

Recordings and Data Acquisition. Recordings of subthalamic neurons were carried out in slices that were superfused with artificial cerebrospinal fluid solution (0.5–1.5 ml/min). The cells were visualized with bright-field illumination by using an upright BX50WI microscope (Olympus, Melville, NY) with a x40 immersion objective (0.8 numerical aperture). They were identified as subthalamic neurons by their location, density, and homogeneous morphology and by established electrophysiological criteria (7, 9, 22–26).

Cells were recorded with borosilicate glass pipettes by using an Axoclamp 2B or Axopatch 200B amplifier (Axon Instruments, Union City, CA). Data filtered at 1 or 5 kHz were digitized at 5 or 25 kHz for better sampling of action potentials with a 16-bit digital-to-analog converter (Instrutech, Great Neck, NY) by using PULSE CONTROL software (29) in IGOR PRO (WaveMetrics, Lake Oswego, OR).

Whole-Cell Recordings. The pipette solution contained 122 mM KCH₃SO₃, 4.5 mM MgCl₂, 0.09 mM EGTA, 9 mM Hepes, 14 mM phosphocreatine (Tris salt), 4 mM MgATP, and 0.3 mM GTP (Tris salt) (pH 7.35) with KOH. In a few experiments, MgCl₂ was substituted with NaCl (n = 10) or Tris·GTP with Na₂GTP (n = 13) to increase intracellular Na concentration, KCH₃SO₃ was replaced with KCH₃SO₄ (n = 5) or KCl (n = 5) to verify that these different recording conditions had no effect on plateau potentials (data not shown). The resistance of the electrodes ranged from 3 to 10 M, with no impact on the response properties of the cells.

Perforated-Patch Recordings. Electrodes (3–5 M) were filled with a solution that contained 122 mM KCH₃SO₃, 4.5 mM MgCl₂, 0.09 mM EGTA, 9 mM Hepes, 50 µg/ml gramicidin, and 0.05% Lucifer yellow. The stock solution of gramicidin (50 mg/ml) was prepared fresh each day in DMSO and stored in the dark. As needed, this stock solution was diluted (1:1,000) into the pipette solution and sonicated for 1 min. It was used within the hour or replaced with newly made solution to ensure that the antibiotic was not degraded.

UV illumination (at 425 ± 40 nm) was used to monitor the distribution of Lucifer yellow. Emitted light (490–590 nm) was separated with a dichroic mirror (460 nm) and imaged with a PowerShot G5 camera (Canon, Chesapeake, VA). In all experiments, the dye was restricted to the pipette at the end of the recording session.

Measures of Input Resistance in Perforated-Patch Recordings. Conventional measures of input resistance could not be implemented in subthalamic neurons recorded with perforated patches because they did not maintain stable membrane potentials between –65 and –60 mV. Measurements below –65 mV were stable but contaminated by inward rectifying conductances (8, 22, 24) and were no longer relevant to the behavior of the cell in the subthreshold range for activation of plateau responses. As a practical alternative, we evaluated the minimal bias current required for silencing the cell pacemaker activity, for an arbitrary (10 s) length of time. In both conditions, cells reached a similar membrane potential (i.e., –64.0 ± 2.1 mV) in perforated-patch recordings during a –14.3 ± 5.7-pA bias current injection (n = 17) and –63.4 ± 1.8 mV in whole-cell recordings during a –5.0 ± 2.8-pA bias current injection (n = 25).

Cell-attached recordings were carried out as described by Morikawa et al. (30) by sealing a patch pipette onto a cell (>1 G) and applying negative pressure to invaginate the cell membrane into the recording pipette. Without disrupting the patch, this -shaped configuration yielded electrical access to the cell, as shown by the identical polarity of hyperpolarizing and depolarizing voltage-steps used in this setting and in whole-cell configuration.

The pipette solution contained 150 mM NaCl, 2.5 mM KCl, 2 mM CaCl₂, 1 mM MgCl₂, 10 mM Hepes, and 25 mM glucose (pH 7.4, with NaOH) or, more recently, 122 mM KCH₃SO₃, 4.5 mM MgCl₂, 0.09 mM EGTA, 9 mM Hepes, and 0.05% Lucifer yellow (pH 7.35, with KOH). Cell firing was identical in both conditions.

Evoked EPSPs and IPSPs. EPSPs and IPSPs were elicited with a bipolar electrode positioned on the internal capsule, 600 µm rostral to the subthalamic nucleus. Most experiments were performed with picrotoxin (100 µM), a GABA_A-receptor antagonist, to isolate EPSPs. As described in ref. 25, these EPSPs are likely to arise from the stimulation of cortical descending fibers. In a few experiments (n = 9), cells were recorded with 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 10 µM) and D-2-amino-5-phosphonovalerate (D-APV, 25 µM) to isolate IPSPs, which are likely to engage pallidal inputs (13). In the absence of picrotoxin, CNQX, and D-APV, subthalamic neurons displayed the same silent plateau potentials, burst firing, and pacemaker activity (n = 12).

Data Analysis. Data are expressed as mean ± SD. Statistical significance was determined with the Mann–Whitney U test. Differences were considered significant at P < 0.05.

View larger version (35K): [in this window] [in a new window]   Fig. 1. Subthalamic plateau potentials in whole-cell recordings. (A) Prototypic plateau potentials elicited by a brief depolarization (Left; bias current, –6 pA) or hyperpolarization (Right; bias current, +2 pA). (B1–B3) Plateau potential elicited by pairing a current step and a train of three EPSPs (B3 Right) in a cell that did not show plateau responses to negative (B1) or positive (B2) current steps nor to synaptic stimulation alone (B3 Left).

	Results

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A small number of cells (n = 19) seemed to lack the ability to fire plateau potentials in response to current steps (Fig. 1B). Their firing patterns resemble those reported in whole-cell or perforated-patch settings (8, 13). At rest, they showed robust pacemaker activity. When hyperpolarized, they responded to brief depolarizing current steps (Fig. 1B2) with sustained firing of action potentials that did not outlast the current step. Their rebound responses to transient hyperpolarization were equally modest (Fig. 1B1). However, in these cells, pairing of EPSPs with a brief current pulse elicited robust plateau potentials (Fig. 1B3; n = 6/6). The timing for pairing was critical, with the train of EPSPs being most effective when applied at the end of the current step (data not shown). The plateau potentials evoked by pairing procedures reached the same up state (–41.75 ± 1.4 mV, n = 6) than conventional plateau responses. They showed the same variability in duration (data not shown). They terminated spontaneously (Fig. 1B3 Right) or could be actively switched off by negative current injection.

View larger version (22K): [in this window] [in a new window]   Fig. 2. Silent all-or-none plateau potentials. (A) Responses of a subthalamic neuron to current steps of increasing intensity (10–30 pA; duration, 50 ms; bias current, –12 pA). (B) In another cell, responses to single EPSPs (0.5 ms, 0.5 mA) in control conditions (eight superimposed traces) and after addition of CNQX (10 µM) and D-APV (25 µM; bias current, –8 pA). (C) In another subthalamic neuron, measures of input resistance during the down state () (Inset) by using small (–1 pA) 2-s-long current steps (four averaged traces) and during the up state using larger current steps (+10, +20, and +30 pA; 2-s duration). For this experiment, plateau potentials were triggered repeatedly by a 200-ms, 50-pA current step and terminated with a 300-ms, –30-pA current step (bias current, –9 pA).

All-or-None, Spike-Shunting Plateau Potentials. Plateau potentials in subthalamic neurons are all-or-none regenerative responses. As shown in Fig. 2 A, subthalamic neurons responded to current steps of increasing intensity, with passive depolarizations, slow after-depolarizing potentials (Fig. 2 A, asterisk), and full-blown plateau potentials. Similar all-or-none plateau potentials were evoked by EPSPs (data not shown) after internal capsule fiber stimulation. The transition between subthreshold responses and plateau potential was abrupt. With repeated stimuli (Fig. 2B), plateau responses showed variable duration, but their up-state depolarization was very stable (Fig. 2 B and C). Bath application of CNQX (10 µM) and D-APV (25 µM) abolished the subthreshold EPSPs and plateau potentials evoked by EPSPs (Fig. 2B) yet had no effect on current-evoked plateau responses (n = 4).

The plateau potentials that were evoked by current injection or EPSPs were compared in 28 cells. They averaged –40.8 ± 5.2 mV and –41.2 ± 5.3 mV, respectively. Burst firing at their onset appeared similarly dominated by spike shunting and/or spike inactivation. In 9 cells, the initial burst showed spikes of diminishing amplitude and increasing rise time (Fig. 2 A and C), suggesting significant inactivation of their underlying voltage-gated Na channels. In 19 cells, the burst of action potentials always terminated abruptly, with minimal change in spike amplitude (Fig. 2B). This behavior suggests an active shunt of action potentials during the up state. Consistent with these findings, measurements of input resistance using small current injections (Fig. 2C) revealed a 5.6 ± 1.0 fold increase in membrane conductance during the up state (n = 7). In contrast, the input resistance of cardiac cells increases during plateau potentials due to the reduction of inwardly rectifying pacemaker currents (34).

Plateau Potentials, Oscillations, and Pacemaker Firing in Single Subthalamic Neurons. In most subthalamic neurons (n = 145/174), silent plateau potentials coexisted with the burst responses and pacemaker firing described in refs. 22–26.

In the cell shown in Fig. 3A, transient burst responses (black traces) followed brief depolarizing or hyperpolarizing stimuli. In the same cell, plateau potentials (blue traces) were triggered by slightly larger or longer stimuli. Back-and-forth transitions between bursts and silent plateau potentials occurred throughout the recording session (which typically lasted several hours). At any single time, removal of the bias current restored stable pacemaker firing (Fig. 3 A3 and A4). Identical transitions were observed in single subthalamic neurons recorded at 32–37°C (Fig. 3D; n = 13).

Synaptic stimuli were equally effective in promoting burst firing and plateau potentials in the same cell. EPSPs triggered silent plateau potentials (Fig. 3B Center) or transient bursts of action potentials (Fig. 3B Left) in hyperpolarized neurons. Again, removal of the bias current immediately restored spontaneous firing (Fig. 3B Right). In cells recorded in conditions that isolated IPSPs (see Methods), trains of IPSP evoked rebound burst firing (Fig. 3C Left) or plateau potentials (Right). Note that the membrane potential reached during trains of IPSPs (–71.2 ± 4.0, n = 5) was close to the reversal potential for chloride ions when measured in conditions that do not alter chloride gradients (35).

These three patterns of activity (i.e., plateau potentials, burst responses, and pacemaker firing) were extremely sensitive to baseline membrane potential. Minor changes in bias current transformed subthalamic neurons in bistable plateauing cells, rhythmic oscillators, or pacemakers (Fig. 4). Fig. 4A shows such transitions in a cell challenged by small current steps (40 or 50 pA) applied with different (–13, –9, and –5 pA) bias currents. Similar transitions occurred in cells that were challenged by EPSPs tested with different (–3.5, –1.5, and 0 pA) bias currents (Fig. 4B).

These results present a surprisingly homogeneous picture of subthalamic firing patterns. With the exception of a few neurons, of which the repertoire seems limited to linear responses and plateau potentials (Fig. 1B), subthalamic neurons displayed quadristable behaviors, because they switched between a hyperpolarized down state, a depolarized silent up state, rhythmic bursts, and a tonic firing mode.

View larger version (27K): [in this window] [in a new window]   Fig. 3. Plateau potentials and burst firing. (A) Responses to depolarizing currents (A1–A2) applied with the same (–13.5 pA) bias current for different duration (A1, 40 pA and 200 or 100 ms) or intensity (A2, 90 or 70 pA and 100 ms) and to hyperpolarizing currents applied with the same (+4 pA) bias current for different duration (A3, –20 pA and 1 or 0.8 s) or amplitude (A4, –25 or –15 pA and 1 s). Negative step currents (A1–A2, –50 pA and 200 ms; A3–A4, –120 pA and 60 ms) were used to terminate the plateau responses (see the occasional failure in A4). (B) Responses to EPSPs (500 µs and 0.5 mA) in another subthalamic neuron recorded with bias currents of –12, –10, or 0 pA. (C) Rebound responses to a train of IPSPs (50 µs, 100 µA, and 20 Hz) recorded in another cell with a bias current of –10 or 0 pA. (D) Plateau potentials, burst firing, and pacemaker activity in a subthalamic neuron recorded at 35°C. Current stimuli were adjusted so that depolarizing step currents (100 ms long) reached the same absolute value of +50 pA when the bias current was set at –10, –15, or 0 pA (Left). The 2-s-long hyperpolarizing current steps reached –20 or –30 pA (Right).

View larger version (37K): [in this window] [in a new window]   Fig. 4. Quadristability in subthalamic neurons. The two cells shown here were challenged by positive step currents (100 ms) applied with a –13, –9, or –5 pA bias current (A) or by EPSPs (one or two 0.5-ms-long stimuli applied with a –3.5, –1, or +2 pA bias current) (B).

Silent Plateau Potentials in Cell-Attached Recordings. To further minimize the influence of recording conditions, we tested whether plateau potentials could be detected in cell-attached recordings (performed as described in ref. 30). Most of the subthalamic neurons (n = 23/24) that were recorded in this configuration showed regular pacemaker firing. Only one of them was a bursting cell (23) and was excluded from this study.

In these conditions, hyperpolarization of the patch membrane with voltage-steps effectively suppressed action potential firing (Fig. 6). The rebound responses to the voltage-steps included burst firing (n = 7/7; data not shown) and plateau potentials (gray bars in Fig. 6; n = 4/7), which were identified by their typical signature (see expanded traces Insets). They started with an initial burst of diminishing action potentials (Figs. 1 A and 6, asterisks), continued with a prolonged period of silence and ended with a single, smaller action potential (Figs. 1 A and 6, triangles). The duration of these plateau responses varied with the amplitude and duration of the voltage-steps. Occasionally, these silent plateau responses became part of robust oscillatory patterns (n = 2/7; Fig. 6A2) that matched the rebound oscillations recorded in whole-cell configuration (Fig. 1 A). Such oscillations were not seen in perforated-patch recordings.

These results indicate that silent plateau potentials and rhythmic bursts occurred in subthalamic neurons unperturbed by dialysis and, thus, were unlikely to represent an artifact of whole-cell recordings.

View larger version (38K): [in this window] [in a new window]   Fig. 5. Subthalamic firing patterns in perforated-patch recordings. (A) Prototypic responses to current steps. (A1) The spontaneous spikes sampled for 40 min at the onset of the recording session (A1 Left, 10 s and 20 mV calibration bars) and the Lucifer yellow distribution at the end of the experiment before (A1 Center) and after (A1 Right) rupturing the patch. (A2 and A3) Cell responses to positive (A2 Left) and negative (A2 Right) current steps and to an EPSP (0.5-ms-long stimulus, 100-µA intensity) (A3; bias current of –22.5 pA). (B) In another cell, plateau potentials evoked by single or train of EPSPs (0.5-ms stimuli, 30-ms apart, bias current of –15 pA). (C) Rebound plateau response to a hyperpolarizing current step (–10 pA, 2 s long, bias current of –0.5 pA). (D) Bias currents required to silence subthalamic neurons in perforated-patch (n = 17) or whole-cell (n = 25) recordings (P < 0.001).

	Discussion

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These silent plateau potentials coexist with conventional burst firing, oscillating, and tonic firing modes (8, 9, 22–25, 36, 37) that has already been described in these cells, resulting in one of the most diverse repertoire of intrinsic firing patterns ever documented in a single cell in the absence of gating-modifying neuromodulators. Thalamic neurons (38–42) and cerebellar Purkinje cells (31, 43–46) generate equally complex and varied patterns, but many of these patterns are uncovered by specific neuromodulators (31, 41). In contrast, single subthalamic neurons can function in the four stable states, namely, (i) a hyperpolarized down state, (ii) a depolarized spike-shunting up state, (iii) an oscillatory mode with rhythmic bursts (23, 24), and (iv) a tonic single-spike firing mode (8, 9, 22, 24, 25, 36). By analogy with bistable, tristable (47), and trimodal (45) neurons, we call them quadristable.

View larger version (36K): [in this window] [in a new window]   Fig. 6. Plateau potentials in cell-attached recordings. Traces show the responses to hyperpolarizing voltage-steps [–150 mV for 6 s (A1) or –100 mV for 3 s (A2)]. In A1, the distribution of Lucifer yellow is shown before (a) and after (b) rupturing the patch at the end of the recording session. (Insets) Gray bars indicate the plateau responses, the asterisk indicates the initial burst of action potentials, the filled triangle indicates the action potential at the end of the plateau response, and the open triangle indicates the action potentials triggered by low-threshold Ca spikes.

In vivo recordings of single subthalamic neurons often reproduce the patterns of tonic firing, rebound bursts, and slow oscillations (18, 19, 52–54) described in vitro as intrinsic to these cells, suggesting that these intrinsic properties might contribute to the shaping of subthalamic neurons output as well as to incoming synaptic inputs.

When plateau potentials are "silent," their contribution to extracellular single-unit recordings are less obvious. However, their stereotypic signature might signal their participation to in vivo activity patterns (in particular, to the subthalamic response to cortical activation).

In vivo, subthalamic neurons typically respond to cortex stimulation with a stereotypic sequence of early excitation, short-latency inhibition, late-latency excitation, followed by a lasting late-latency inhibition (16, 17). Early excitation reflects monosynaptic excitation by cortical afferents (16, 55), short-latency inhibition involves the subthalamo-pallido-subthalamic loop (14, 56–60), and late-latency excitation results from the delayed disinhibition supplied by indirect corticostriatopallidal inputs to subthalamic neurons (21, 61, 62).

Although the contribution of these pathways is well established, the most stereotypic features of late-latency excitation and late-latency inhibition (20, 54) also suggest a role for intrinsic plateau potentials recruited as a rebound response to short-latency IPSPs. The abrupt onset, precise duration, and abrupt termination of late-latency excitation match the stereotypic burst of spikes seen at the onset of silent plateau potentials. The subsequent long-lasting inhibition suggests a silent up state. In this scenario, disinhibition by the indirect pathway remains critical because it is timed perfectly to increase the cells input resistance after the short-latency IPSPs, turning their rebound response from a modest burst [as seen after genetic (19, 63) or pharmacological (62) impairment of the indirect pathway] into a full-blown silent plateau potential.

	Acknowledgements

 
We thank Drs. Steven H. DeVries, Marco Martina, Gianmaria Maccaferri, and Gary Blasdel for editorial comments and Drs. Nelson Spruston, Bruce P. Bean, and D. James Surmeier for helpful suggestions. This work was supported by National Institutes of Health Grant R0136795 and a Student Interest Group in Neurology Medical Student Summer Research Scholarship from the American Academy of Neurology (to J.I.K.).

	Footnotes

 
Author contributions: J.I.K. and I.M.M. designed research; J.I.K. performed research; and J.I.K. and I.M.M. analyzed data and wrote the paper.

Conflict of interest statement: No conflicts declared.

This paper was submitted directly (Track II) to the PNAS office.

Abbreviations: EPSP, excitatory postsynaptic potential; IPSP, inhibitory postsynaptic potential; CNQX, 6-cyano-7-nitroquinoxaline-2,3-dione; D-APV, D-2-amino-5-phosphonovalerate.

To whom correspondence should be addressed. E-mail: i-mintz{at}northwestern.edu.

© 2006 by The National Academy of Sciences of the USA

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