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Department of Anatomy and Neurobiology, College of Medicine, University of Tennessee, Memphis, Tennessee
Submitted 17 October 2007; accepted in final form 26 January 2008
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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; Nini et al. 1995; Wichmann and Soares 2006).
Recent studies suggest that serotonin [5-hydroxytryptamine (5-HT)] plays significant roles in the control of pallidal activity in normal and pathophysiological conditions (Castro et al. 1998; Doder et al. 2003; Jackson et al. 2004; Kita et al. 2007; Querejeta et al. 2005). Anatomical studies have shown that GPe receives abundant 5-HT innervations from the dorsal raphe (Charara and Parent 1994; Pasik et al. 1984; Vertes 1991). Immunohistochemical (Neumaier et al. 2001; Sari et al. 1999), receptor binding (Appel et al. 1990; Vilaro et al. 1996; Waeber and Moskowitz 1995), and in situ hybridization studies (Ullmer et al. 1996; Wright et al. 1995) localized several 5-HT receptor subtypes in GPe. The 5-HT innervations decrease in advanced stages of Parkinson's disease (Chinaglia et al. 1993; Halliday et al. 1990; Jellinger 1990; Kish 2003). The receptor binding is also altered in degenerative movement disorders (Castro et al. 1998). Furthermore, treatments with 5-HT1 receptor (5-HT1R; R denotes receptor) and 5-HT4R agonists and 5-HT2R antagonists are beneficial for Parkinson's disease patients (Asai et al. 2005; Bara-Jimenez et al. 2005; Bonuccelli and Del Dotto 2006; Henderson et al. 1992; Johnston and Brotchie 2004; Mignon and Wolf 2007; Nicholson and Brotchie 2002).
However, physiological studies of 5-HT on GPe are scarce. Querejeta et al. (2005) found that local application of 5-HT or a 5-HT1BR agonist excites most of the GPe neurons in anesthetized rats. Our recent study in monkeys suggested that 5-HT provides both presynaptic and postsynaptic modulations of GPe neurons (Kita et al. 2007). The aim of this study was to explore the presynaptic and postsynaptic actions of 5-HT, which were suggested from the earlier monkey study, using rat brain slice preparations.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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This study was performed in compliance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals. Sprague–Dawley juvenile rats (16–21 days old) were anesthetized with an intraperitoneal injection of a mixture of ketamine (85 mg/kg) and xylazine (15 mg/kg) and were perfused through the heart with cold oxygenated artificial cerebrospinal fluid (ACSF) containing (in mM): 126 NaCl, 3 KCl, 1.24 NaH2PO4, 26 NaHCO3, 6 MgSO4, and 10 glucose. After decapitation, the brain was removed quickly and a block containing the GPe was obtained. Oblique sagittal or horizontal slices (350 µm thick) were cut from the blocks on a vibrating blade microtome (Leica VT1000S; Leica Microsystems, Nussloch, Germany) after preincubation in ice-cold oxygenated ACSF containing (in mM): 126 choline chloride, 3 KCl, 1.24 NaH2PO4, 26 NaHCO3, 0.5 CaCl2, 6.3 MgSO4, 0.2 thiourea, 0.2 ascorbic acid, and 20 D-glucose (pH 7.4). The slices were then incubated in a standard ACSF containing (in mM): 126 NaCl, 3 KCl, 1.24 NaH2PO4, 26 NaHCO3, 2.4 CaCl2, 1.3 MgSO4, 0.2 thiourea, 0.2 ascorbic acid, and 10 D-glucose (300 mOsm, pH 7.4 at 34°C) equilibrated with a 95% O2-5% CO2 gas mixture.
Electrophysiological recordings
The slices were transferred to a recording chamber with oxygenated ACSF continuously superfused at a flow rate of 1–2 ml/min. The temperature of the recording chamber was kept at 34 ± 1°C. Whole cell patch-clamp recording pipettes with a tip diameter of about 1.5 µm were pulled from 1.5-mm, thin-wall, borosilicate glass capillaries on a horizontal electrode puller (P-97; Sutter Instrument, Novato, CA). The whole cell recording pipettes contained (in mM): 135 K-gluconate, 5 KCl, 10 HEPES, 2 Mg-ATP, and 0.2 Na-GTP (pH 7.2, 280 mOsm). For recording inhibitory postsynaptic currents (IPSCs), we used high-Cl electrodes containing 90 K-gluconate, 50 KCl, 10 HEPES, 2 Mg-ATP, and 0.2 Na-GTP (pH 7.2, 270 mOsm, ECl = –26 mV). The pipette resistance was 4 to 8 M
. The liquid junction potential was about 8 mV and was not corrected for. Neurons and recording pipettes were visualized using an infrared-differential interference contrast microscope (BX50WI; Olympus, Tokyo, Japan) with a x40 water-immersion objective and a CCD camera (4990 series; Cohu Electronics, San Diego, CA). Data were collected using an Axopatch 200B amplifier and AxoGraph 4.6 (Axon Instruments, Foster City, CA). Signals were filtered at 2 kHz, digitized at 5 kHz with a computer interface ITC-18 (InstruTECH, Port Washington, NY), and stored on the hard disc drive of a Macintosh G4 computer. For later off-line analysis, signals were also digitized and stored on a data recorder (CDAT4; Cygnus Technology, Delaware Water Gap, PA).
To activate striato-GPe or subthalamo-GPe fibers, electrical stimulation (
300 µA, 200 µs duration) was applied through a bipolar stimulating electrode with a tip distance of 0.2–0.3 mm placed on the Str or on the internal capsule (IC). To isolate GABAergic IPSCs, the 
-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptor antagonist, 1,2,3,4-tetrahydro-6-nitro-2,3-dioxobenzo[f]quinoxaline-7-sulfonamide (NBQX, 5–10 µM) was applied to the bath. To isolate glutamatergic excitatory postsynaptic currents (EPSCs), the 
-aminobutyric acid type A (GABAA)–receptor antagonist gabazine (10 µM) was applied to the bath. To record action potential–independent miniature (m)EPSCs or mIPSCs, tetrodotoxin (TTX, 1 µM) was applied to the bath in addition to the GABA or glutamate antagonists. All group data were expressed as means ± SD and were analyzed statistically using Student's t-test and nonrepeated- or repeated-measures ANOVA with a post hoc Bonferroni test.
Iontophoretic application of GABA and glutamate
Two-barreled pipettes, one barrel containing monosodium L-glutamate (0.1 M, pH 7.0) or GABA (0.1 M, pH 4.8) and the other saline, were placed approximately 30 µm from the neuron recording. Ejection current pulses with an intensity of 10–50 nA and duration of 30–100 ms were applied between the drug- and the saline-containing barrels using a constant-current pump Neuro Phore BH-2 (Medical Systems, Greenvale, NY).
Chemicals
3-[3-(dimethylamino)propyl]-4-hydroxy-N-[4-(4-pyridinyl) phenyl] benzamide dihydrochloride (GR55562), 2-[5-[3-(4-methylsulfonylamino) benzyl-1,2,4-oxadiazol-5-yl]-1H-indol-3-yl] ethanamine (L694247), [8b(S)]-9,10-didehydro-N-[1-(hydroxymethyl)propyl]-1,6-dimethylergoline-8-carboxamide maleate (methysergide), 5-carboxamidotryptamine maleate (5-CT), and 4-ethylphenylamino-1,2-dimethyl-6-methylaminopyrimidinium chloride (ZD7288) were obtained from Tocris Cookson (Ellisville, MO). 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP), gabazine (SR-95531), N'-[(8)-1,6-dimethylergolin-8-yl]-N,N-dimethylsulfamide hydrochloride (mesulergine), NBQX, 5-HT, TTX, and N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide maleate (WAY100635) were obtained from Sigma–Aldrich RBI (St. Louis, MO).
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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The neurons included in this report had spontaneous firing of <20 Hz and spike amplitudes >60 mV under control conditions. On depolarizing current injection, the neurons generated repetitive firings without prominent spike accommodation, and hyperpolarizing currents induced either prominent or moderate sags due to inwardly rectifying hyperpolarization–cyclic nucleotide-activated (HCN) current. These neurons included both type A and type B of Cooper and Stanford (2000) or the type I and type II neurons of Poisik et al. (2003).
Postsynaptic responses
Bath application of 5-HT (50 µM) for 3–5 min induced various changes in GPe neurons. 5-HT reversibly depolarized the somatic membrane >3 mV and increased spontaneous firing rates in 5 of 12 neurons tested. The depolarization value was estimated from the membrane potential between spikes (i.e., at spike afterhyperpolarizations; Fig. 1, A and C). The 3 mV is an arbitrarily cut line based on the observations that the membrane potential of established recording neurons seldom shift >3 mV. In 4 neurons, 5-HT hyperpolarized >3 mV (Fig. 1D). The membrane potential of 3 other neurons was not altered >3 mV by 5-HT. These results suggested that 5-HT activates multiple types of receptors in GPe.
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; Bobker and Williams 1990; Chapin and Andrade 2001). To test the possible involvement of HCN current, 5-CT (3 µM) was applied to neurons pretreated with TTX (1 µM), WAY100635 (5 µM), and ZD7288 (50 µM) or CsCl (2 mM). 5-CT failed to depolarize any of these neurons (Fig. 2G). In 10 neurons pretreated with the 5-HT2/7R–selective antagonist mesulergine (10 µM), 5-CT (1 µM) induced small but significant hyperpolarizations (Fig. 3, A and B, P < 0.001, n = 10) without accompanying large conductance changes (Fig. 3, C–E). Because 5-CT–induced hyperpolarizations were small and were not accompanied by changes in the input resistance, we did not perform further investigations.
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To evoke glutamatergic EPSCs, electrical stimulation (300 µA, 200 µs duration) was applied through a bipolar electrode (0.3 to 0.5 mm tip distance) placed on the internal capsule (IC) immediately caudal to GPe. EPSCs were isolated using gabazine (10 µM) and were recorded from neurons voltage-clamped at –70 mV. Bath application of 5-HT or 5-CT reversibly reduced IC stimulation–induced EPSCs in GPe neurons in a dose-dependent manner (Fig. 4, A–C). The IC50 of the 5-CT effect on EPSCs was about 0.04 µM and was nearly 25 times lower than the effect of 5-CT on the postsynaptic depolarization described earlier (Fig. 5A). The reduction of EPSCs was accompanied by an increase in the paired-pulse ratio that was calculated from responses to double stimulation at a 20 ms interval (Fig. 5, B and C). Pretreatment of preparations with the 5-HT1B/DR–selective antagonist GR55562 (10 µM) for 10 min blocked the effects of 5-CT (Fig. 5D). However, 5-CT (0.1 µM) exerted similar degrees of reduction of EPSCs compared with controls (55.8 ± 10.1%, P < 0.001, n = 6) in preparations pretreated with the 5-HT1/2/5/6/7R–selective antagonist methysergide (10 µM, 47.2% EPSC reduction, P < 0.01, n = 4), WAY100635 (10 µM, 43.7% EPSC reduction, P < 0.01, n = 5), and with mesulergine (30 µM, 48.4% EPSC reduction, P < 0.01, n = 4). The 5-HT1B/1DR–selective agonist L694247 (10 µM) also suppressed the EPSCs by 26.8 ± 8.0% (Fig. 5E, n = 5) without changing the holding currents of neurons. Application of 1 µM L694247 had no significant effect (P > 0.05, n = 5).
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To evoke GABAergic IPSCs, electrical stimulation (200 µs duration, 200 µA) was applied through a bipolar electrode (0.3 to 0.5 mm tip distance) placed on the Str. IPSCs were recorded with high Cl-containing pipettes in the presence of the AMPA/kainate receptor antagonist NBQX (5 µM) and N-methylD-aspartate antagonist CPP (30 µM). To minimize contamination of IPSCs mediated by local GPe axon–collateral synapses, the IPSCs with latencies >5 ms were evoked by adjusting stimulus current intensities (Kita 2007; Ogura and Kita 2000).
Bath application of 5-HT or 5-CT reversibly reduced Str stimulation–induced IPSCs in GPe neurons (Fig. 7A). The reduction was dose dependent and was accompanied by an increase in the paired-pulse ratio (Fig. 7, B–D). The IC50 of the 5-CT reduction of IPSCs was about 0.05 µM and was nearly 20 times lower than the effect of 5-CT on the postsynaptic depolarization described earlier. The pretreatment of preparations with methysergide (10 µM) for 10 min blocked the effects of 5-CT (Fig. 7E). However, 5-CT (0.1 µM) exerted similar degrees of reduction of IPSCs to control (56.8 ± 14.5%, P < 0.005, n = 5) in preparations pretreated with WAY100635 (10 µM, 48.2% IPSC reduction, P < 0.01, n = 4), GR55562 (10 µM, 44.6% IPSC reduction, P < 0.001, n = 6), and mesulergine (30 µM, 52.2% EPSC reduction, P < 0.005, n = 4). L694247 (10 µM) also suppressed Str stimulation–induced IPSCs by 32.2 ± 18.4% (Fig. 7F, n = 5), whereas the effects were not antagonized by GR55562 (10 µM, 25.4 ± 17.5%, P > 0.05, n = 4).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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The present results suggest that 5-HT activates multiple receptors and can depolarize or hyperpolarize GPe neurons. In the slices pretreated with WAY100635, 5-CT depolarized neurons by increasing the ZD7288 and cesium-sensitive HCN currents. The GPe neurons capable of generating repetitive firings without prominent spike accommodation express both HCN1 and HCN2 channels that play crucial roles in controlling autonomous firing of GPe neurons (Chan et al. 2004). Which HCN channel was activated by 5-CT could not be determined because 5-CT depolarized both neurons with a prominent sag in response to strong hyperpolarizing current pulses, an indication of strong HCN2 current, and those without prominent sags. The effects of 5-CT were about 30-fold more potent than those of 5-HT and were blocked by mesulergine. The receptor that is selective to these agonists and the antagonist is 5-HT7R. The involvements of HT7R and activation of HCN current in the 5-HT–induced depolarization have been reported in other brain areas (Bengtson et al. 2004; Bobker and Williams 1990; Chapin and Andrade 2001). The GPe expresses a low level of mRNA and immunoreactivity for 5-HT7R (Neumaier et al. 2001).
WAY100635 blocked the hyperpolarizing response to 5-CT and 5-CT hyperpolarized neurons pretreated with mesulergine. These results suggested all GPe neurons have 5-HT1AR. The 5-HT1AR–mediated hyperpolarization was reported in several brain areas (e.g., Bobker and Williams 1990; Jeong et al. 2001; Levita et al. 2004; Stanford et al. 2005; Stevens et al. 1992). Our study in monkey GPe also suggested 5-HT1AR–mediated the inhibitory effect of 5-HT (Kita et al. 2007). However, we did not perform further investigations because the hyperpolarizing response of rat GPe neurons to 5-HT and 5-CT was small and was not accompanied with clear conductance changes.
Suppression of glutamatergic inputs
The stimulation of the IC nonselectively activates afferent fibers to GPe, including those from the subthalamic nucleus, the intralaminar thalamic nuclei, the cerebral cortex, and the pedunculopontine tegmentum. Among those, the subthalamic boutons are most numerous in GPe (Okoyama et al. 1987). The present results revealed that 5-HT and 5-CT presynaptically reduce glutamate release in GPe. The IC50 of the 5-CT effect on EPSCs was about 0.04 µM and was comparable to that of the suppression of IPSCs. The IC50 of the 5-CT effect on the suppression of EPSCs was about 25 times lower than that of the postsynaptic effect, suggesting that 5-HT mainly modulates presynaptic sites in GPe. The higher IC50 for postsynaptic effects also suggests the reduction of synaptic responses by 0.1 µM 5-CT did not involve significant changes in postsynaptic membrane conductance. The antagonistic effect of GR55562 suggested an involvement of 5-HT1B/1DR. L694247, a selective 5-HT1B/1DR agonist, had an agonistic effect but the effective concentration was much higher than that of 5-CT, suggesting activation of receptors other than 5-HT1B/1DR. The involvement of 5-HT1BR in presynaptic suppressions of glutamatergic responses was reported in a number of other brain areas (Chen and Regehr 2003; Li and Bayliss 1998; Mlinar et al. 2003; Muramatsu et al. 1998; Pickard et al. 1999; Singer et al. 1996; Smith et al. 2001). Another possible receptor involved in the suppression of glutamatergic excitations is 5-HT1AR (Bouryi and Lewis 2003; Schmitz et al. 1998). We have also suggested an involvement of 5-HT1AR in the suppression of glutamatergic excitations in monkey pallidum because local application of WAY100635 blocked the effect of subsequent applications of 5-CT in suppressing cortical stimulation–induced excitations (Kita et al. 2007). In the present study using rat brain slices, WAY100635 was ineffective.
Suppression of GABAergic inputs
The present results suggested that activation of presynaptic 5-HTR on the Str–GPe afferent fibers reduces GABA release from their synaptic boutons. The receptor appears to be much more sensitive to 5-CT than to 5-HT. The 5-CT on the presynaptic effects was also about 20-fold more sensitive than that on postsynaptic depolarization as discussed earlier. If our speculation that the involvement of 5-HT7R in the latter effect is correct, the presynaptic receptor should have higher sensitivity or be a more efficient receptor than 5-HT7R. However, the presynaptic receptor type is still uncertain. The most commonly described presynaptic receptor on GABAergic terminals in other brain areas is 5-HT1BR (Matsuoka et al. 2004; Umemiya and Berger 1995; Yan and Yan 2001). Our recent unit recording study of pallidal neurons in monkeys also suggested possible involvement of 5-HT1BR (Kita et al. 2007). Immunohistochemical studies localized an abundant level of 5-HT1BR on Str–GPe fibers (Castro et al. 1998; Riad et al. 2000; Sari 2004). A 5HT1BR agonist inhibited 3H-GABA release from rat GPe slices (Chadha et al. 2000). These previous studies suggested the involvement of 5-HT1BR. A recent study reported local application of the 5-HT1BR agonist N-[4- [[5-[3-(2-aminoethyl)-1H-indol-5-yl]-1,2,4-oxadiazol-3-yl] methyl]phenyl]-methanesulfonamide excites most GPe neurons, which can be due to presynaptic suppression of GABAergic inhibitions, in anesthetized rats (Querejeta et al. 2005). The 5-HT1B/1DR–selective agonist L694247 mimicked the effects of 5-CT. However, the effective concentration of L694247 was much higher than 5-CT and the 5-HT1B/DR–selective antagonist GR55562 failed to block 5-CT effects. The effects of 5-CT were blocked by the broad 5-HT12,5,6,7R antagonist methysergide. As expected, the 5-HT1A–and 5-HT2,7R–selective antagonists WAY100635 and mesulergine, respectively, did not block the effects of 5-CT. The possibilities are that 5-HT1B/1DR is involved in the presynaptic suppression of GABA release but, for some reason, GR55562 cannot act as an antagonist or that 5-HT5R, 5-HT6R, or other unknown receptors are involved in the suppression of the IPSCs, although both 5-HT5 and 5-HT6Rs are expressed in low levels in rat brains (Erlander et al. 1993; Nelson 2004; Roberts et al. 2002).
Identification of 5-HTRs
The differences in the actions of 5-HT agonists and antagonists between the present and previous studies summarized earlier are difficult to understand. It is conceivable that different receptors exert similar effects in different brain areas or in different animal species. This speculation is based on the fact that 5-HTRs can be grouped based on similarity of signaling pathways and that previous studies suggest that the post- and presynaptic effects of 5-HT reported in different brain areas do not share a single receptor. It is also possible that activation of combinations of 5-HTRs or combinations of 5-HTRs and dopamine or noradrenergic receptors exerted synergistic effects (e.g., Bishop and Walker 2003; Carta et al. 2007) and blockade of any one of the synergistic receptors exerted similar effects. We also think that most of the agonists and antagonists used are selective but are not specific enough to identify receptors involved, especially when used in relatively high concentrations in both in vivo and in vitro physiological experiments.
Functional implication
The present results provided evidence that 5-HT exerts significant control over the synaptic inputs and the autonomous activity of GPe neurons. Presynaptically, 5-HT can suppress the synaptic release of glutamate and GABA, which means 5-HT can dampen Str and STN inputs and increase or decrease the spontaneous activity of in vivo GPe neurons (Galvan et al. 2005; Kita et al. 2004, 2007). 5-HT can also postsynaptically increase or decrease firing. More detailed studies on the receptors involved and on their localizations are required to understand the roles of these two opposing effects. It has been postulated that parkinsonisms are associated with increased activity of striato-pallidal and subthalamo-pallidal projections, which increase synchronized burst activity in GPe (Bergman et al. 1998; Boraud et al. 1998; Magill et al. 2001; Nini et al. 1995; Wichmann and Soares 2006; Wichmann et al. 1999). The potent effects of 5-HT agonists on the modulation of GPe activity suggest a great potential for therapeutic applications of 5-HT–related drugs. For instance, administration of 5-HT1BR agonist may decrease burst activity and suppress some parkinsonisms, as was shown in a rodent model of Parkinson's disease (Chadha et al. 2000). However, more studies are required for understanding the diverse effects of 5-HT involving multiple receptor types and the plastic changes in the receptor distributions and expressions that might occur in advanced stages of Parkinson's disease with decreased numbers of 5-HT neurons and 5-HT uptake sites in the basal ganglia (Chinaglia et al. 1993; Halliday et al. 1990; Jellinger 1990; Kish 2003).
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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ACKNOWLEDGMENTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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FOOTNOTES |
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Address for reprint requests and other correspondence: H. Kita, Department of Anatomy and Neurobiology, College of Medicine, The University of Tennessee Memphis, 855 Monroe Avenue, Memphis, TN 38163 (E-mail: hkita{at}utmem.edu)
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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