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1Division of Fundamental Neurobiology, Toronto Western Research Institute, Toronto Western Hospital, University Health Network; and 2Department of Medicine (Neurology) and Physiology, University of Toronto, Toronto, Ontario, Canada
Submitted 25 September 2007; accepted in final form 25 February 2008
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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), pain (Franzini et al. 2003), depression (Mayberg et al. 2005), tremors (Benabid et al. 1987), dystonia (Kumar et al. 1999), Parkinson's disease (see reviews by Breit et al. 2004; Perlmutter and Mink 2006), obsessive-compulsive disorder (Abelson et al. 2005; Gabriels et al. 2003), and epilepsy (Zumsteg et al. 2006; review by Theodore 2005) are now being treated with HFS, yet its underlying mechanisms of action remain unclear. Some researchers believe that HFS inhibits the targeted area via HFS-induced depletion of neurotransmitters (Rav-Acha et al. 2005; Urbano et al. 2002), whereas others believe that HFS causes a depolarization block (Benazzouz et al. 1996; Beurrier et al. 2001; Bikson et al. 2001). Another mechanism underlying HFS is the repatterning of signals into, and out of, the targeted nuclei (Brown et al. 2004; Garcia et al. 2003). Others suggest HFS-induced release of inhibitory neurotransmitters (Dostrovsky et al. 2000). Finally, some researchers believe that HFS inhibits the soma while exciting the efferent axons (McIntyre and Grill 1999, 2002).
HFS-induced increases in Ke+ have been reported extensively in excitable tissue (Gardner-Medwin 1983; Lian et al. 2003; Poolos et al. 1987; Shin et al. 2007; reviews by Somjen 1979, 2002) and the direct effect of raised Ke+ is thought to be via a depolarizing effect, represented by the Goldman–Hodgkins–Katz (GHK) equation, since the resting membrane potential is influenced primarily by the K+ concentration gradient. We recently found that HFS increased Ke+ in the entopeduncular nucleus (EP), a commonly targeted area of HFS for Parkinson's disease (Shin et al. 2007). HFS or raised Ke+ (6 mM) caused a depression in EP neuronal activity by an unidentified ionic conductance that depolarized EP neurons. A depolarization block did not fully account for these effects and this phenomenon was not synaptically mediated by 
-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), 
-aminobutyric acid type A (GABAA), or N-methyl-D-aspartate (NMDA) receptors (Shin et al. 2007). These effects could be mediated by mechanisms concomitant with, but not exclusive to, the GHK effect since the application of Ke+ from 2.5 to 6 mM depolarized the resting membrane potential to values exceeding the predicted value.
A possible candidate that could underlie the HFS or elevated K+-mediated depression of EP neuronal activity is the hyperpolarization-activated nonspecific cationic channel (Ih). It was previously reported that type 1 EP neurons possess a strong anomalous rectification at hyperpolarizing potentials, suggesting the presence of Ih channels (Nakanishi et al. 1990; Ogura and Kita 2002). These channels were first reported in sinoatrial node cells of the heart as the "funny" current (Brown et al. 1977; DiFrancesco 1981) and later identified in hippocampal pyramidal cells (Halliwell and Adams 1982). These channels are thought to mediate the intrinsic oscillatory-rhythmic activity observed in many neuronal cell types such as the hippocampal CA1 interneurons (Maccaferri and McBain 1996), thalamic relay neurons (Luthi and McCormick 1998b; Pape 1996), and neurons of the hypoglossus nucleus and pre-Bötzinger complex in the medulla (Thoby-Brisson et al. 2000). Funahashi and colleagues (2003) showed in area postrema neurons that increasing Ke+ increased the conductance of the Ih channel and altered the half-activation and the reversal potential of the channel toward more depolarized values. It seems plausible that the previously reported depolarization and depression of EP neuronal activity, from HFS or raised Ke+, may involve enhancement of the Ih channel.
The aim of this in vitro study was to determine whether Ih channels underlie the mechanism of HFS or elevated K+-induced depression of EP neuronal activity. Here we show that Ih channel inhibition prevented the HFS or elevated K+-mediated depression of EP neuronal activity. In addition, the application of 6 mM K+ enhanced Ih channel current activity. Therefore it appears that the enhancement of Ih channel activity does play a role in the HFS and raised K+-mediated depolarization and depression of EP neuronal activity. These results may explain how HFS in output basal ganglia nuclei attenuates or inhibits neuronal activity in patients undergoing deep brain stimulation.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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The basic procedures were described by Shin et al. (2007). Experiments were conducted on male Sprague–Dawley rats (P14–P21) in compliance with the University Health Network Animal Care Committee. Rats were deeply anesthetized with halothane and decapitated; the brain was quickly removed and transferred to ice-cold dissecting solution containing (in mM): 207 sucrose, 2.5 KCl, 2 MgCl2, 26 NaHCO3, 1.2 NaH2PO4, 1 CaCl2, and 10 D-glucose, pH adjusted to 7.4 with 95% O2-5% CO2 (carbogen). The brain was secured into a vibratome 1000 series (Warner Instruments, Hamden, CT) and 300-µm coronal slices, containing the EP, were obtained. Afterward, slices were left in an incubation chamber for 1 h at room temperature to allow for tissue stabilization before recording. The incubation solution was artificial cerebral spinal fluid (aCSF) containing (in mM): 125 NaCl, 2.5 KCl, 25 D-glucose, 25 NaHCO3, 1.25 NaH2PO4, 1 MgCl2, and 2 CaCl2 and was continually aerated with 95% O2-5% CO2.
Experimental protocol
The slice was placed in a RC-26 open bath recording chamber (Warner Instruments) and perfused with aCSF at 2–3 ml/min, aerated, and pH balanced with 95% O2-5% CO2 at 31.5°C. Neurons were visualized with an Olympus BX51WI upright microscope (Olympus Optical, New York, NY) equipped with a x40 water-immersion lens with differential interference contrast optics with infrared. The EP was recognizable within the internal capsule and recorded neurons were identified as type 1 by electrophysiological properties such as an anomalous rectification at hyperpolarizing potentials, strong rebound activation at the offset of membrane hyperpolarization, and the capacity for producing high, nonadapting repetitive firing (Nakanishi et al. 1990); type 2 and other neurons were rarely recorded and were not included in this study.
Whole cell patch-clamp recordings were performed with electrodes made from borosilicate glass (World Precision Instruments, Sarasota, FL) pulled to a resistance of 5–8 M
using a PP-830 vertical puller (Narishige, East Meadow, NY). The intracellular solution in the recording pipette contained the following (in mM): 8 NaCl, 20 KCl, 110 K-gluconate, 0.0001 CaCl2, 1 MgCl2, 10 Na-HEPES, 0.3 Na-GTP, and 2 Na-ATP, pH balanced to 7.4.
Constant 0.005-nA current steps, 850 ms in duration, were injected to obtain a current–voltage (I–V) curve to measure input resistance, the number of induced action potentials (APs), AP amplitude, and threshold. The slope of the I–V plot represented the input resistance. AP threshold was calculated as the membrane voltage potential at which point the slope of the first action potential was >10 V/s. Since EP neurons display tonically firing activity, the resting membrane potential was defined as the membrane potential halfway between the most repolarized potential after an AP and the threshold potential. AP amplitude was measured from the AP threshold to the AP peak. For experiments involving Ke+ treatment, 5 min of control aCSF (2.5 mM K+) perfusion was followed by 5 min of aCSF perfusion containing 6 mM K+. To quantify spontaneous AP activity, spontaneous neuronal activity was recorded in the I = 0 mode and the total number of APs was detected using the threshold discriminator available in Clampfit 9.2 (Axon Instruments, Foster City, CA) before, during, and after treatment. The cumulative average 5 min before treatment was obtained and compared statistically with the cumulative average of spontaneous AP activity 5 min after treatment. Spontaneous AP activity was quantified in this fashion in most experiments, unless stated otherwise.
For experiments involving inhibitors of the Ih channel, 50 µM 4-(N-ethyl-N-phenylamino-1,2-dimethyl-6-methylamino)pyrimidinium chloride (ZD7288) or 2 mM CsCl was bath perfused onto EP neurons for 3 min prior to 10 s of HFS or 5-min application of 6 mM K+. These blockers are commonly used to inhibit Ih channel activity (Aponte et al. 2006; Bayliss et al. 1994; Funahashi et al. 2003; Harris and Constanti 1995). To determine the role of calcium in the raised K+-mediated depression of EP neuronal activity observed in washout, slices were perfused for 5 min with 0 Ca2+ aCSF prior to and throughout bath perfusion of 6 mM K+. In another set of experiments, slices were bath perfused with 50 µM NiCl2 for 5 min, to block the activity of T-type Ca2+ channels (Bean 1989; Fox et al. 1987; Wang et al. 1997) prior to and throughout the bath perfusion of 6 mM K+. For experiments concerning the inhibition of the persistence Na+ channel, 25 nM tetrodotoxin (TTX) was bath perfused for 5 min prior to the bath application of 6 mM K+. In all cases, slices were reperfused for 5–20 min with aCSF for recovery and washout.
All recordings were obtained using a Digidata 1322A interface connected to a 200B Axopatch amplifier (Axon Instruments), filtered at 5 kHz, digitized at 10 kHz on-line with clampex 9.0, and analyzed off-line using Clampfit 9.2 (Axon Instruments). The liquid junction potential was calculated as 6.2 mV, using the Clampex 9.2 liquid junction potential calculator (Axon Instruments) with the Donnan equilibrium in mind (Zhang and Krnjevic 1993), and was not corrected for in this study. The addition of aCSF, containing 6 mM K+, changed the liquid junction potential correction by only 0.1 mV and was not predicted to significantly alter EP neuronal parameters.
To measure whole cell Ih currents, slices were bath perfused for 5 min in Ih "isolation solution" used by Funahashi et al. (2003) containing (in mM): 104 NaCl, 20 tetraethylammonium, 2.5 KCl, 1 BaCl2, 1 MgCl2, 26 NaHCO3, 2 4-aminopyridine, 0.001 TTX, 25 D-glucose, and 1 CoCl2, prior to and during voltage-clamp experiments. EP neurons were initially voltage-clamped to –60 mV and then stepped down to –140 mV for 1 s in 10-mV increments. A 1-s step duration of the voltage-clamp was required to allow for stable current values since these channels have slow activating and deactivating kinetics (Aponte et al. 2006; Funahashi et al. 2003; Harris and Constanti 1995). The Ih current was measured from the instantaneous current (current value 5–10 ms after the inward capacitative transient; Funahashi et al. 2002) to the steady-state constant current (value at the end of the current trace prior to release of the voltage-clamp).
To measure the reversal potential (Erev) of the Ih channel during aCSF and 6 mM K+ treatment, the extrapolation procedure was used (Bayliss et al. 1994; Mayer and Westbrook 1983; Spain et al. 1987; Takahashi 1990). Once whole cell configuration was obtained, EP neurons were voltage-clamped from –60 to –140 mV in 10-mV increments. The instantaneous current immediately following the capacitative transient was measured. Afterward, EP neurons were voltage-clamped from –100 to –60 mV in 10-mV increments. Again, the instantaneous currents were obtained and plotted against values obtained from the previous voltage-clamp paradigm. A linear fit for both plots was produced and extrapolated. The point of intersection was denoted as the Erev. All recordings were obtained using a Digidata 1322A interface connected to a 200B Axopatch amplifier (Axon Instruments), filtered at 5 kHz, digitized at 10 kHz on-line with Clampex 9.0, and analyzed off-line using Clampfit 9.2 (Axon Instruments).
HFS in white matter surrounding the EP was induced using a Grass S44 stimulator (Grass Instruments, Rockland, MA) coupled to an A-M Systems isolated pulse stimulator (model 2100) and applied through a biconcentric bipolar platinum/iridium electrode (125-µm OD, 50-µm ID; FHC, Bowdoin, ME). The monophasic constant-current stimulation parameters were set to 150 Hz, 100–300 µA, 60-µs pulse width, and 10 s in stimulus duration. The rationale for these parameters is described in Shin et al. (2007).
Chemicals
ZD7288 was purchased from Tocris Bioscience (Ellisville, MO) and TTX was obtained from Alamone Labs (Jerusalem, Israel), whereas all other chemicals were purchased from Sigma Chemical (Burlington, ON, Canada).
Statistical analysis
Whole cell data were analyzed using a one-way repeated-measures (RM) ANOVA with a Student–Newman–Keuls post hoc analysis, unless stated otherwise. For analysis, normalized data were converted to a normal distribution using a root arcsine conversion. Significance was determined from aCSF values at P < 0.05. Each sample size (n) equated to a single recorded neuron from one slice. In each experiment slices were obtained from at least five different rats. All data are expressed as means ± SE.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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Electrophysiological properties of recorded neurons in aCSF (n = 109) resembled those reported in other studies (Nakanishi et al. 1990; Ogura and Kita 2002) such as a spontaneous AP frequency of 4.9 ± 0.5 Hz with a resting membrane potential of –52.7 ± 0.8 mV. When 850-ms current steps were injected into the recorded neuron, the previously reported anomalous rectification at hyperpolarizing potentials and a strong rebound activation at the offset of membrane hyperpolarization were usually observed (Fig. 1 A). The input resistance was 396.6 ± 14.5 M, AP threshold was –44.5 ± 1.2 mV, and the peak AP amplitude was 94.6 ± 1.7 mV. The maximum number of APs produced with an 850-ms depolarizing current step was nonaccommodating with 21.3 ± 1.0 observable APs (
25 Hz). Whole cell recordings and I–V were monitored in aCSF for 20 min, every 5 min, to confirm recording and neuronal stability during and after which no significant changes were observed in input resistance, resting membrane potential, induced AP activity, AP threshold, and spontaneous AP activity (n = 20; data not shown).
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HFS of the white matter, beside the EP, or perfusion of aCSF containing 6 mM K+ onto EP neurons was performed in separate experiments to confirm the previously reported depression of EP neuronal activity (Shin et al. 2007). EP neuronal spontaneous spiking activity was monitored 5 min before, during, and 5 min after HFS, with the stimulating and whole cell patch-clamp electrode <150 µm away from each other. During 10 s of HFS, EP neuronal spontaneous spiking activity (6.3 ± 1.7 Hz) did not significantly change from pre-HFS values of 6.2 ± 1.5 Hz (n = 7; Fig. 1B). Five minutes following HFS, EP neurons were significantly depolarized by 12.6 ± 2.3 mV and spontaneous spiking activity decreased by 42 ± 6% (Figs. 1, A and B and 3), requiring 1.4 ± 1.1 s for observable decreases in spontaneous spiking activity and 22.8 ± 2.6 s to reach maximal inhibition (n = 7). Five minutes after HFS, 850-ms +ve current steps showed a 25 ± 6% decrease in input resistance, a 28 ± 9% decrease in AP amplitude, a 6.4 ± 1.6 mV increase in AP threshold, and a 49 ± 10% decrease in induced AP activity (n = 7) [Figs. 1A and 3; all changes were significant (RM-ANOVA; P < 0.05)]. Ten minutes after HFS, input resistance was still 70 ± 20% of pre-HFS values and the resting membrane potential was depolarized by 16 ± 4.7 mV from pre-HFS values, whereas spontaneous spiking was abolished.
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) and are not due to HFS or raised K+-mediated cell injury for reasons and evidence previously described (Shin et al. 2007). Ih channel inhibitors, ZD7288 (50 µM) or CsCl (2 mM), prevented the HFS-mediated decrease in EP neuronal activity
Slices were perfused with aCSF for 5 min followed by 3 min of 50 µM ZD7288 prior to and 5 min post-HFS. In our study, 3 min of ZD7288 bath perfusion was sufficient to affect Ih channel activity since the normally tonically spiking activity of EP neurons showed periods of interruption 3 min into ZD7288 application (Fig. 2 B), resulting in a 69 ± 17% decrease in spontaneous spiking activity; accompanied by a hyperpolarization of 3.3 ± 2.1 mV in the resting membrane potential, a 26 ± 8% increase in input resistance, and the attenuation of the Ih "sag." When HFS was applied to the white matter surrounding the EP, in the presence of ZD7288, the previously observed depression of EP neuronal activity was not seen. Although the induced AP frequency did not significantly change 5 min after HFS, EP neurons were significantly depolarized by 4.5 ± 1.6 mV, although less than without Ih blockade; input resistance increased 26 ± 8% (rather than decreased); and the total number of spontaneous APs significantly increased (67.0 ± 7.4%, n = 9), instead of decreasing (Figs. 2, A and B and 3A). In Fig. 2B HFS was repeatedly applied to EP neurons and the previously observed prolonged depression in spontaneous spike activity, in Fig. 1, was not observed.
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). In the next experiment we applied a mixture of synaptic blockers along with ZD7288 to observe whether a decrease in neuronal activity was present from HFS. A combination of blockers containing CAGZ [10 µM 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), 60 µM 2-amino-5-phosphonovaleric acid (APV), 10 µM gabazine, 50 µM ZD7288] was applied to EP neurons for 5 min prior to, throughout, and 5 min after HFS. Consistent with the previous experiment, EP neuronal activity was not depressed after HFS in the presence of CAGZ. In contrast, input resistance increased by 22 ± 6% and the resting membrane potential was depolarized by 4.1 ± 2 mV (n = 5) (Figs. 2C and 3, A and B). In addition, spontaneous spiking activity significantly increased 20 ± 15% after HFS with CAGZ treatment (Figs. 2D and 3A). To further corroborate the involvement of the Ih channel in the HFS-mediated depression of activity, another Ih channel inhibitor, 2 mM CsCl, was bath perfused onto EP neurons for 5 min prior to, throughout, and 5 min after HFS. During CsCl application, cells significantly hyperpolarized by 2.3 ± 1.4 mV, input resistance increased by 33 ± 2%, induced AP activity decreased by 23 ± 7%, and spontaneous spiking activity significantly decreased by 77 ± 17% (n = 5) (Figs. 4 and 5). Five minutes after HFS in the presence of CsCl, cells depolarized 4.1 ± 2.0 mV from pretreatment values, input resistance increased 30 ± 3%, induced AP activity increased by 21 ± 8%, and spontaneous spiking activity increased by 41 ± 35% from aCSF values (Figs. 4 and 5).
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Cells were perfused with ZD7288 for 3 min prior to a 5-min treatment of raised K+. The application of ZD7288 significantly increased input resistance by 21 ± 6%, hyperpolarized the resting membrane potential by 3.5 ± 1.2 mV, and decreased the spontaneous spiking activity by 34 ± 8%. No significant change was seen in the induced AP activity throughout the ZD7288 treatment. Afterward, 6 mM K+ was bath perfused onto EP neurons (n = 7) (Fig. 6). Five minutes after 6 mM Ke+ bath application, in the presence of ZD7288, cells depolarized 4.4 ± 2.1 mV compared with values seen in aCSF. The input resistance significantly increased 21 ± 11% and both induced and spontaneous spiking activity significantly increased 51 ± 33 and 146 ± 50%, respectively (n = 7) (Fig. 6).
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EP neurons were voltage-clamped from –60 to –140 mV in 10-mV increments for 1-s durations in Ih "isolation solution" aCSF (see METHODS) to obtain voltage–current responses in aCSF, 5 min of 6 mM K+, 5 min of 6 mM K+, and 2 mM CsCl, followed by a 15-min washout period of aCSF. CsCl was used in this experiment, whereas ZD7288, which has long-lasting effects (Gasparini and DiFrancesco 1997), was not used because we wanted to observe and measure Ih currents in washout. Figure 8 B shows voltage-clamp data of EP neurons clamped from –60 to –140 mV (n = 9). The Ih current was prominent at –140 mV and was significantly enhanced by 70 ± 7.2% at –140 mV in the presence of 6 mM K+. The Ih current was abolished with 2 mM CsCl perfusion and returned to aCSF values after 15-min washout. Figure 8C shows the Erev of one EP neuron. In this case, the reversal potential of the Ih channel depolarized from –27 to –18 mV. The group data showed that 6 mM K+ treatment significantly depolarized the Erev of EP Ih channel current by 19.6 ± 5.8 mV from –40 ± 6.7 to –20.3 ± 5.8 mV (n = 6).
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It is plausible that the marked depolarization of EP neurons observed after HFS or raised K+ application could activate voltage-gated Ca2+ channels and subsequent second-messenger cascades. This phenomenon could underlie the prolonged depression of EP neurons seen in washout. To validate this scenario EP neurons were bath perfused with 0 Ca2+ aCSF for 5 min prior to 6 mM K+ exposure. The perfusion of 0 Ca2+ aCSF abolished the Ih sag and significantly decreased spontaneous AP frequency by 44 ± 13% (Fig. 9, A and B). Other neuronal parameters did not significantly change, although a trend toward slightly more hyperpolarized membrane potentials (–1.34 ± 0.61 mV) were observed (n = 10; Fig. 9). The bath perfusion of 6 mM K+, concomitant with 0 Ca2+, resulted in a significant decrease of 23 ± 7% in input resistance and a 6.1 ± 2.0- mV depolarization in the resting membrane potential (Fig. 9, C and D). Spontaneous AP activity increased by 120 ± 71% (n = 10; Fig. 9, A, C, and D), whereas induced AP activity significantly decreased by 53 ± 14%. Afterward, EP neurons were reperfused with aCSF, which resulted in a rapid and complete return of all measured parameters, as well as the Ih sag, to pretreatment values (n = 10).
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Since our previous experiment showed that Ca2+ channel activity is involved in the 6 mM K+-induced depression of EP neuronal activity, we investigated whether the low-threshold T-type Ca2+ channel could underlie this effect. Therefore EP neurons were bath perfused for 5 min with 50 µM NiCl2 to block the activity of these channels. This treatment did not significantly change any EP neuronal parameters after 5 min (n = 9). Then, EP neurons were concomitantly bath perfused with NiCl2 and 6 mM K+. The addition of 6 mM K+ and 50 µM NiCl2 resulted in the previously observed depression of EP neuronal activity with raised K+ or HFS (Fig. 10); input resistance significantly decreased by 12 ± 6%, the resting membrane potential depolarized by 8.5 ± 2.6 mV, the AP threshold depolarized by 3.8 ± 2.53 mV (Fig. 10D), and induced (Fig. 10, A and C) and spontaneous (Fig. 10, B and C) AP activity decreased 53 ± 12 and 65 ± 15%, respectively (n = 9). Furthermore, this depression was observed after 20 min of washout characterized by a 17 ± 6% decrease in input resistance and a 69 ± 12 and 61 ± 18% decrease in induced and spontaneous AP activity, respectively (Fig. 10, B and C). However, after 20 min of washout the resting membrane potential returned to pretreatment values (Fig. 10D) (n = 9).
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To exclude the possibility that the persistent Na+ channel could mediate the previously described depression in EP neuronal activity, 25 nM TTX, a concentration used for the inhibition of the persistent Na+ channel (Pace et al. 2007; 20 nM used), was bath applied for 5 min prior to a 5-min bath application of 6 mM K+ (with TTX). After 5 min of TTX application, the resting membrane potential hyperpolarized 2.3 ± 0.9 mV, the input resistance significantly increased by 26 ± 16%, induced AP activity decreased by 18 ± 7%, and spontaneous AP activity did not change (n = 10; Fig. 11). When 6 mM K+ was applied, concomitantly with TTX, input resistance significantly decreased by 20 ± 8%, whereas induced and spontaneous AP activity decreased by 79 ± 7 and 71 ± 14%, respectively (Fig. 11C). In addition, the resting membrane potential depolarized by 5.6 ± 1.2 mV compared with pre-TTX values (n = 10; Fig. 11D). These effects were consistent with those observed with 6 mM K+ bath application alone (Fig. 1, C and D).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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who emphasized the importance for elucidating the mechanism(s) underlying deep brain stimulation.
In a previous study (Shin et al. 2007) we studied the underlying mechanism of HFS in the rat EP, the rat homologue of the human globus pallidus interna—a commonly targeted area for the treatment of Parkinson's disease (Kumar et al. 2000; Siegfreid and Lippitz 1994) and dystonia (Kumar et al. 1999). In that study, we demonstrated that HFS, in the white matter surrounding the EP, increased [K+]e to 9.6 ± 1.4 mM and depressed induced and spontaneous EP neuronal activity by 49 ± 10 and 60 ± 10%, respectively. In addition, an 11.1 ± 2.5-mV depolarization in the resting membrane potential and a 25 ± 6% decrease in input resistance were reported; a depolarization block did not fully account for these effects. Furthermore, this depression in neuronal activity was not AMPA-, NMDA-, or GABAA-receptor mediated. The perfusion of raised Ke+ from 2.5 to 6 or 10 mM mimicked these effects. In addition, HFS increased [K+]e in a similar fashion consistent with HFS-mediated increases in [K+]e in the cortex, hippocampus, and medulla (see reviews by Kofuji and Newman 2004; Somjen 2002; Walz and Hertz 1983). From these data, we postulated a novel mechanism underlying the inhibitory actions of HFS, but did not identify the underlying ionic conductance mediating these effects.
In this study, we used HFS and raised Ke+ to reestablish and reproduce the depression in EP neuronal activity. Interestingly, although the decrease in induced AP amplitude was the same from HFS and elevated Ke+ (28 ± 9 vs. 30 ± 4%, respectively; unpaired two-tailed Student's t-test) at the end of the 5-min recording period, a decline in spontaneous AP amplitude was observed only after HFS, and not during elevated K+ treatment, as AP frequency declined. This phenomenon may be associated with the mechanism underlying the Ke+ elevation. HFS has been shown to increase [K+]e to 17.9 mM in the basal ganglia within seconds after stimulation (Shin et al. 2007), yet 6 mM K+ is continuously bath perfused onto EP neurons at 2–3 ml/min. Since HFS-induced Ke+ elevation occurs faster than bath perfusion of elevated Ke+, this difference may underlie the difference in spontaneous AP amplitudes, since the faster elevation in Ke+ will result in faster depolarization (from an increase in ionic conductance, a GHK-related phenomenon, or both) and a diminished electrochemical gradient. In fact, HFS-induced depolarization occurred within tens of seconds, whereas bath-perfused K+ depolarized EP neurons within minutes. It is plausible that the faster and larger [K+]e could elicit the shortened AP amplitude. In our previous study (Shin et al. 2007), as AP frequency decreased, spontaneous AP amplitude after HFS did not differ from that seen after 6 mM K+ treatment (unpaired two-tailed Student's t-test). When we compared maximum inhibition from HFS in both studies, 22.8 ± 2.6 s was required for maximum inhibition in this study, whereas 48 ± 13.3 s was needed in the previous study. This coincided with closer proximity of the stimulating and recording electrodes in this study (<100 µm apart). A major assumption in this interpretation is that faster inhibition of EP neuronal activity results from faster and larger Ke+ elevation. The literature supports this assumption since others have reported an inverse relationship between the speed of onset and the amount of Ke+ accumulation with distance: as distance from the source of K+ accumulation (from stimulation or neuronal activity) decreases, faster and larger [K+]e are observed (Kryjevic et al. 1982; Wallraff et al. 2006; Yaari et al. 1986), presumably since larger distances enable larger passive and active glial and neuronal processes to act as K+ sinks (D'Ambrosio et al. 2001; Leis et al. 2005).
In this study we examined whether the hyperpolarization-activated nonspecific cationic current (HCN or Ih) could mediate the inhibitory effects of HFS or raised K+ application. These channels are sensitive to Ke+ levels; raised Ke+ increased Ih conductance and current in neurons from the cat sensorimotor cortex (Spain et al. 1987) and in area postrema neurons (Funahashi et al. 2003), and up-regulated HCN subunits in hippocampal neurons (Fan et al. 2005). These channels are expressed in basal ganglia neurons (Deng et al. 2007; Harris and Constanti 1995; Hashimoto and Kita 2006; Nakanishi et al. 1990) and play an important role in neuronal oscillations. They remain active after HFS of the subthalamic nucleus (STN), in contrast to persistent Na+ and Ca2+ channels (Beurrier et al. 2001), indicating their probable role in the effects of HFS and resultant K+ effects in output basal ganglia neurons. Finally, since the K+-induced depolarization of EP neurons is close to the reversal potential of the Ih channel of –25 to –40 mV (see review by Robinson and Siegelbaum 2003), it is plausible that the Ih channel underlies the driving force for this depolarization.
Herein we report that 2 mM CsCl or 50 µM ZD7288 prevented the previously observed depression of EP neuronal activity by HFS or raised Ke+ treatment (Shin et al. 2007). ZD7288 or CsCl, alone resulted in the abolishment of the Ih sag, a slight but significant hyperpolarization of the resting membrane potential, and an increase in input resistance. These effects are consistent with those observed in the literature. In particular, the application of 2 mM CsCl hyperpolarized area postema neurons by 5 mV (Funahashi et al. 2003) and the application of ZD7288 hyperpolarized CA1 hippocampal pyramidal neurons by 4 mV (Gasparini and DiFrancesco 1997) and almost 6 mV in fast-spiking hippocampal interneurons (Aponte et al. 2006). When 5 µM ZD7288 was applied to cholinergic interneurons in the striatum, the resting membrane potential hyperpolarized 6 mV (Deng et al. 2007). Gasparini and DiFrancesco (1997) also reported an 18% increase in input resistance that was consistent with changes observed in our study. Interestingly, ZD7288 did not affect the resting membrane potential in substantia nigra compacta neurons (Harris and Constanti 1995).
Another effect of Ih channel block is the interruption of spontaneous spiking activity, which is a result of the inhibition of the "pace-making" properties of Ih channel function. We report that Ih channel blockade resulted in a 51.5 ± 12.5 or 80 ± 13.5% decrease in spontaneous AP activity during ZD7288 or CsCl treatment, respectively (averaged from HFS and 6 mM K+ experiments). Funahashi et al. (2003) found that 100 µM ZD7288 decreased spontaneous AP activity by 54.6 ± 5.8% in area postema neurons and Deng et al. (2007) found that 30 µM ZD7288 decreased spiking activity from 3.2 to 0.5 Hz in striatal interneurons, leading to eventual quiescence after 20 min of Ih channel blockade.
We found that the reversal potential of the Ih channel in EP type 1 neurons was in the range of –27 to –50 mV (Schlicter et al. 1991; Spain et al. 1987). In particular, Gasparini and DiFrancesco (1997) found that the Erev for Ih channels in area postema neurons was –35.9 mV and McCormick and Pape (1990) reported an Erev of –43 ± 9 mV in thalamic relay neurons, whereas Mayer and Westbrook (1983) found an Erev of –34 mV (from –8 to –42 mV) in spinal sensory ganglion neurons. The calculated Erev of Ih channels in EP neurons was –40 ± 6.7 mV and is in good agreement with these published values. Furthermore, this Erev suggests that EP neuronal Ih channels are permeable to Na+ and K+, as shown before (Funahashi et al. 2003; Halliwell and Adams 1982; Harris and Constanti 1995).
When 6 mM K+ was bath perfused onto EP neurons, whole cell Ih channel current amplitude was enhanced by 70 ± 7.2% at –140 mV and the Erev shifted almost +20 mV from –40 to –20 mV. From these data, we conclude that raised K+ enhances Ih channel activity, thereby causing a depolarization of EP neuronal resting membrane potential and subsequent depression of their activity. Funahashi and colleagues (2003) reported a positive (depolarizing) shift of 12 ± 2.5 mV in the reversal potential of area postrema neurons in the presence of 20 mM Ke+. McCormick and Pape (1990) reported that changing [K+]e from 2.5 to 7.5 mM resulted in an inward current, an increase in membrane conductance, and an enhancement of Ih from 1.5 to 4 nA at –85 mV. The increase in Ih is thought to be either from elevated K+-mediated increase in the Na+ conductance of Ih (Hestrin 1987) or due to multiple ion binding sites for K+ and Na+ with differential affinity for these ions (DiFrancecso 1982; Wollmuth 1995).
Although ZD7288 and CsCl reduced spontaneous AP activity, the bath perfusion of 6 mM K+ or HFS throughout Ih channel blockade caused an increase in spontaneous AP activity. The likely reason for this phenomenon is that the blockade of Ih channel function allowed the raised [K+]e (from HFS or bath perfusion) to depolarize the resting membrane of EP neurons, as predicted from the GHK equation. Our results support this since the amount of depolarization from HFS and raised K+, in the presence of Ih channel blockade, was 3.4 mV (combined from HFS and 6 mM K+ experiments), consistent with the GHK-predicted value of elevating K+ aCSF from 2.5 to 6 mM. This depolarization alone, without a significant change in input resistance from Ih channel blockade, results in a closer proximity to AP firing threshold, which explains the increased spontaneous spiking activity of EP neurons.
Although our data demonstrate that raised [K+]e enhanced Ih and the blockade of Ih prevented the HFS or raised Ke+-mediated depolarization and depression of EP neuronal activity, the fact that Ih currents returned to baseline values with washout is not consistent with the prolonged attenuation and depolarization observed from HFS or raised K+. This suggests that the activation of Ih initiates the depression, but is not the mechanism sustaining this effect. From our previous study (Shin et al. 2007), we know that AMPA, NMDA, and GABAA receptors do not underlie the sustained depolarization and therefore other candidates must be considered. One such candidate is the family of voltage-gated Ca2+ channels. Since enhanced Ih channel activity initiated the marked depolarization in resting membrane potential, the sustained depolarization may induce the activity of these voltage-gated channels and initiate second messengers that could underlie the prolonged depression of EP neuronal activity seen in washout (see reviews by Berridge 1997; Moreno 1999). Nonetheless, our data do not fully support this postulation. Initially, one can conclude that prolonged depression is Ca2+ dependent since the removal of Ca2+ from the bathing solution resulted in a complete and rapid return of all neuronal parameters, from 6 mM K+ treatment, to control values within minutes of reperfusion with aCSF. However, this effect can be mediated by the inhibition of Ih channel activity. In fact, the removal of Ca2+ from the aCSF coincides with results from Ih channel blockade experiments with ZD7288 or CsCl; the removal of Ca2+ from the aCSF abolished the Ih sag in EP neurons, which resulted in the attenuation of spontaneous spiking frequency; the addition of 6 mM K+ increased spontaneous spiking frequency. Therefore it is unclear whether the removal of extracellular Ca2+ prevented the prolonged depression of EP neuronal activity by preventing an accumulation of intracellular [Ca2+] by inhibiting Ca2+ influx or by inhibiting the Ih channel. Hagiwara and Irisawa (1989) reported that lowering intracellular [Ca2+] decreased the amplitude of the Ih channel in rabbit sinoatrial node cells, whereas increasing intracellular [Ca2+] produced the opposite effect. This Ca2+-dependent effect on Ih amplitude did not coincide with changes in the reversal potential or kinetics of the channel. When extracellular [Ca2+] was increased or decreased, the activation curve of the Ih channel shifted in a positive or negative direction, respectively. After observing no effect of pharmacological blockers of calmodulin and protein kinase inhibitors on the Ca2+-dependent effect of Ih channel activity, the authors concluded that Ca2+ directly affected the Ih channel. Schwindt et al. (1992) reported similar findings in cat neocortical neurons when they chelated intracellular [Ca2+] with BAPTA and observed the abolishment of the Ih sag. In the guinea pig sinoatrial node, Rigg et al. (2003) showed that Ca2+ affected Ih channel activity via the activation of calmodulin, whereas Malcolm et al. (2003) reported that both protons and Ca2+ affected Ih channel activity in salamander rod photoreceptors. Luthi and McCormick (1998a) showed that Ca2+ shifted the Ih channel activation curve in ferret thalamic neurons. However, others did not observe any effect of Ca2+ on Ih channel activity (Budde et al. 1997; Zaza et al. 1991).
If we hypothesize that the removal of extracellular Ca2+ prevented the attenuation of EP neuronal activity independently from Ih channel modulation, then one particular Ca2+ channel that could mediate the prolonged depression in EP neuronal activity, after 6 mM K+ treatment, is the low-threshold T-type Ca2+ channel. It has been reported that T-type Ca2+ channels act in concert with Ih channel activity to trigger APs and phasic burst discharges (Couto and Michel 1994; Crepel and Penit-Soria 1986). However, when T-type Ca2+ channel activity was blocked with 50 µM NiCl2, the bath perfusion of 6 mM K+ depressed EP neuronal activity in a similar fashion as before, and this depression in AP activity was still present when aCSF was reperfused, even after 20 min, suggesting that T-type Ca2+ channels do not mediate the prolonged depression induced by raised K+. In addition, results from our previous study (Shin et al. 2007) also suggest that the T-type Ca2+ channels are not involved since depolarization of EP neurons with +ve current, through the recording electrode, did not mimic the HFS or raised K+-mediated phenomenon nor the prolonged depression observed in washout. Thus other Ca2+ channels could mediate this prolonged effect or the removal of extracellullar Ca2+ in our experiment mediated its effects by blocking Ih channel activity. Many future experiments are needed to clarify the role of Ca2+ on the modulation of the raised Ke+ effects on EP neuronal activity.
Aside from enhanced Ih channel activity, another possible candidate that could initiate and mediate the inhibitory effects of HFS and raised K+ is the persistent Na+ current (INaP) channel. A critical role for the INaP channel, in maintaining depolarization block (based on the observations of phenytoin and veratridine effects in hippocampus), has been proposed (Bikson et al. 2003). Although our previous data do not show a complete potassium-mediated depolarization block, it is possible that the INaP could mediate the sustained depolarization of EP neurons. In thalamic (Anderson et al. 2004) and subthalamic nucleus neurons (Garcia et al. 2003), activation of TTX-sensitive sodium channels (together with Ca2+ channels) contributed to the effects of HFS. In cultured myotubes obtained from patients with hereditary hyperkalemic periodic paralysis, some Na+ channels display a noninactivating gating mode favored by moderately increasing Ke+. These channels remain in the open state longer and more frequently, eventually resulting in muscle weakness from cell depolarization and the inability to produce APs (Cannon et al. 1991). However, our data show that the application of 25 nM TTX, which blocks INaP (Astman et al. 2006; Pace et al. 2007), did not prevent the K+-mediated decrease in EP neuronal activity. A possible explanation for the inability for TTX to prevent the K+-mediated depression of EP neuronal activity is that a 5-min application of 25 nM TTX was not long enough. However, this scenario seems unlikely since the application of TTX after 5 min induced a 26% increase in input resistance and a hyperpolarization of 2.3 mV.
Another consideration to keep in mind when interpreting our results is the role of glial cells in [K+]e buffering. Janigro et al. (1994) identified hyperpolarization-activated–like channel (Iha) in rat endothelial cells, whereas Guatteo et al. (1996) reported Ih channel activity in rat cortical and spinal astrocytes. Therefore it is plausible that ZD7288 and CsCl application, used in our study, may exert EP neuronal depression via the blockade of these channels in nonneuronal cell types by disrupting K+ buffering. In fact, Janigro et al. (1997) showed that CsCl application in rat hippocampal slices interfered with the induction of long-term depression and caused epileptiform activity, which was not exclusively due to neuronal Ih blockade, but from astrocytic origin, it is currently unknown whether astrocytes in the basal ganglia possess Ih or Ih-like channels. However, our application of CsCl and ZD7288 had direct effects on neuronal activity and parameters such as resting membrane potentials, input resistance, and spontaneous AP activity as reported in the literature (see earlier text in this section), which substantiates our interpretation of the results. It is predicted that HFS, in the presence of ZD7288 or CsCl, would result in EP neuronal depression if Ke+ buffering was compromised. In our previous study, we reported that HFS increased [K+]e to 9.6 ± 1.4 mM. The impairment of Ke+ buffering, via the blockade of glial Ih channel activity with ZD7288 or CsCl, would cause a marked depolarization of EP neurons and subsequent depolarization block. This was not the case in our experiments.
In conclusion, our results demonstrate that raised K+, either from HFS or bath perfusion, enhances Ih in EP neurons, thereby depressing EP neuronal activity via a marked depolarization and a decrease in input resistance. We are the first to report a link between HFS, elevated K+, and the Ih channel, a novel mechanism underlying the inhibitory effects of HFS, an important therapy for many neurological diseases.
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Address for reprint requests and other correspondence: D. Shin, Toronto Western Research Institute, Toronto Western Hospital, University Health Network, 399 Bathurst Street, MCL 12-413, Toronto, ON M5T 2S8, Canada (E-mail: damian.shin{at}uhnresearch.ca)
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