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. 2008 Feb 21;586(Pt 8):2121–2142. doi: 10.1113/jphysiol.2008.151118

D2-like dopamine receptor-mediated modulation of activity-dependent plasticity at GABAergic synapses in the subthalamic nucleus

Jérôme Baufreton 1,2, Mark D Bevan 1
PMCID: PMC2465193  PMID: 18292127

Abstract

Reciprocally connected glutamatergic subthalamic nucleus (STN) and GABAergic external globus pallidus (GP) neurons normally exhibit weakly correlated, irregular activity but following the depletion of dopamine in Parkinson's disease they express more highly correlated, rhythmic bursting activity. Patch clamp recording was used to test the hypothesis that dopaminergic modulation reduces the capability of GABAergic inputs to pattern ‘pathological’ activity in STN neurons. Electrically evoked GABAA receptor-mediated IPSCs exhibited activity-dependent plasticity in STN neurons, i.e. IPSCs evoked at frequencies between 1 and 50 Hz exhibited depression that increased with the frequency of activity. Dopamine, the D2-like dopamine receptor agonist quinpirole and external media containing a low [Ca2+] reduced both the magnitude of IPSCs evoked at 1–50 Hz and synaptic depression at 10–50 Hz. Dopamine/quinpirole also reduced the frequency but not the amplitude of miniature IPSCs recorded in the presence of tetrodotoxin. D1-like and D4 agonists were ineffective and D2/3 but not D4 receptor antagonists reversed the effects of dopamine or quinpirole. Together these data suggest that presynaptic D2/3 dopamine receptors modulate the short-term dynamics of GABAergic transmission in the STN by lowering the initial probability of transmitter release. Simulated GABAA receptor-mediated synaptic conductances representative of control or modulated transmission were then generated in STN neurons using the dynamic clamp technique. Dopamine-modulated transmission was less effective at resetting autonomous activity or generating rebound burst firing than control transmission. The data therefore support the conclusion that dopamine acting at presynaptic D2-like receptors reduces the propensity for GABAergic transmission to generate correlated, bursting activity in STN neurons.

The glutamatergic subthalamic nucleus (STN) is a key component of the basal ganglia, a group of subcortical brain nuclei important for normal voluntary movement and the primary site of dysfunction in movement disorders such as Parkinson's disease (PD) (Carlsson, 1969; Albin et al. 1989; DeLong, 1990; Hornykiewicz, 2006). Together with the reciprocally connected external globus pallidus (GP), STN and GP neurons form a network that is pivotal to the operation of the basal ganglia (DeLong, 1972; Fujimoto & Kita, 1993; Shink et al. 1996; Maurice et al. 1998). Under normal conditions, neurons in this network exhibit weakly correlated, irregular activity (Wichmann et al. 1994; Magill et al. 2000; Urbain et al. 2000), whereas in idiopathic and experimental PD the network exhibits strongly correlated, low-frequency (4–8 Hz and 13–30 Hz), rhythmic, bursting activity that is associated with the manifestation of the motor symptoms of the disease (Filion, 1979; Bergman et al. 1994; Nini et al. 1995; Levy et al. 2000; Raz et al. 2000; Heimer et al. 2002; Levy et al. 2002). ‘Correction’ of the pathological activity pattern by dopamine receptor agonists and/or dopamine replacement therapy and/or direct high-frequency electrical stimulation and/or ablation of the STN leads to a dramatic amelioration of motor symptoms (Filion, 1979; Bergman et al. 1990; Brown et al. 2001; Levy et al. 2001; Benabid, 2003; Alvarez et al. 2005; Hamani et al. 2006). Intense effort has therefore been directed towards elucidation of the mechanisms underlying aberrant STN–GP activity, with the long-term goal of developing more effective and non-surgical therapeutic strategies for pattern correction in PD.

It is not known whether pathological activity in PD is due to the mutual interaction of STN and GP neurons alone and/or their altered responsiveness to afferent synaptic inputs. It is also not known precisely how the loss of dopaminergic neuromodulation in the basal ganglia leads to pathological activity. Depletion of striatal dopamine, which may lead to the relative overactivity of the GABAergic projection to the GP (Albin et al. 1989), has been proposed to alter the interaction of STN and GP neurons (Terman et al. 2002). Other studies have suggested that dopamine depletion at the level of the STN and GP may enhance the sensitivity of the network to low-frequency rhythms emanating from the cortex (Ni et al. 2000, 2001; Brown et al. 2001; Magill et al. 2001). Substantia nigra dopamine neurons that project to the striatum and degenerate in PD also send collateral projections to the STN–GP network (Lavoie et al. 1989; Hassani et al. 1997; Cossette et al. 1999; Hedreen, 1999; Francois et al. 2000; Ni et al. 2001; Cragg et al. 2004) where dopamine acts directly on STN neurons via D2-like and D5 dopamine receptors linked to a variety of signalling pathways (Zhu et al. 2002a,b; Baufreton et al. 2003; Tofighy et al. 2003; Cragg et al. 2004; Zhu et al. 2007; Ramanathan et al. 2008) and also on glutamatergic and GABAergic afferent synaptic inputs via presynaptic D2-like receptors (Shen & Johnson, 2000; Shen et al. 2003; Zhu et al. 2007). Extrastriatal dopaminergic modulation may therefore facilitate the normal interaction of STN and GP neurons and its loss may conversely contribute to pathological activity (Bevan et al. 2006).

In this study, we have focused on the dopaminergic modulation of GABAergic inputs to STN neurons, the majority of which arise from the GP (Smith et al. 1998), because they have been demonstrated to powerfully pattern the activity pattern of STN neurons in vitro (Bevan et al. 2002; Baufreton et al. 2005a; Hallworth & Bevan, 2005) and in vivo (Fujimoto & Kita, 1993; Maurice et al. 1998; Nambu et al. 2000; Paz et al. 2005). Thus, transient GABAergic input acting at GABAA receptors can produce variable shifts or completely reset the phase of autonomous STN activity through partial or complete deactivation, respectively, of voltage-dependent Na+ (Nav) channels that underlie autonomous firing (Baufreton et al. 2005a; Hallworth & Bevan, 2005). In contrast, synchronous barrages of GABAergic input acting via GABAA and/or GABAB receptors can generate rebound burst firing in STN neurons through deinactivation of class 1 and 3 voltage-dependent Ca2+ (Cav1 and Cav3) channels (Beurrier et al. 1999; Hallworth et al. 2003; Hallworth & Bevan, 2005; Paz et al. 2005). Because the functional impact of GABAergic input to the STN is related to the pattern of presynaptic activity and synapses exhibit a range of activity-dependent plasticities from facilitation to depression to a combination of the two (Zucker & Regehr, 2002; Abbott & Regehr, 2004), our first objective was to characterize the activity-dependent plasticity of GABAAR-mediated IPSCs in STN neurons under control conditions. We observed that GABAergic transmission in the STN exhibited activity-dependent depression within a physiological range of frequencies.

Neuromodulators like dopamine, which often act at presynaptic receptors, can regulate the probability transmitter release and thus the activity-dependent nature of transmission. At synapses which exhibit activity-dependent depression, reduction in the initial probability of synaptic release can greatly alter the short-term dynamics of transmission and even elevate the frequency at which transmission can be sustained (Zucker & Regehr, 2002; Abbott & Regehr, 2004). Our next objective was therefore to determine how dopamine regulates activity-dependent plasticity at GABAergic synapses in STN neurons. We found that dopamine and low Ca2+ external media reduced activity-dependent synaptic depression and decreased the frequency but not the amplitude of miniature IPSCs. Together, these data suggest that dopamine acts presynaptically to reduce the initial release probability of GABA at GP–STN synapses (Zucker & Regehr, 2002; Abbott & Regehr, 2004).

D1- and D2-like presynaptic dopamine receptors have been reported to modulate GABAergic transmission (Cameron & Williams, 1993; Momiyama & Sim, 1996; Cooper & Stanford, 2001; Baimoukhametova et al. 2004; Hjelmstad, 2004; Geldwert et al. 2006; Mizuno et al. 2007; Tecuapetla et al. 2007). Our next objective was therefore to utilize subtype-selective drugs to determine which dopamine receptors modulate evoked and miniature transmission in the STN. Our final objective was to determine how presynaptic dopaminergic modulation regulates the functional impact of GABAergic transmission in the STN. Using the dynamic clamp technique (Robinson & Kawai, 1993; Sharp et al. 1993) to inject conductances that mimic modulated GABAergic transmission and GABAergic transmission under control conditions, we found that dopamine-modulated inputs were less effective at resetting autonomous STN activity and generating rebound activity in STN neurons.

Methods

Ethical information

All procedures involving animals were carried out in accordance with Northwestern and Bordeaux Universities’ Institutional Animal Care and Use Committees, the National Institutes of Health (USA) and the CNRS (France).

Slice preparation

Electrophysiological recordings were performed using brain slices prepared from 78 18- to 25-day-old Sprague–Dawley or Wistar rats (Charles River Laboratories, Wilmington, MA, USA), as previously described (Baufreton et al. 2005a). Activity-dependent plasticity and dopaminergic neuromodulation of GABAergic synaptic transmission were not significantly different in the two strains (data not shown). Animals were anaesthetized deeply by intraperitoneal injection of a mixture of ketamine (87 mg kg−1) and xylazine (13 mg kg−1) and perfused transcardially with ice-cold modified artificial CSF (ACSF) that was equilibrated with 95% O2 and 5% CO2 and contained (mm): 230 sucrose, 26 NaHCO3, 2.5 KCl, 1.25 Na2HPO4, 0.5 CaCl2, 10 MgSO4 and 10 glucose. The brain was then removed, blocked in the sagittal plane, glued to the stage of a vibrating microtome (3000 Deluxe, Vibratome, St Louis, MO, USA:VT1000S, Leica, Bannockburn, IL, USA), and submerged in ice-cold modified ACSF. Slices, 300 μm thick, containing the STN were cut and transferred to a holding chamber at room temperature containing ‘traditional’ ACSF that was equilibrated with 95% O2 and 5% CO2 and contained (mm): 126 NaCl, 26 NaHCO3, 2.5 KCl, 1.25 Na2HPO4, 2 CaCl2, 2 MgSO4 and 10 glucose.

Electrophysiological recordings

Slices were transferred to a recording chamber and perfused with media at 35–37°C that more closely mimicked rodent brain interstitial fluid than ‘traditional’ ACSF (Sanchez-Vives & McCormick, 2000). ‘Synthetic interstitial fluid’ was equilibrated with 95% O2 and 5% CO2 and contained (mm): 126 NaCl, 26 NaHCO3, 3 KCl, 1.25 Na2HPO4, 1.6 CaCl2, 1.5 MgSO4 and 10 glucose. In some cases, extracellular [Ca2+] was lowered to 0.6 mm and extracellular [Mg2+] was increased to 2.5 mm to reduce the probability of transmitter release (Katz, 2003) and to maintain a constant concentration of divalent cations, respectively. Slices were visualized with infrared gradient contrast video microscopy (Infrapatch workstation, Luigs & Neumann, Ratingen, Germany/Eclipse workstation, Nikon, Japan) and a 40× or 60× water-immersion objective (Axioskop FS2, Zeiss, Oberkochen, Germany/E600FN, Nikon, Tokyo, Japan). Somatic patch clamp recordings were made using pipettes (impedance, 2–5 MΩ) prepared from borosilicate glass capillaries (G150-4; Warner Instruments, Hamden, CT, USA) with a micropipette puller (P-97; Sutter Instrument Co., Novato, CA, USA). For the recording of evoked and miniature IPSCs in the whole cell voltage clamp configuration, patch pipettes were filled with (mm): 135 CsCl, 3.6 NaCl, 1 MgCl2, 10 Hepes, 10 QX-314, 0.1 Na4EGTA, 0.4 Na3GTP and 2 Mg1.5ATP (pH 7.2, 290 mosmol l−1); or 130 potassium gluconate, 3.6 sodium gluconate, 1 MgCl2, 10 Hepes, 10 QX-314, 5 TEA-Cl, 0.1 Na4EGTA, 0.4 Na3GTP and 2 Mg1.5ATP (pH 7.2, 290 mosmol l−1). For the injection of simulated synaptic conductances in current clamp mode, patch pipettes were filled with (mm): 135 KMeSO4, 3.8 NaCl, 1 MgCl2, 10 Hepes, 0.1 Na4EGTA, 0.4 Na3GTP and 2 Mg1.5ATP (pH 7.2, 290 mosmol l−1). In the majority of cases, current clamp recordings employed the perforated patch configuration, in which case gramicidin D (Sigma-Aldrich, St Louis, MO, USA) was added to the patch solution at a concentration of ∼15 μg ml−1.

Data were recorded using a Multiclamp 700B or an Axopatch 1D amplifier controlled by Clampex 9.0 (Molecular Devices, Union City, CA, USA), or an EPC 9/2.C amplifier (HEKA Elektronik, Lambrecht, Germany) controlled by Pulse 8.5 software (HEKA Elektronik). Signals were digitized at 10–50 kHz and low-pass filtered at 3–10 kHz, respectively. During perforated patch recording, deliberate or accidental establishment of the whole-cell configuration was recognized as a sudden drop in series resistance and an ∼5 mV offset in membrane potential (Baufreton et al. 2005a). Whole-cell voltage clamp recordings with CsCl-filled electrodes or potassium gluconate-filled electrodes were corrected for a junction potential of 4 mV or 15 mV, respectively (Barry, 1994). Perforated patch and whole-cell current clamp recordings were corrected off-line for a junction potential of 4 mV or 9 mV, respectively (Barry, 1994; Baufreton et al. 2005a).

Voltage clamp experiments

Evoked IPSCs

Trains of IPSCs were evoked at 1, 10 and 50 Hz by bipolar electrical stimulation of the internal capsule rostral to the STN (0.05–0.5 mA; DS-3, Digitimer, Welwyn Garden City, UK/ISO-Flex, API, Jerusalem, Israel) using a custom-built matrix of 20 stimulation electrodes (MX54CBWMB1, Frederick Haer Co., Bowdoinham, ME, USA) or a bipolar electrode (SNEX-200, Phymep, France). Internal solutions containing Cs+ and QX-314 or potassium gluconate, TEA and QX-314 were employed in the patch electrode to improve voltage control and to minimize the engagement of postsynaptic voltage-independent/dependent ion channels. Evoked GABAA receptor-mediated IPSCs were recorded at −60 mV (CsCl-filled pipettes) or at −50 mV (potassium gluconate-filled pipettes) in the presence of 1 μm (2S)-3-[[(1S)(3,4-dichlorophenyl)ethyl]amino-2-hydroxypropyl] (phenylmethyl)phospinic acid (CGP55845), 50 μm d-(–)-2-amino-5-phosphonopentanoic acid (APV) and 20 μm 6,7-dinitroquinoxaline-2,3-dione (DNQX), to block GABAB receptors, NMDA glutamate receptors and AMPA-kainate glutamate receptors, respectively. In some cases, 20 μm 4-[6-imino-3-(4-methoxyphenyl) pyridazin-1-yl] butanoic acid hydrobromide (GABAzine/SR-95531) was applied to confirm that the remaining synaptic events were indeed sensitive to a selective GABAA receptor antagonist. CGP55845, APV, DNQX and GABAzine were obtained from Tocris Bioscience (Ellisville, MO, USA). Six to ten repetitions were carried out at each frequency in the presence and absence of dopamine receptor agonists and antagonists (the D1-like dopamine receptor agonist, 6-chloro-2,3,4,5-tetrahydro-1-phenyl-1H-3-benzazepine hydrobromide (SKF81297), the D2-like dopamine receptor agonist (4aR-trans)-4,4a,5,6,7,8,8a,9-octahydro-5-propyl-1H-pyrazolo[3,4-g]quinoline hydrochloride (quinpirole), the D2-like dopamine receptor antagonist (S)-(–)-5-aminosulphonyl-N-[(1-ethyl-2-pyrrolidinyl)methyl]-2-methoxybenzamide (sulpiride), the D4 dopamine receptor antagonist N-[[4-(2-cyanophenyl)-1-piperazinyl] methyl]-3-methyl-benzamide maleate (PD 168077) and the D4 dopamine receptor agonist, 3-[(4-[4-chlorophenyl] piperazin-1-yl)methyl]-1H-pyrrolo[2,3-b]pyridine hydrochloride (LY745870) with 30 s intervals between repeats to allow recovery of transmission.

Miniature IPSCs

GABAA receptor-mediated miniature IPSCs (mIPSCs) were recorded as for evoked IPSCs but in the presence of 0.5–1 μm tetrodotoxin (TTX) in order to block Nav channels. Pipettes were filled with CsCl-based solution to enhance the detection of mIPSCs. The frequency and peak amplitude of mIPSCs were detected and analysed with miniAnalysis (Synaptosoft Inc., Decatur, GA, USA). The quantal conductance (g) underlying each miniature event was calculated using:

graphic file with name tjp0586-2121-m1.jpg

where mIPSCpeak is the peak amplitude of the mIPSC and Vm is the holding voltage. The reversal potential of GABAA current (EGABA-A) was estimated from the Nernst equation and the relative permeabilities of Cl− and HCO3− through GABAA receptors. Thus:

graphic file with name tjp0586-2121-m2.jpg

where R is the gas constant, T is the temperature, F is the Faraday constant, []i is the intracellular ionic concentration and []o is the extracellular ionic concentration. The rising and decay kinetics of mIPSCs were obtained using monoexponential and biexponential fitting (Clampfit 9.0; Molecular Devices). For biexponential fits the weighted decay was calculated from:

graphic file with name tjp0586-2121-m3.jpg

where A and τ refer to the amplitude and decay constants, respectively.

Current clamp experiments

Synaptic conductance injection

Simulated IPSPs were generated through the patch pipette using a synaptic module (SM-1) conductance injection amplifier (Cambridge Conductance, Cambridge, UK), as previously described (Baufreton et al. 2005a). The applied conductance waveforms were based on the magnitude and kinetics of evoked GABAA receptor-mediated IPSCs observed under voltage clamp and the intact equilibrium potential of GABAA IPSPs in STN neurons (Bevan et al. 2002). Conductance waveforms had a rise time of 0.8 ms and monoexponential (τ= 10 ms) or biexponential decay (A1= 89.7%, τ1= 7 ms; A2= 10.3%, τ2= 35 ms). The impact of brief, small or larger, more prolonged inputs was studied.

Brief/small inputs

Waveform 1 was based on two representative IPSCs that were evoked at an interval of 20 ms under control conditions and in the presence of 2 μm quinpirole. The conductance underlying the first IPSP was scaled to 5 nS for the control waveform and 3.75 nS for the modulated waveform in order to mimic reduction in initial release probability due to modulation. Waveform 2 comprised five IPSCs that were digitally generated at intervals of 20 ms. Initial conductances were set to 5 nS and 3 nS for the control and the dopamine-modulated waveforms, respectively, in order to mimic a reduction in initial release probability due to modulation. The degree of depression in each condition was quantified using the equation: y = y0+A1exp− ((x−x0)/τ1) +A2exp−((x−x0)/τ2), where the parameters A1, A2, τ1 and τ2 were determined from fitting the time course of the depression of 100 phasic IPSCs evoked at 50 Hz in six neurons. This equation was then applied to scale the magnitude of consecutive control and modulated simulated conductances.

Prolonged, large inputs

A burst of 10 IPSCs was digitally generated in a similar manner to waveform 2. The initial conductance of the control waveform was adjusted for each cell in order to trigger a post-inhibitory rebound burst (typically between 15 and 25 nS) and the initial conductance of the dopamine-modulated waveform was then scaled to 60% of the control waveform (see Fig. 2).

Figure 2. Reduction in extracellular [Ca2+] leads to a reduction in synaptic depression.

Figure 2

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A, IPSCs evoked at 50 Hz in a representative neuron under control conditions (Aa; extracellular [Ca2+]= 1.6 mm), in the presence of reduced extracellular [Ca2+] (Ab; extracellular [Ca2+]= 0.6 mm) and upon return to control conditions (Ac). B, population data arising from 6 neurons. Plots of IPSC amplitude against IPSC number. Ba, the amplitudes of total (phasic + tonic) IPSCs were reduced throughout the period of evoked transmission by lowering extracellular [Ca2+]. Bb and c, total (b) and phasic (c) IPSC amplitude expressed as a percentage of the amplitude of the first evoked IPSC. Ba–c, in the presence of reduced extracellular [Ca2+] synaptic depression was reduced and facilitation was observed. *P < 0.05.

Statistics

Descriptive and comparative statistics were generated using Origin 7.0 (OriginLab Corp., Northampton, MA, USA) and SigmaStat 3.0 (Systat Software Inc., San Jose, CA, USA). Data are reported as the mean ± standard error of the mean. Individual paired and unpaired data sets were compared using Student's paired t test and unpaired t test, respectively. Data were considered to be significantly different when P < 0.05. Multiple group comparisons were carried out using analysis of variance (ANOVA) and a post hoc Bonferroni t test (significance level, P < 0.05). Cumulative distributions were compared using the Kolmogorov–Smirnov test (K-S test) and were considered to be significantly different when P < 0.01. Probability values are reported to 3 decimal places.

Results

Activity-dependent depression at GABAergic synapses in the STN

GABAA receptor-mediated synaptic transmission was evoked by bipolar electrical stimulation of the internal capsule rostral to the STN and isolated by bath application of APV and DNQX to block ionotropic glutamate receptors and CGP55845 to block GABAB receptors. Electrical stimulation evoked outward or inward GABAA receptor-mediated synaptic currents when recorded with potassium gluconate- or CsCl-filled electrodes, respectively. The data obtained with the two electrode solutions were otherwise similar and were therefore pooled. For the purpose of illustration, evoked IPSCs are plotted as outward currents.

In order to determine the activity dependence of GABAA receptor-mediated transmission, IPSCs were evoked at 1, 10 and 50 Hz. The amplitudes of IPSCs were calculated from the baseline preceding the sequence of stimulation and/or the baseline current prior to individual stimulation artifacts. The former measurement includes the contribution of preceding IPSCs that have not fully decayed, whereas the latter approach more accurately isolates the contribution of individual IPSCs (Telgkamp & Raman, 2002). The measurements are termed total and phasic IPSCs, respectively. In some cases, amplitudes were then normalized to the amplitude of the first evoked IPSC (%). GABAA receptor-mediated IPSCs exhibited activity-dependent synaptic depression at each frequency of stimulation and in each neuron studied (Fig. 1). The total IPSC amplitude at the end of each stimulation sequence, decreased in an activity-dependent manner to 83.6 ± 2.8% (n = 26), 60.8 ± 3.3% (n = 38) and 43.9 ± 2.7% (n = 40) of the initial IPSC at 1, 10 and 50 Hz, respectively (Fig. 1A–D). At 10 and 50 Hz, a tonic current was apparent (Fig. 1E). Close inspection of the decay of IPSCs revealed that tonic current was most likely due to the summation of evoked IPSCs that decayed more slowly than the intervals between electrical stimulation and not to release that was asynchronous with stimulation (Hefft & Jonas, 2005). At 10 Hz, the tonic current (6.6 ± 0.2 pA; n = 14) was constant throughout stimulation and observed in 54% of neurons (14/26 neurons). At 50 Hz, the tonic current was observed in each neuron and reached its maximum by the third IPSC (86.7 ± 13.2 pA; n = 40) and then decreased in an exponential manner to ∼55% of its maximal amplitude by the end of stimulation (46.9 ± 8.1 pA; n = 40) (Fig. 1E). The amplitude of the phasic IPSC at the end of each stimulation sequence also decreased in an activity-dependent manner to 83.6 ± 2.8% (n = 26), 59.9 ± 3.5% (n = 38) and 31.9 ± 2.2% (n = 40) of the initial IPSC at 1, 10 and 50 Hz, respectively (Fig. 1F). The decline in phasic IPSC amplitude was well fitted by monoexponential decay at 1 Hz (τ= 2740 ms; R2= 0.90), whereas biexponential decay better approximated depression at 10 Hz (τ1= 85.7 ms; τ2= 1370.1 ms; R2= 0.96) and 50 Hz (τ1= 29.4 ms; τ2= 682.9 ms; R2= 0.99) (Fig. 1F).

Figure 1. GABAA receptor-mediated synaptic transmission exhibits activity-dependent depression.

Figure 1

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A–C, IPSCs evoked by stimulation at a frequency of 1 Hz, 10 Hz and 50 Hz for a duration of 20 s, 5 s and 2 s, respectively, in a representative neuron. D, total IPSC amplitude expressed as a percentage of the amplitude of the first IPSC plotted against time for each frequency of stimulation (1 Hz: □ 10 Hz: ○ 50 Hz: ▵; n = 26, 38 and 40 cells for stimulation at 1, 10 and 50 Hz, respectively). E, mean amplitude of the ‘tonic’ current measured immediately prior to each stimulus artifact plotted against time for 10 and 50 Hz stimulation. A sizeable current was detected in 14 of 26 cells at 10 Hz (○) and in all neurons at 50 Hz (▵). F, phasic IPSC amplitude (total IPSC amplitude – tonic IPSC amplitude) expressed as a percentage of the amplitude of the first IPSC plotted against time for each frequency. Grey lines depict fits to the depression of phasic IPSCs at each frequency.

The kinetics of activity-dependent synaptic depression may reflect complex, multiple dynamic processes including depletion and replenishment of release-ready vesicles and/or the inactivation of presynaptic voltage-dependent Ca2+ (Cav) channels and/or desensitization of postsynaptic receptors (Overstreet et al. 2000; Brenowitz & Trussell, 2001; von Gersdorff & Borst, 2002; Zucker & Regehr, 2002; Blitz et al. 2004; Xu & Wu, 2005; Xu et al. 2007). By reducing the initial probability of transmitter release through a reduction in extracellular [Ca2+], synaptic depression due to some of these mechanisms may be reduced. Thus, the depression of IPSCs evoked at 50 Hz under control (1.6 mm) and reduced extracellular Ca2+ (0.6 mm) was studied (Fig. 2). At 50 Hz stimulation, lowering extracellular [Ca2+] reduced the initial amplitude of IPSCs by 65.1% (control = 286.1 ± 31.4 pA, reduced Ca2+= 99.8 ± 24.2 pA, n = 6, P < 0.001, Student's paired t test; Fig. 2A and Ba). The total and phasic IPSCs at the end of 50 Hz stimulation were also reduced by lowering extracellular Ca2+ (total IPSC100: control = 144.4 ± 17.1 pA, reduced Ca2+= 84.4 ± 16.2 pA, n = 6, P < 0.001, Student's paired t test; phasic IPSC100: control = 92.6 ± 13.1 pA, reduced Ca2+= 58.6 ± 11.0 pA, n = 6, P < 0.001, Student's paired t test). However, normalization of synaptic transmission revealed that reduction of extracellular [Ca2+] led to a reduction in synaptic depression, i.e. during the initial phase of transmission IPSCs exhibited facilitation and steady-state depression (SSD) represented by the fraction of the final evoked IPSC to the first evoked IPSC (%) was reduced (total IPSC: control SSD = 51.2 ± 4.0%, reduced Ca2+ SSD = 97.1 ± 17.7%, n = 6, P < 0.001, Student's paired t test; Fig. 2Bb; phasic IPSC: control SSD = 32.4 ± 2.6%, reduced Ca2+ SSD = 63.4 ± 7.7%, n = 6, P < 0.001, Student's paired t test; Fig. 2Bc). Together these data are consistent with the conclusion that a reduction in the initial probability of transmission leads to a reduction in synaptic depression at inhibitory GABAergic synapses in the STN.

Dopamine reduces activity-dependent depression

In order to determine how GABAergic transmission is regulated by dopamine, synaptic transmission in the presence and absence of 10 μm dopamine was compared in each neuron. The first IPSC was attenuated by dopamine by 41.8 ± 12.7% (n = 7, P = 0.042, Student's paired t test), 48.4 ± 9.5% (n = 8, P = 0.038, Student's paired t test) and 45.4 ± 7.5% (n = 10, P = 0.006, Student's paired t test) at 1, 10 and 50 Hz, respectively (Fig. 3A–C). This reduction was persistent at 1 Hz, but was significant only for the initial phase of transmission at 10 Hz and 50 Hz (Fig. 3C). At the end of each train, total and phasic IPSCs at 10 Hz and 50 Hz were of similar magnitude in control conditions and in the presence of dopamine (10 Hz, total IPSC50: control = 156.5 ± 56.0 pA, dopamine = 154.7 ± 37.7 pA, n = 8, P = 0.977, Student's paired t test; 50 Hz, total IPSC100: control = 141.0 ± 54.0 pA, dopamine = 133.8 ± 58.6 pA, n = 10, P = 0.737, Student's paired t test; 10 Hz, phasic IPSC50: control = 155.9 ± 55.9 pA, dopamine = 153.3 ± 37.4 pA, n = 8, P = 0.969, Student's paired t test; 50 Hz, phasic IPSC100: control = 94.3 ± 39.0 pA, dopamine = 94.3 ± 43.5 pA, n = 10, P = 0.99, Student's paired t test). Normalization of synaptic transmission to the first evoked IPSC revealed that synaptic depression was reduced by dopamine in an activity-dependent manner (Fig. 3D). At 1 Hz, normalized IPSCs were unaffected by dopamine (Fig. 3Da). At 10 Hz SSD of the total and phasic IPSCs were significantly reduced by dopamine (Fig. 3Db; total IPSC: control SSD = 37.7 ± 8.4%, dopamine SSD = 57.7 ± 7.6%, n = 8, P = 0.006, Student's paired t test; phasic IPSC: control SSD = 37.7 ± 8.4%, dopamine SSD = 57 ± 7.2%, n = 8, P = 0.006, Student's paired t test). Similarly, SSD at 50 Hz stimulation was reduced by dopamine (Fig. 3Dc; total IPSC: control SSD = 29.3 ± 4.9%, dopamine SSD = 47 ± 7.0%, n = 10, P = 0.008, Student's paired t test; SSD of phasic IPSC: control = 22.2 ± 4.4%, dopamine = 37.0 ± 7.3%, n = 10, P = 0.003, Student's paired t test). Together these data suggest that dopamine reduces synaptic depression by lowering the initial probability of GABAergic transmission in the STN, which leads to a reduction in the range of transmission strength.

Figure 3. Dopamine reduces activity-dependent depression.

Figure 3

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A and B, IPSCs evoked at 1 (panels a), 10 Hz (panels b), and 50 Hz (panels c) in a representative neuron under control conditions (A) and in the presence of dopamine (B; 10 μm). Dopamine reduced the amplitude of evoked IPSCs at each frequency tested but only reduced synaptic depression at 10 and 50 Hz. Ca–c, total IPSC amplitude (pA) plotted against IPSC number for the sample population. Ca, the amplitude of IPSCs evoked at 1 Hz was consistently reduced by dopamine throughout the sequence of stimulation (n = 7). Cb and c, at 10 (b) and 50 (c) Hz, the amplitude of evoked IPSCs was significantly reduced in the early but not the later phase of the stimulation sequence (10 Hz: n = 8; 50 Hz: n = 10). Da–c, total IPSC amplitude expressed as a percentage of the first evoked IPSC, plotted against IPSC number for the sample population (a, 1 Hz, n = 7; b, 10 Hz, n = 8; c, 50 Hz, n = 10). Dopamine significantly reduced synaptic depression at 10 and 50 Hz and unmasked synaptic facilitation at 50 Hz. *P > 0.05.

Dopamine reduces the frequency but not the amplitude of miniature GABAergic synaptic transmission

In order to more definitively determine the site of dopaminergic modulation, GABAergic mIPSCs were recorded at −60 mV in voltage clamp mode using CsCl-based electrode solution. Perfusion of 10 μm dopamine reduced the frequency of mIPSCs, as illustrated by a rightward shift in the cumulative distribution of interevent intervals (K-S test, n = 7, P < 0.001; Fig. 4A, Ba and Ca). In contrast, dopamine neither affected the cumulative distribution of the conductances underlying mIPSCs (K-S test, n = 7, P = 0.99; Fig. 4A, Bb and Cb) nor the decay kinetics of mIPSCs (τw control 7.4 ± 0.8 ms, τw dopamine = 8.4 ± 0.6 ms, n = 7, P = 0.098, Student's paired t test). Thus, the mean frequency of mIPSCs decreased by 47.9% (control = 3.53 ± 0.79 Hz, dopamine = 1.84 ± 0.26 Hz, n = 7, P = 0.026, Student's paired t test; Fig. 4 Da), whereas the mean conductance was unaltered (control = 0.84 ± 0.14 nS, dopamine = 0.82 ± 0.11 nS, n = 7, P = 0.765, Student's paired t test; Fig. 4Db). These data are therefore consistent with the conclusion that presynaptic rather than postsynaptic dopamine receptors modulate GABAergic transmission in the STN.

Figure 4. Dopamine reduces the frequency but not the conductance of mIPSCs in the STN.

Figure 4

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Aa and b, examples of mIPSCs recorded in voltage clamp at −60 mV under control conditions (a; black trace) and in the presence of 10 μm dopamine (b; grey trace) in a representative neuron. Ba and b, cumulative distributions of intervals between mIPSCs (a) and conductances underlying mIPSCs (b) before (black) and after the perfusion of dopamine (grey) for the neuron illustrated in A. Dopamine caused a significant increase in the intervals between mIPSCs but no alteration in their conductance. Ca and b, composite cumulative distributions of mIPSC intervals (a) and conductances (b) generated from 6 neurons recorded under control conditions (black) and then in the presence of 10 μm dopamine (grey) confirm at the population level the effect of dopamine on miniature GABAergic synaptic transmission. Da and b, line plots illustrating the actions of dopamine on the frequency and conductance of mIPSCs in each neuron. Black horizontal bars represent the mean frequency/conductance. *P < 0.001 (Ba, Ca); *P < 0.05 (Da).

Dopamine receptors mediating the modulation of GABAergic transmission

In order to characterize the presynaptic dopamine receptors responsible for the modulation of GABA release, experiments were conducted with agonists and antagonists of the D1-like and D2-like dopamine receptor families and compared to the effects of dopamine. For the purposes of brevity, comparisons between total IPSCs are reported in this section. Quinpirole (2 μm), a broad spectrum D2-like receptor agonist, mimicked the effects of dopamine on synaptic depression (Fig. 5Aa–c). At 1 Hz stimulation, quinpirole did not affect SSD (control = 79.6 ± 7.1%, quinpirole = 86.2 ± 2.5%, n = 9, P = 0.459, Student's paired t test; Fig. 5 Da), whereas at higher stimulation frequencies, SSD was significantly reduced (10 Hz: control = 61.9 ± 3.5%, quinpirole = 71.4 ± 3.6%, n = 13, P = 0.013, Student's paired t test; 50 Hz: control = 46.2 ± 3.2%, quinpirole = 63.4 ± 3.6%, n = 15, P < 0.001, Student's paired t test; Fig. 5Db–c).

Figure 5. D2 and/or D3 dopamine receptors but not D1-like or D4 dopamine receptor activation reduces activity-dependent depression.

Figure 5

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A–C, population plots of total IPSC amplitude (expressed as a percentage of the first IPSC) against IPSC number for 1 (panels a), 10 (panels b) and 50 Hz (panels c) stimulation under control conditions (black) and in the presence of the D2-like receptor agonist quinpirole (2 μm) (A, red) or the D4 dopamine receptor agonist PD168077 (1 μm) (B, blue) or the D1-like dopamine receptor agonist SKF81297 (5 μm) (C, green). Quinpirole significantly reduced activity-dependent depression of IPSCs at 10 (Ab; n = 13) and 50 Hz (Ac; n = 15). Neither PD168077 (Ba–c; n = 6) or SKF81297 (Ca–c; n = 4, 6 and 6 at 1, 10 Hz and 50 Hz, respectively) altered activity-dependent depression. D, summary plots of SSD at 1 (a), 10 (b) and 50 (c) Hz under control conditions (black) and in the presence of quinpirole (red) or PD168077 (blue) or SKF81297 (green). SSD at 10 and 50 Hz was significantly reduced by quinpirole only; *P < 0.05.

As GP neurons express each class of the D2-like receptor family (Gurevich & Joyce, 1999; Shin et al. 2003; Araki et al. 2007) the effect of the specific D4 receptor agonist, PD168077 (1 μm), was assessed. In contrast to quinpirole, PD168077 did not alter evoked synaptic transmission (Fig. 5Ba–c). SSD was similar in control conditions and in the presence of the D4 agonist at all frequencies tested (1 Hz: control = 80.9 ± 2.5%, PD168077 = 82.5 ± 2.1%, n = 6, P = 0.476, Student's paired t test; 10 Hz: control = 63.5 ± 4.3%, PD168077 = 66.7 ± 1.8%, n = 7, P = 0.357, Student's paired t test; 50 Hz: control = 59.3 ± 7.3%, PD168077 = 60.1 ± 6.6%, n = 7, P = 0.748, Student's paired t test; Fig. 5Da–c). The selective D1-like receptor agonist SKF81297 (5 μm) also failed to modulate SSD (1 Hz: control = 87.6 ± 3.8%, SKF81297 = 85.9 ± 1.5%, n = 4, P = 0.514, Student's paired t test; 10 Hz: control = 65.6 ± 8.5%, SKF81297 = 62.4 ± 8.9%, n = 7, P = 0.379, Student's paired t test; 50 Hz: control = 51.8 ± 2.7%, SKF81297 = 53.2 ± 6.1%, n = 6, P = 0.775, Student's paired t test; Fig. 5C and D). Finally, sulpiride (2 μm), a selective D2-like receptor antagonist, was found to reverse the reduction in SSD at 50 Hz transmission that was mediated by quinpirole (control = 44.5 ± 3.1%, quinpirole = 70.2 ± 5.1%, n = 3; P = 0.003, ANOVA; quinpirole + sulpiride = 51.2 ± 4.7%, n = 3, P = 0.237, ANOVA; Fig. 6A and B). Together these data suggest that D2 and/or D3 dopamine receptors modulate GABAergic transmission in the STN.

Figure 6. The D2/3 dopamine receptor antagonist sulpiride reverses the action of quinpirole and dopamine on activity-dependent depression.

Figure 6

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Aa–c, examples of IPSCs evoked at 50 Hz in control conditions (a), in quinpirole (2 μm) (b) and in quinpirole (2 μm) and sulpiride (2 μm; c). B, population plots of IPSC amplitude (expressed as a percentage of the first IPSC) against IPSC number for 3 neurons in the 3 conditions (control: black; quinpirole: red; quinpirole + sulpiride: blue). Ca–d, examples of IPSCs evoked at 50 Hz in control conditions (a), in dopamine (10 μm; b), in dopamine and the D4 receptor antagonist LY745870 (1 μm; c) and in dopamine, LY745870 and sulpiride (2 μm; d) in a typical neuron. Only sulpiride reversed the effect of dopamine. Da, population plots of total IPSC amplitude (expressed as a percentage of the first IPSC) against IPSC number for the 4 conditions (n = 5; control, black; dopamine, red; dopamine + LY745870, green; dopamine + LY745870 + sulpiride, blue). Db, SSD in the 4 conditions (n = 5). *P < 0.05.

Another set of experiments was carried out, in which the dopamine-mediated reduction of SSD (Fig. 6Ca and b) was challenged by the perfusion of D2-like receptor selective antagonists. The D4 receptor selective antagonist LY745870 (1 μm; Fig. 6Cc) and then sulpiride (2 μm) were applied. The dopamine-mediated reduction in SSD persisted in the presence of 1 μm LY745870 but was reversed by 2 μm sulpiride (Fig. 6Cd). Thus the normalized SSD in dopamine and in dopamine combined with LY745870 were significantly different from control SSD (control = 44.8 ± 10.6%, dopamine = 59.7 ± 11.4%, n = 5, P = 0.029, ANOVA; dopamine + LY745870 = 60.3 ± 12.2%, n = 5, P = 0.024, ANOVA; Fig. 6Da and b), whereas, the addition of sulpiride to dopamine and LY745870 restored SSD to control values (control = 44.8 ± 10.6%, dopamine + LY745870 + sulpiride = 49.9 ± 7.0%, n = 5, P = 0.964, ANOVA; Fig. 6 Da and b). Together these data provide further evidence that dopaminergic modulation of GABAergic synaptic transmission is mediated by D2 and/or D3 but not D4 dopamine receptors.

Application of 2 μm quinpirole also reduced the frequency of mIPSCs but did not modify their conductance (Fig. 7). Thus cumulative distributions of intervals between mIPSCs were significantly shifted to the right (Fig. 7Ba and Ca), whereas cumulative distributions of mIPSC conductance were unaltered (Fig. 7Bb and Cb). The mean frequency of mIPSCs was also decreased by quinpirole by 37.9% (control = 2.91 ± 0.60 Hz, quinpirole = 1.81 ± 0.27 Hz, n = 7, P = 0.031, Student's paired t test; Fig. 7A and Da) with no alteration in mean conductance (control =0.65 ± 0.06 nS, quinpirole = 0.64 ± 0.05 nS, n = 7, P = 0.662, Student's paired t test; Fig. 7A and Db). The D1-like dopamine receptor agonist SKF81297 (5 μm) had no effect on either aspect of miniature GABAergic transmission (frequency: control = 2.59 ± 0.55 Hz, SKF81297 =2.70 ± 0.61 Hz, n = 4, P = 0.273, Student's paired t test; conductance: control = 0.62 ± 0.08 nS, SKF81297 = 0.64 ± 0.06 nS, n = 4, P = 0.472, Student's paired t test; Fig. 7E–H). Together these results suggest that D2-like but not D1-like dopamine receptors, modulate the miniature release of GABA in the STN.

Figure 7. D2-like but not D1-like dopamine receptor activation reduces the frequency of mIPSCs.

Figure 7

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A, examples of mIPSCs recorded in voltage-clamp at −60 mV under control conditions (a; black) and in the presence of 2 μm quinpirole (b; grey) in a representative neuron. B and C, cumulative distributions of intervals between mIPSCs (Ba) and mIPSC conductances for the neuron in A (Bb) and for the sample population (Ca and b; n = 7) under control conditions (black) and in the presence of quinpirole (grey). Da and b, Line plots illustrating the actions of quinpirole on the frequency and conductance of mIPSCs in each neuron. Black horizontal bars represent the mean frequency/conductance. E–H, as for A–D but in the presence of 5 μm SKF81297 (grey). SKF81297 did not modify the frequency (Fa, Ga, Ha) or conductance (Fb, Gb, Hb) of mIPSCs in a representative neuron (E and F) or the sample population (G and H; n = 4). *P < 0.001 (Ba, Ca); *P < 0.05 (Da).

Functional impact of dopaminergic modulation of GABAergic transmission in the STN

In order to determine how dopaminergic modulation of GABAergic transmission affects the patterning of STN neurons, the dynamic clamp technique was utilized to inject synaptic conductances representative of GABAergic transmission under control conditions and in the presence of dopamine receptor agonists. The impact of brief GABAergic inputs arising from a small number of synapses (< 10) on the resetting of autonomous STN activity was assessed through the injection of two or five simulated IPSPs (Figs 8 and 9). The two-IPSP waveforms were derived from voltage clamp recordings of IPSCs evoked at 50 Hz in a STN neuron in the absence and presence of 2 μm quinpirole, as described in Methods (Fig. 8Aa and Ba). The five-IPSP waveforms were also based on the voltage-clamp recordings of control and dopamine receptor-modulated transmission but were generated digitally (Fig. 9Aa and Ba), as described in Methods. Observations were made in 12 neurons of which 11 were recorded in the perforated patch configuration and one was recorded in the whole cell configuration.

Figure 8. Presynaptic dopaminergic modulation reduces the capability of GABAergic synaptic transmission to reset autonomous activity.

Figure 8

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A and B, data from a representative neuron that was recorded in the perforated patch configuration. Aa, top, dynamic clamp waveform mimicking GABAergic synaptic transmission at 50 Hz under control conditions. Bottom, resetting of neuronal activity by the control waveform (50 superimposed trials). Ab, raster plot from the neuron in Aa. B, a dynamic clamp waveform mimicking GABAergic synaptic transmission at 50 Hz in 2 μm quinpirole was less effective at resetting autonomous activity (arrangement of panels as for A). C, differences in the latency (Ca), variability (Cb; s.d. of latency) and threshold (Cc; APth) of action potentials following the control and modulated waveform. The variability of the first action potential following the modulated waveform was significantly greater than for the control waveform. *P < 0.05.

Figure 9. Presynaptic dopaminergic modulation reduces the effect of GABAergic inhibition on the threshold of autonomously generated action potentials.

Figure 9

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A and B, data from a representative neuron that was recorded in the perforated patch configuration. Aa, top, dynamic clamp waveform mimicking GABAergic synaptic transmission at 50 Hz under control conditions. Bottom, resetting of neuronal activity by the control waveform (50 superimposed trials). Ab, raster plot from the neuron in Aa. Ac, phase plot of an autonomously generated action potential before (black) and immediately after inhibition (blue). Inset illustrates the lowering of action potential threshold (dots) by inhibition. B, effects of a dynamic clamp waveform mimicking GABAergic synaptic transmission at 50 Hz in the presence of 10 μm dopamine (arrangement of panels as for A). The modulated waveform less powerfully reduces the threshold of action potentials compared to the control waveform. C, differences in the latency (a), variability (b; s.d. of latency) and threshold (c; APth) of action potentials following the control and modulated waveform. The latency and the threshold of the first action potential following the modulated waveform were significantly shorter and greater than for the control waveform, respectively. *P < 0.05.

The two-IPSP waveforms briefly interrupted autonomous activity (Fig. 8Aa, Ab, Ba and Bb) as previously described; however, the interruption was similar in duration for control and modulated inhibition, i.e. the latencies of action potentials that followed the control and modulated waveforms were not significantly different (Fig. 8Ca). Although both waveforms also reset autonomous firing, the modulated waveform less consistently reset autonomous activity than the control waveform, as evidenced by the greater dispersion of action potentials in raster plots (Fig. 8Ab and Bb) and the increased variability in the timing of action potentials immediately following inhibition (s.d. of latency; Fig. 8Cb) (control = 14.3 ± 3.7 ms, modulated = 18.7 ± 5.1 ms, n = 5, P = 0.034, Student's paired t test). Each waveform also lowered the threshold of subsequently generated action potentials, as previously described (Baufreton et al. 2005a); however, the degree to which threshold was lowered was not significantly different (Fig. 8Cc). The five-IPSP waveform (Fig. 9) more consistently reset autonomous activity than the two-IPSP waveform (Fig. 8) as evidenced by a reduction in the s.d. of the latency of the action potential following inhibition (control 2 IPSP = 14.3 ± 3.7 ms, n = 5; control 5 IPSP = 5.1 ± 1.0 ms, n = 7; P = 0.003, Student's unpaired t test) but, in contrast to the two-IPSP waveforms, the control and modulated five-IPSP waveforms did not differ in their resetting of autonomous activity (control = 5.1 ± 1.0 ms, modulated = 5.6 ± 0.9 ms, n = 7, P = 0.387, Student's paired t test; Fig. 9A, B and Cb). Also in contrast to the two-IPSP waveforms, the latency of action potentials immediately following the modulated five-IPSP waveform was slightly but significantly shorter compared to the control IPSP waveform (control = 161.6 ± 11.5 ms, modulated = 153.8 ± 12.1 ms, n = 7, P = 0.004, Student's paired t test; Fig. 9Ca) and the degree to which action potential threshold was lowered by the five-IPSP waveforms was significantly smaller for the modulated waveform compared to the control waveform (control = 1.4 ± 0.2 mV, modulated = 1.1 ± 0.2 mV, n = 7, P = 0.044, Student's paired t test; Fig. 9Ac, Bc and Cc). Together, these data suggest that presynaptic dopaminergic modulation regulates the effects of GABAergic inhibition on autonomous STN activity in a manner that is dependent on the pattern of presynaptic activity.

High-frequency bursts of GABAergic IPSPs can produce sufficient hyperpolarization of the membrane potential to deinactivate postsynaptic Cav1 and Cav3 channels to trigger a postinhibitory rebound burst in STN neurons (Bevan et al. 2002; Hallworth & Bevan, 2005). In order to determine how presynaptic dopaminergic modulation of GABAergic transmission affects the generation of rebound burst firing, trains of 10 IPSPs at 50 Hz were generated using the dynamic clamp technique with profiles of transmission observed under control conditions or in the presence of dopamine (Fig. 10Aa and Ba). The conductance of the first IPSP of the control waveform was adjusted (range 15–25 nS) in order to trigger a rebound burst in the recorded STN neuron. The conductance of the first IPSP of the dopamine-modulated waveform was then scaled to 60% of the control waveform (range 9–15 nS) in order to mimic the effect of dopamine on the initial probability of transmitter release. Observations were made in seven neurons that were recorded in the perforated patch configuration. Both dynamic clamp waveforms generated rebound burst firing (defined as action potentials occurring at a frequency in excess of mean spontaneous firing + 3 s.d.) in each of seven neurons tested. However, the peak instantaneous frequency of rebound burst firing was lower for the modulated waveform (control = 50.0 ± 14.5 Hz, modulated = 40.8 ± 11.6 Hz, n = 7, P = 0.04, Student's paired t test; Fig. 10). The duration of rebound bursts and the number of action potentials associated with each rebound burst were also significantly lower for the modulated waveform (burst duration: control = 434.0 ± 72.4 ms, modulated = 362.5 ± 56.9 ms, n = 7, P = 0.047, Student's paired t test; action potentials per burst: control = 6.1 ± 1.1, modulated = 4.9 ± 0.8, n = 7, P = 0.012, Student's paired t test). Together these data suggest presynaptic dopaminergic modulation reduces the capability of GABAergic inputs to generate rebound burst firing in STN neurons.

Figure 10. Presynaptic dopaminergic modulation reduces the capability of GABAergic transmission to evoke rebound activity.

Figure 10

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A–D, data from a representative neuron that was recorded in the perforated patch configuration. Aa, top, dynamic clamp waveform mimicking GABAergic synaptic transmission at 50 Hz under control conditions. Bottom, a rebound burst induced by the control waveform. Ab, instantaneous frequency (Inst freq) of discharge associated with the trial in Aa. Dashed line = basal firing rate + 3 s.d.Ba, top, dynamic clamp waveform mimicking GABAergic synaptic transmission at 50 Hz in dopamine (10 μm). Bottom, a rebound burst induced by the modulated waveform. Bb, instantaneous frequency of discharge associated with the trial in Ba. Note that the maximum frequency of discharge is lower than for A. Ca and Da, expanded view of rebound bursts evoked by control (Ca) and modulated (Da) waveforms. Raster plots (Cb and Db) and peristimulus time histograms (Cc and Dc) for the control (Cb and c) and modulated (Db and c) waveforms. E, results for seven neurons (each represented by a distinct symbol). The maximum instantaneous rebound burst frequency (a), rebound burst duration (b) and number of action potentials (APs) per rebound burst (c) were significantly lower for the modulated waveform. Black horizontal bars represent mean values. *P < 0.05.

Discussion

GABAergic transmission in the STN is subject to activity-dependent depression

GABAergic transmission in the STN was subject to activity-dependent synaptic depression, i.e. the degree of synaptic depression increased with the frequency of evoked transmission. Similar to other GABAergic synapses, the onset of depression was best fit by the sum of two or three exponential processes, with time constants ranging from less than 100 ms to much greater than 100 ms (Galarreta & Hestrin, 1998; Hefft et al. 2002; Telgkamp & Raman, 2002; Zucker & Regehr, 2002). The factors contributing to synaptic depression were not studied in detail here but may include the depletion of release-ready vesicles and/or inactivation of presynaptic voltage-dependent Cav channels and/or desensitization of postsynaptic receptors (Overstreet et al. 2000; Brenowitz & Trussell, 2001; Schneggenburger et al. 2002; von Gersdorff & Borst, 2002; Zucker & Regehr, 2002; Blitz et al. 2004; Xu & Wu, 2005; Xu et al. 2007). Therefore, reduction of the initial probability of synaptic transmission (which was achieved by lowering extracellular [Ca2+]) may have limited synaptic depression by conserving release-ready vesicles and/or reducing Ca2+-dependent inactivation of presynaptic Cav channels and/or reducing desensitization of postsynaptic receptors. Lowering extracellular [Ca2+] also unmasked facilitation in the early phase of GABAergic transmission. In the presence of low extracellular [Ca2+] it is likely that accumulation of residual Ca2+ in the synaptic terminals was responsible for the initial facilitation of transmitter release (Katz & Miledi, 1968; Zucker & Regehr, 2002; Felmy et al. 2003).

Although GABAergic synaptic transmission exhibited depression, robust transmission was observed at the end of long sequences of stimulation. The level of steady-state transmission was similar to that observed at other central GABAergic synapses (Galarreta & Hestrin, 1998; Kraushaar & Jonas, 2000; Hefft et al. 2002; Telgkamp & Raman, 2002; Telgkamp et al. 2004). The relative stability of GABAergic transmission compared to glutamatergic transmission in cortical and subcortical networks has been proposed to be important for maintaining the balance of neuronal network activity and the prevention of excessive excitability. Several mechanisms have been proposed to counteract synaptic depression including spillover activation of multiple active zones associated with individual terminals (Telgkamp et al. 2004), Ca2+-dependent facilitation of vesicle cycling and docking (Dittman & Regehr, 1998; Wang & Kaczmarek, 1998; Zucker & Regehr, 2002; Habets & Borst, 2007) and sustained but slow release from a relatively ‘reluctant’ subpopulation of synaptic vesicles (Schneggenburger et al. 2002).

GABAA receptor-mediated synaptic transmission in the STN is thought to be predominantly mediated by the phasic activation of synaptic receptors rather than the tonic activation of extrasynaptic receptors (Farrant & Nusser, 2005) because voltage clamp recordings have revealed that GABAA receptor antagonists eliminate spontaneous phasic IPSCs but have no effect on baseline holding current (Hallworth & Bevan, 2005) and the density of GABAA receptors is far greater at synapses than at extrasynaptic sites (Galvan et al. 2004). GABAergic transmission that was aynchronous with electrical stimulation was also not apparent (cf. Hefft & Jonas, 2005). Thus, the appreciable ‘tonic’ current that was observed at 10–50 Hz electrical stimulation (Telgkamp & Raman, 2002) was most likely due to summation of phasic IPSCs that decayed less quickly than the intervals between stimulation. While tonic currents of this type are incapable of precisely patterning action potential generation in postsynaptic neurons they appear to be important for determining the overall level and/or mode of postsynaptic activity (Bevan et al. 2002; Telgkamp & Raman, 2002). The combination of depression and summation at high frequencies of transmission will therefore be predicted to greatly alter the manner in which GABAergic synaptic inputs pattern STN activity compared to transmission at low frequencies.

Dopaminergic modulation of activity-dependent plasticity at GABAergic synapses

Dopamine reduced the absolute amplitude of the first evoked IPSC by ∼40–50%. However, transmission at the end of sequences of 10–50 Hz stimulation was of similar amplitude to that observed under control conditions. Normalization of transmission at 10–50 Hz to the amplitude of the first evoked IPSC confirmed that dopamine reduced synaptic depression and unmasked synaptic facilitation. Together, these data are consistent with the conclusion that dopamine acting at presynaptic receptors reduces the initial probability of transmitter release at GABAergic terminals in the STN, which retards the onset of synaptic depression due to vesicle depletion and/or postsynaptic receptor desensitization (Schneggenburger et al. 2002; Zucker & Regehr, 2002). If dopamine reduces the conductance of presynaptic Ca2+ channels necessary for transmission, depression due to the Ca2+-dependent inactivation of presynaptic Cav channels may also be reduced (Xu & Wu, 2005; Xu et al. 2007). If postsynaptic dopamine receptors had been largely responsible for the modulation of GABAergic transmission, the amplitude of transmission would presumably have been altered in an activity-independent manner. Our findings are therefore consistent with an earlier report in the STN that showed that dopaminergic modulation increased the relative amplitude of the second IPSC of a pair of IPSCs that were evoked with a 30–50 ms interval (Shen & Johnson, 2000). Presynaptic rather than postsynaptic dopaminergic modulation of GABAergic transmission in the STN was further supported by the action of dopamine on miniature GABAergic transmission. Thus dopamine reduced the frequency but did not alter the amplitude or kinetics of mIPSCs, findings that are classically associated with a reduction in the probability of transmitter release (Miller, 1998). Together the effects of dopamine on evoked and miniature synaptic transmission suggest that dopaminergic neuromodulation of GABAergic transmission in the STN appears to be mediated largely if not exclusively by presynaptic receptors despite the expression of functional postsynaptic D1- and D2-like dopamine receptors in STN neurons (Flores et al. 1999; Svenningsson & Le Moine, 2002; Zhu et al. 2002b; Baufreton et al. 2003; Tofighy et al. 2003; Ramanathan et al. 2008) and evidence for postsynaptic dopamine receptor-mediated modulation of GABAergic transmission in a variety of brain regions (Yan & Surmeier, 1997; Flores-Hernandez et al. 2000; Liu et al. 2000; Wang et al. 2002; Shin et al. 2003).

Dopaminergic modulation of activity-dependent plasticity at GABAergic synapses is mediated by D2-like dopamine receptors

Use of dopamine receptor-selective agonists demonstrated that D2-like dopamine receptors but not D1-like dopamine receptors mimicked the effects of dopamine on evoked and miniature GABAergic transmission. The effects are consistent with the action of presynaptic D2-like receptors on GABAergic transmission in a variety of brain regions including the striatum (Tecuapetla et al. 2007), nucleus accumbens (Hjelmstad, 2004; Mizuno et al. 2007), globus pallidus (Cooper & Stanford, 2001) and lateral hypothalamus (Baimoukhametova et al. 2004). Use of subtype selective agonists and antagonists of the D2-like dopamine receptor family further suggest that D2 and/or D3 but not D4 dopamine receptors mediate the effect of dopamine on GABAergic transmission despite the fact that GP neurons, which supply the major GABAergic projection to the STN, express each class of D2-like dopamine receptor (Gurevich & Joyce, 1999; Shin et al. 2003; Araki et al. 2007). The mechanisms underlying presynaptic D2/3 dopamine receptor-mediated modulation of GABAergic synaptic transmission in the STN were not addressed here but could include a reduction in the conductance of axon-terminal Cav channels (Dittman & Regehr, 1996; Qian et al. 1997; Isaacson, 1998; Miller, 1998) and/or modulation of axon-terminal voltage-dependent K+ channels (Thompson & Gahwiler, 1992; Ponce et al. 1996; Nicola & Malenka, 1997; Vervaeke et al. 2006) and/or modulation of the molecular machinery underlying the cycling, positioning and fusion of synaptic vesicles (Dittman & Regehr, 1996; Nicola & Malenka, 1997; Kubota et al. 2003; Sakaba & Neher, 2003; Blackmer et al. 2005; Gerachshenko et al. 2005). Although few data are available concerning the signalling pathways and targets of dopamine receptors in GP neurons, one report suggests that D2-like dopamine receptors inhibit the conductance of Cav2.2 channels (Stefani et al. 2002) that along with Cav2.1 channels are important for transmission at the majority of central synapses (Evans & Zamponi, 2006).

Patterning of STN activity by control and dopamine-modulated GABAergic transmission

Recent studies have demonstrated that GABAergic input acting at GABAA receptors can generate a range of firing patterns in STN neurons. The manner in which STN activity is patterned is dependent on the pattern and strength of input and the interaction of input with the intrinsic membrane properties of STN neurons (Bevan et al. 2006). Thus, large, single, evoked GABAA receptor-mediated IPSPs can, through the complete deactivation of postsynaptic Nav channels (which underlie the persistent, transient and resurgent currents that drive autonomous STN activity) (Bevan & Wilson, 1999; Beurrier et al. 2000; Do & Bean, 2003; Baufreton et al. 2005a), consistently reset the autonomous firing of STN neurons, whereas, smaller IPSPs, through less complete and consistent deactivation of postsynaptic Nav channels, generate variable shifts in the phase of autonomous activity (Bevan et al. 2002; Baufreton et al. 2005a). Spontaneous, poorly correlated GP inputs also acting at synaptic GABAA receptors disrupt the regularity and reduce the frequency of autonomous STN activity, presumably through the deactivation of Nav channels (Baufreton et al. 2005a; Hallworth & Bevan, 2005). Paradoxically, GABAA receptor-mediated inhibition can also, through the deinactivation of postsynaptic Nav channels, transiently enhance the sensitivity of STN neurons to subsequent and/or rhythmic excitatory synaptic inputs (Baufreton et al. 2005a). Finally, more synchronous, prolonged barrages of GABAA receptor-mediated inhibition can produce sufficient hyperpolarization to deinactivate postsynaptic Cav1 and Cav3 channels, which upon cessation of inhibition can generate a rebound burst of activity (Bevan et al. 2002; Hallworth & Bevan, 2005).

Using the dynamic clamp technique (Robinson & Kawai, 1993; Sharp et al. 1993), rather than the direct application of dopamine receptor agonists, we were able compare the manner in which ‘control’ and ‘dopamine-modulated’ inputs pattern STN activity, without a confounding alteration in postsynaptic excitability (Zhu et al. 2002a,b; Baufreton et al. 2003; Tofighy et al. 2003; Ramanathan et al. 2008). It is estimated that STN neurons each receive approximately 300 synaptic inputs (Bevan et al. unpublished observations), each with a mean conductance of approximately 0.8 nS (this study). Thus the magnitude of conductances utilized here (5–25 nS) mimics inputs from ∼6–30 or ∼2–10% of all GABAergic synapses. It is likely that the somatic injection of synaptic conductances more effectively mimicked inputs to the proximal parts of STN neurons than inputs to more distal compartments because (1) somatic and not dendritic voltage was used to guide conductance injection and (2) conductances were applied directly to the soma and not to distal dendrites. However, our application of the dynamic clamp technique is expected to reasonably mimic GABAergic inhibition of STN neurons because the majority of GABAergic inputs are directed to their somata and proximal dendrites (Smith et al. 1998).

As predicted from earlier studies, ‘weak’, brief, inhibitory inputs reset autonomous activity and lowered the threshold of subsequently generated action potentials but did not generate rebound burst firing. However, dopamine-modulated input was less effective at deactivating postsynaptic Nav channels and thus resetting autonomous activity. Dopamine-modulated inputs were also less effective at deinactivating postsynaptic Nav channels than the control input. Although the different degree to which action potential threshold was lowered by control versus modulated inputs was small, it was robust. Furthermore, a similar difference in threshold reflects a quite large difference in the availability of postsynaptic Nav channels, which in turn profoundly impacts the manner in which subsequent excitatory synaptic inputs are integrated (Baufreton et al. 2005b). Interestingly, the precise differences in the effects of modulated versus control inputs depended on the input pattern that was employed. Thus, less effective resetting was observed for the two-IPSP but the not the five-IPSP modulated waveform, whereas less effective Nav channel deinactivation was observed for the five-IPSP but not the two-IPSP modulated waveform. Presumably, the two-IPSP waveforms less completely deactivated Nav channels than the five-IPSP waveforms, thus allowing differences in the degree of deactivation/resetting by control and modulated waveforms to be detected (Baufreton et al. 2005a). In contrast, the five-IPSP waveforms may have more effectively deinactivated Nav channels than the two-IPSP waveforms, thus allowing differences in the degree of channel deinactivation by control and modulated waveforms to be detected (Baufreton et al. 2005a). When simulated inhibition was increased in magnitude and duration sufficient to evoke a rebound burst of activity, the dopamine-modulated form of inhibition consistently generated burst activity of lower frequency and duration than the control waveform. Thus modulated input most likely less effectively hyperpolarized and deinactivated postsynaptic Cav1 and Cav3 channels than control inputs.

Functional implications

Taken together, the data described here demonstrate that dopamine acting at presynaptic D2/3 receptors potently modulates the manner in which GABAergic inputs (that predominantly arise from the GP) pattern the activity of STN neurons. Under normal conditions, dopamine may therefore reduce the amplitude and range of amplitude of inhibition arising from the GP. The impact of inhibition may be further modified by the action of postsynaptic dopamine receptors, which together will lead to the relative depolarization, increased autonomous activity and altered responsiveness of STN neurons to excitation (Zhu et al. 2002a,b; Baufreton et al. 2003, 2005b; Tofighy et al. 2003; Cragg et al. 2004; Ramanathan et al. 2008). Presynaptic and postsynaptic dopaminergic modulation of the excitatory STN–GP connection may further act to normalize the interaction between reciprocally connected STN and GP neurons (Hernandez et al. 2006).

In PD, reduced presynaptic dopaminergic neuromodulation may cause GABAergic GP inputs to more powerfully and phasically pattern STN activity and thus contribute to abnormal correlated, burst firing in STN neurons. The abnormal patterning of STN activity by the GP may be further enhanced by hypoactivation of postsynaptic dopamine receptors in STN neurons, which may contribute to the abnormal hyperpolarization of STN neurons in PD models (Zhu et al. 2002a; Wilson et al. 2006) and the deinactivation of Cav1 and Cav3 channels that mediate rebound burst activity. An increase in whole-cell GABAA current in STN neurons that follows dopamine depletion (Shen & Johnson, 2005) could further contribute to the abnormal patterning of STN neurons by the GP. Finally, hypoactivation of pre- and postsynaptic dopamine receptors that modulate the activity-dependent plasticity and potency of the STN–GP pathway (Hernandez et al. 2006) could further contribute to abnormally powerful and phasic interactions between reciprocally connected STN and GP neurons.

In summary, our and other recent studies have revealed that the effects of dopamine in the STN and GP are potent and complex and suggest that direct dopaminergic neuromodulation is likely to be critical for the normal interaction of STN and GP neurons.

Acknowledgments

This research was supported by NIH-NINDS Grants NS041280, NS047085 and NS20702 (M.D.B.), the National Parkinson Foundation (M.D.B.), and L’Association France Parkinson (J.B.).

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