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Actions of Adenosine A_2A Receptors on Synaptic Connections of Spiny Projection Neurons in the Neostriatal Inhibitory Network

Department of Anatomy and Structural Biology, University of Otago, Dunedin, New Zealand; and Neurobiology Research Unit, Okinawa Institute of Science and Technology, Okinawa, Japan

Submitted 15 November 2007; accepted in final form 12 February 2008

	ABSTRACT

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There is growing evidence that adenosine plays a crucial role in basal ganglia function, particularly in the modulation of voluntary movement. An adenosine-based treatment for Parkinson's disease shows promise in recent clinical studies. Adenosine A_2A receptors, the receptors involved in this treatment, are highly expressed in the neostriatum. Previous studies have suggested opposing actions of these receptors on synaptic transmission at striatal and pallidal terminals of the same spiny projection neurons, but the cells of origin of the intrastriatal terminals mediating these actions have not been identified. We used dual whole cell recordings to record simultaneously from pairs of striatal cells; this enabled definitive identification of the presynaptic and postsynaptic cells mediating the effects of A_2A receptors. We found that A_2A receptors facilitate GABAergic synaptic transmission by intrastriatal collaterals of the spiny projection neurons, consistent with their previously reported actions on synaptic transmission at pallidal terminals. This neuromodulatory action on lateral inhibition in the striatum may underlie, in part, the therapeutic efficacy of adenosine-based treatments for Parkinson's disease.

	INTRODUCTION

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The neostriatum is a central component of the basal ganglia and is crucial for control of voluntary movement and intentional behavior. Dysfunction of the striatum underlies the symptoms of Parkinson's disease, Huntington's disease, and several other movement disorders. The principal neuron of the neostriatum is a spiny projection neuron (Somogyi et al. 1981; Wilson and Groves 1980), which accounts for the great majority of neurons in the rat neostriatum (Oorschot 1996). The spiny projection neurons produce local axon collaterals that make GABAergic synapses (Fujiyama et al. 2000) with other spiny projection neurons to form an interconnected network in which several classes of interneuron also participate (Tepper and Bolam 2004). The operation of this microcircuitry is crucial for normal movement and behavior.

The electrophysiological operation of the neostriatal network has only begun to be elucidated. Recent reports show that spiny projection neurons provide functional synaptic input to one another via their local axon collaterals (Czubayko and Plenz 2002; Koos et al. 2004; Tunstall et al. 2002; Venance et al. 2004). Spiny projection neurons also receive inputs from several types of GABAergic interneuron, including a fast-spiking (FS) interneuron that has been shown to exert strong inhibitory control over neostriatal output (Koos and Tepper 1999). This GABAergic circuitry, comprising feedback inhibition by spiny projection neurons and feedforward inhibition by FS interneurons, plays a critical role in integrating cortical inputs and regulating basal ganglia output activity (Kita 1993; Koos and Tepper 1999; Plenz 2003).

There is growing evidence that adenosine plays an important role in basal ganglia function (Richardson et al. 1997; Svenningsson et al. 1999). Adenosine is an endogenous purine released (or generated) intracellularly and extracellularly. It is present at low levels (20–300 nM) in the extracellular space and interacts with specific receptors. Adenosine has four G-protein-coupled, membrane-bound receptor subtypes designated A₁, A_2A, A_2B, and A₃. Of these subtypes, the adenosine A_2A receptor is highly expressed in the striatum, particularly on striatopallidal projection neurons (Dixon et al. 1996). Recently, antagonists of adenosine A_2A receptors have emerged as an important new class of effective anti-parkinsonian agents (Hauser and Schwarzschild 2005; Jenner 2005).

Previous brain slice electrophysiological studies have shown that A_2A receptors facilitate GABAergic transmission in the globus pallidus, a major projection area of the neostriatal spiny projection neurons (Shindou et al. 2003). Paradoxically, it has been reported that A_2A receptors decrease GABAergic transmission in the neostriatum (Mori et al. 1996), suggesting opposite effects of A_2A receptors on the pallidal and striatal terminals of the same spiny neurons. However, because field stimulation was used to evoke IPSCs in the neostriatum (Mori et al. 1996), both FS interneurons and spiny projection neurons may have been activated. Thus it is important to determine the effects of A_2A receptors on GABAergic transmission in the neostriatum that are mediated by spiny projection neurons.

We used dual whole cell recording to measure the effects of adenosine A_2A agonists on GABAergic synaptic transmission in the striatum. We investigated postsynaptic responses to single action potentials evoked in the presynaptic neuron before and after exposure to an adenosine A_2A agonist drug. By intracellular labeling of the recorded cells, we were able to identify the presynaptic neurons definitively, allowing us to determine the adenosine A_2A receptor actions that are mediated specifically by spiny projection neurons.

	METHODS

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Animals were handled in accordance with protocols approved by the University of Otago Animal Ethics Committee. The experiments were performed on male Wistar rats (age: 21–28 days). Animals were deeply anesthetized with pentobarbital sodium (SIGMA). They were perfused transcardially for 2 min with cold modified-artificial cerebrospinal fluid (ACSF) containing the following (in mM): 126.0 NaCl, 2.5 KCl, 0.5 CaCl₂, 4.5 MgCl₂, 26.0 NaHCO₃, 1.0 NaHPO₄, and 20.0 glucose and saturated with 95% O₂-5% CO₂. Slices containing the striatum were cut on a VT1000S microtome (Leica) at a thickness of 300 µm in an oblique plane, 45° rostral-up to the horizontal (Tunstall et al. 2002). Slices were then incubated in oxygenated standard ACSF maintained at a temperature of 32–33°C for 1 h. The standard ACSF had the following composition (mM): 126.0 NaCl, 2.5 KCl, 2.4 CaCl₂, 1.2 MgCl₂, 26.0 NaHCO₃, 1.0 NaHPO₄, and 11.0 glucose. After incubation, a single slice was transferred to a recording chamber placed on the stage of an upright microscope, and was continuously perfused (3–4 ml/min) with oxygenated ACSF at 30°C. The remaining slices were kept in a holding chamber containing oxygenated ACSF at room temperature.

Whole cell recordings were obtained from neostriatal neurons with patch pipettes (2–4 M) filled with internal solution containing the following (in mM): 64.0 K-gluconate, 60.0 KCl, 8.0 NaCl, 10.0 HEPES, 0.5 EGTA, 4.0 ATP, 0.3 GTP, and 0.5% biocytin; pH 7.2–7.4. The series resistance was not compensated but was monitored continuously using 5-mV voltage pulses. Recordings showing >20% change in series resistance were discarded.

Recordings were made in a solution containing blockers of excitatory transmission, namely D-2-amino-5-phosphonovaleric acid (APV, 50 µM), and 6-cyano-7-nitroquionexanline-2,3-dione (CNQX, 10 µM). Unitary IPSCs were elicited at 0.066–0.2 Hz by single action potentials generated in the presynaptic cells by depolarizing somatic current pulse (duration, 5 ms) and measured in postsynaptic neurons voltage clamped at –80 mV. In the case of paired-pulse experiments, IPSCs were evoked at 0.066 Hz. For drug effects on spiny-spiny IPSCs, 15–20 successive IPSCs were averaged (including failures) and normalized by dividing by the average obtained during the control period. In paired-pulse recording experiments, paired-pulse ratio and failure rate of 15–20 successive IPSCs were measured before and after drug application.

Data analysis was performed using custom software written in AxoGraph. All data are given as means ± SE unless stated otherwise. Responses to agonists are expressed as a percentage of the control obtained before the addition of the agonists. Paired t-tests were performed to compare the control period with the responses in the presence of agonists and wash period on the same cell. For analysis of individual cells, the nonparametric Mann-Whitney U test was applied between the control (15–20 consecutive IPSCs, over 4–5 min, stimulation every 15 s) and treatment period (15–20 consecutive IPSCs from last 1–2 min of drug application until 2–3 min after application) and between control and washout periods.

For morphological identification of recorded cells, 0.5% biocytin was included in the pipette solution and cells were filled by diffusion. After a recording was completed, slices containing biocytin-loaded cells were fixed by immersion in 4% paraformaldehyde in 0.1 M phosphate buffer (PB) overnight at 4°C. They were rinsed in PB for 30 min and incubated in PB containing 0.5% H₂O₂ for 30 min. They were then incubated in 15 and 30% sucrose for 30 min and 1 h, respectively. The slices were then washed with Tris-buffered saline (TBS) containing 0.5% Triton X and streptavidin-Alexa fluor 488 (1:1000, Mol Probe) for 2 h at room temperature. To determine the localization of A_2A receptors in spiny projection neurons, we incubated the slices in TBS containing 0.5% Triton X, 10% normal donkey serum (NDS), and a mouse anti-adenosine A_2A receptor antibody (1:1,000, Upstate, Lake Placid, NY) for 4 days at 4°C. We then incubated the slices overnight at 4°C in 0.3% Triton X, 10% NDS, and anti-mouse conjugated Alexa Fluor 543 (1:200, Chemicon). After washing with TBS, the slices were mounted on a glass slide and were observed under a confocal laser scanning microscope (LSM 410, Zeiss) with a confocal laser depth of 0.5 µm.

Drugs (APV and CNQX) were bath-applied in the solution superfusing the slice. For experiments with CGS21680, the solution superfusing the slice was replaced with one containing a set concentration of active drug. APV and CNQX were obtained from Tocris Cookson (Bristol, UK); CGS21680 was from Research Biochemicals International (Natick, MA).

	RESULTS

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Recordings were obtained from 194 pairs of spiny projection neurons in which direct connections were tested for by inducing action potentials in one neuron while simultaneously recording the response in the other. The recorded spiny projection neurons were identified by their characteristic electrophysiological properties and also by staining of intracellularly injected biocytin. Spiny projection neurons exhibited characteristic delay in action potential firing and onset of firing at low rates in response to depolarizing current pulses, heavily spine-encrusted distal dendrites, and a local plexus of axon collaterals. The electrophysiological characteristics, unitary synaptic responses and morphology of a typical connected spiny projection neuron pair are shown in Fig. 1 (A–C).

View larger version (42K): [in this window] [in a new window]   FIG. 1. Morphological and physiological characteristics of spiny projection neuron pair. A: confocal image of connected spiny projection neuron pair showing biocytin-filled soma, axonal ramifications, and spiny dendrites of presynaptic (pre) and postsynaptic (post) neurons. Both cells show morphological features of spiny projection neurons. Images were obtained using streptavidin-Alexa fluor 488. Scale bars, 50 µm. B: whole cell recording from the presynaptic neuron of the same pair, showing response to hyperpolarizing and depolarizing current pulases. The neuron exhibited the characteristic electrophysiological properties of a spiny projection neuron. C: an inhibitory postsynaptic current (IPSC) in the postsynaptic neuron evoked by a single action potential in the presynaptic spiny projection neuron. Postsynaptic currents were recorded at –80 mV. Traces show averages of 50 consecutive responses. D: summary of connectivity detected and calculated probability of connections between spiny projection neuron pairs. Numbers of connected pairs and total number of pairs tested are indicated in parentheses.

Next we examined the action of A_2A receptors on spiny projection neuron interactions. The effects of an adenosine A_2A receptor agonist CGS21680 on the IPSCs were tested in 17 connected spiny projection neuron pairs. An example pair is shown in Fig. 2 (A and B). Bath application of CGS21680 0.1 µM had no significant effect on the IPSC amplitudes, but 0.3 and 1.0 µM of CGS21680 increased the amplitude of the IPSCs. Group averages showed these effects were statistically significant, with CGS21680 producing excitatory PSC (EPSC) amplitudes 100 ± 3% (n = 7), 140 ± 11% (P < 0.05, n = 6), and 150 ± 28% (P < 0.05, n = 4) of control at 0.1, 0.3 and 1.0 µM, respectively (Fig. 2C).

View larger version (13K): [in this window] [in a new window]   FIG. 2. Adenosine A2A receptor agonist-induced enhancement of IPSCs between spiny projection neuron pairs. A: increase in amplitude of IPSCs between a spiny projection neuron pair during application of an adenosine A2A receptor agonist, CGS21680 (1 µM). B: superimposed traces of an average of consecutive spiny projection neuron IPSCs (15 traces) before (control) and during application of CGS21680. C: summary of CGS21680-induced IPSCs of spiny projection neuron pairs. Data are normalized values expressed as a percentage of control values. Box plots show interquartile range, median, and whiskers show maximum and minimum values. The number of pairs examined is given in parentheses. *P < 0.05 vs. control by paired t-test.

The CGS21680 (0.3 µM)-induced enhancement of spiny projection neuron IPSCs was accompanied by a reduction in the paired-pulse ratio (PPR, Fig. 3A, 1 and 2). Synaptic responses were elicited at 50-ms interesponse intervals. Before application of CGS21680, the ratio of the amplitudes was 0.95 ± 0.07 (n = 6). Application of CGS21680 (0.3 µM) led to an increase of the first IPSC, accompanied by a reduction in the PPR to 0.74 ± 0.07 in the same neurons (n = 6, P < 0.05, Fig. 3A2).

View larger version (56K): [in this window] [in a new window]   FIG. 3. Presynaptic locus of action of adenosine A2A receptor agonist-induced enhancement of IPSCs between spiny projection neuron pairs. A: electrophysiological evidence for presynaptic locus of action. A1: superimposed traces of spiny projection neuron IPSCs (average of 15 consecutive traces) evoked by paired stimulation (50-ms interval) before (control) and during application of CGS21680 (0.3 µM). A2: mean paired-pulse ratio (PPR) in 6 different pairs under control conditions and in the presence of CGS21680 (0.3 µM). A3: failure rate in same 6 pairs under control conditions and in the presence of CGS21680 (0.3 µM). Error bars represent SE, *P < 0.05 vs. control (paired t-test). B: localization of A2A receptors on biocytin-filled spiny projection neurons. B1: laser-scanning confocal image showing immunolabeled A2A receptors. B2: spines and axon terminals of biocytin-filled spiny projection neuron in same section. B3: superimposed images to show double-labeling. , biocytin-filled axons labeled with a monoclonal antibody to A2A receptors. Biocytin-filled dendritic spines were also labeled with the A2A receptor antibody (). Scale bar, 10 µm.

The changes in failure rate and PPR indicate that A_2A receptors act presynaptically at the terminals of spiny neurons to enhance the probability of GABA release. The effects of antagonists of A_2A receptors were not examined, but the concentration (0.3 and 1 µM) of CGS21680 used in this study was confirmed to selectively activate A_2A receptors for modulation of IPSCs in the striatum (Mori et al. 1996) and globus pallidus (Shindou et al. 2001, 2002) using rat brain slices.

To determine the localization of A_2A receptors in axon collaterals of spiny projection neurons, we performed double-labeling with immunostaining of A_2A receptor antibody and biocytin labeling of intracellularly filled spiny projection neurons (Fig. 3B). Double-labeling of A_2A receptors (Fig. 3B1) and biocytin-filled spiny projection neurons (B2) was evident in axon terminals (B3, ) and also in some dendritic spines (B3, ). The presence of A_2A receptors on dendritic spines suggests potential postsynaptic actions on the glutamatergic afferents to the striatum, which terminate on dendritic spines. The labeling of axon terminals of spiny projection neurons, which synapse with somata, dendrites, and spine shafts of other spiny projection neurons, is consistent with the presynaptic locus of action suggested by the actions of CGS21680 on PPRs and failure rates.

The action of CGS21680 on IPSC amplitude had a slow onset and was slow to reverse, as previously described (Mori et al. 1996; Shindou et al. 2003). The decrease in the PPR also had a slow onset and was slow to reverse. To demonstrate the time course of effect onset and its subsequent reversal, the data for all cases combined is shown in Fig. 4, A and B. In the figure, data for IPSCs from CGS21680 0.3 and 1.0 µM groups were pooled, there being no significant differences between them. Although washout was slow, the effects reversed, as evidenced by finding no significant differences between baseline and washout after CGS21680 0.3 µM (P = 0.4123, n = 6) or 1.0 µM (P = 0.1516, n = 4).

View larger version (14K): [in this window] [in a new window]   FIG. 4. Time course of effects of CGS21680. A: group averages of change in IPSC amplitude in response to CGS21680 (0.3 and 1.0 µM groups pooled, n = 10) to show time course of drug action. B: group averages of change in paired-pulse ratio (PPR) in response to CGS21680 (0.3 µM group only, n = 6, effects of 1.0 µM on PPR were not tested). Values are means ± SE.

	DISCUSSION

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Previous work has shown that A_2A receptors facilitate GABAergic transmission in the globus pallidus (Shindou et al. 2003) yet decrease GABAergic transmission in the neostriatum (Mori et al. 1996) in contrast to the present results. The present findings suggest a parsimonious explanation for these apparently opposite effects of A_2A receptors on the pallidal and striatal terminals of the spiny projection neurons. We show that A_2A receptors facilitate GABAergic transmission in the striatal terminals of the spiny projection neurons as previously shown for the pallidal terminals of the same cell type. In the present case, the presynaptic neurons could be definitively identified. In contrast, Mori et al. (1996) used intrastriatal field stimulation, which would preferentially activate the more excitable FS interneurons (Tecuapetla et al. 2005) rather than the strongly hyperpolarized spiny projection neurons. Furthermore, the A_2A-mediated decrease in field IPSC reported by Mori et al. was measured at an early stage of development (p9–p12) at which stage lateral inhibition by projection neurons may not be detectable (Koos et al. 2004). This suggests that the effects of A_2A receptors in juvenile rat slices may be largely mediated by FS interneurons. Previous studies (Koos and Tepper 1999, 2002; Koos et al. 2004) show that GABAergic interneurons have a high probability of being connected to nearby neostriatal cells and that the connection strength can be several times greater than the effects of projection neurons on each other. Therefore actions of A_2A receptors on inhibition mediated by interneurons may be significant under some conditions.

Several pieces of evidence suggest a presynaptic locus of action by A_2A receptors on spiny projection neuron terminals in the striatum. We found that the increase in GABAergic synaptic transmission by projection neurons was associated with a reduction in the PPRs and a decreased failure rate, consistent with a presynaptic action of A_2A receptors. Also our immunohistochemical results showed that A_2A receptors were expressed on presynaptic terminals of spiny projection neurons. Although we also observed postsynaptic A_2A receptors on spiny dendrites, as previously reported (Hettinger et al. 2001), these postsynaptic receptors are unlikely to mediate the effects we observed. First Mori et al. (1996) found no effects of A_2A agonists on postsynaptic responses of spiny neurons to exogenously applied GABA, as would be expected if A_2A receptors acted postsynaptically to modulate GABAergic responses. Second, the localization of postsynaptic A_2A receptors to dendritic spines is more suggestive of a modulatory effect on the glutamatergic, excitatory inputs to projection neurons (Ferre et al. 2002; Kachroo et al. 2005; Norenberg et al. 1997; Popoli et al. 1995; Wirkner et al. 2000), which synapse on dendritic spines, than inhibitory inputs, which commonly synapse on dendritic shafts. Collectively, these considerations argue for a presynaptic locus of action of the modulatory effect of A_2A receptors on GABAergic transmission between spiny projection neurons in the striatum.

The data in the present study demonstrate that presynaptic A_2A receptors enhance GABAergic transmission of spiny projection neurons via their local axon collaterals. This action of A_2A receptors may play an important role in striatal function. In particular, A_2A receptors may alter the ratio of feedback inhibition (mediated by lateral inhibition) to feedforward inhibition (mediated by interneurons), leading to a change in neurodynamics. Theoretical studies suggest that feedback inhibition leads to competitive neurodynamic modes in which the initially most active neurons can suppress activity in others (Fukai and Tanaka 1997). Although it has been argued that the sparse connectivity of spiny projection neurons is not consistent with "winner-take-all" dynamics (Koos et al. 2004; Tepper et al. 2004) realistic values of connectivity have been shown to be consistent with feedback regulation of activity and competitive modes of activity (Wickens et al. 2007). Modulating the efficacy of the spiny neuron connections may significantly alter striatal dynamics.

	GRANTS

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This work was supported by grants from the Health Research Council of New Zealand and the New Zealand Neurological Foundation.

	ACKNOWLEDGMENTS

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We thank Dr. Mayumi Ochi-Shindou and Mr. Peter Zhao for technical assistance.

	FOOTNOTES

 
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Address for reprint requests and other correspondence: J. R. Wickens, Neurobiology Research Unit, Okinawa Institute of Science and Technology, Initial Research Project, 12-22 Suzaki, Uruma, Okinawa 904-2234, Japan (E-mail: wickens{at}oist.jp)

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This Article Abstract Full Text (PDF) All Versions of this Article: 99/4/1884    most recent 01259.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Shindou, T. Articles by Wickens, J. R. Search for Related Content PubMed PubMed Citation Articles by Shindou, T. Articles by Wickens, J. R.