Brain, Vol. 124, No. 9, 1855-1865,
September 2001
© 2001 Oxford University Press
Adenosine-mediated inhibition of striatal GABAergic synaptic transmission during in vitro ischaemia
Clinica Neurologica, Dipartimento di Neuroscienze, Università di Tor Vergata and IRCCS Fondazione Santa Lucia, Rome, Italy
Correspondence to:
Dr Paolo Calabresi, Clinica Neurologica, Dipartimento di Neuroscienze, Università di Tor Vergata, Via di Tor Vergata 135, 00133 Rome, Italy E-mail: calabre{at}uniroma2
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Abstract |
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 Top Abstract IntroductionMethodsResultsDiscussionSource of inhibitory inputs...Activation of adenosine A1...ATP-sensitive potassium channels...ConclusionsAcknowledgementsReferences |
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Several reports have shown that energy deprivation, as a result of hypoxia, hypoglycaemia or ischaemia, depresses excitatory synaptic transmission in virtually all brain areas. How this pathological condition affects inhibitory synaptic transmission is still unclear. In the present in vitro study, we coupled whole-cell patch clamp recordings from striatal neurones with focal stimulation of GABAergic nerve terminals in order to characterize the electrophysiological effects of combined oxygen and glucose deprivation (in vitro ischaemia) on inhibitory postsynaptic currents (IPSCs) in this brain area. We found that brief periods (2–5 min) of in vitro ischaemia invariably caused a marked depression of IPSC amplitude. This inhibitory effect was fully reversible on removal of the ischaemic challenge. It was coupled with an increased paired-pulse facilitation, suggesting the involvement of presynaptic mechanisms. Accordingly, the ischaemic inhibition of striatal GABAergic IPSCs was not caused by a shift in the reversal potential of GABAA-receptor mediated synaptic currents, and was independ- ent of postsynaptic ATP concentrations. Endogenous adenosine, acting on A1 receptors, appeared responsible for this presynaptic action as the ischaemic depression of IPSCs was prevented by CPT [8-(4-chlorophenylthio) adenosine] and DPCPX, two adenosine A1 receptor antagonists, and mimicked by the application of adenosine in the bathing solution. Conversely, ATP-sensitive potassium channels were not involved in the inhibition of IPSCs by ischaemia, as demonstrated by the fact that tolbutamide and glipizide, two blockers of these channels, were ineffective in preventing this electrophysiological effect. The early depression of GABA-mediated synaptic transmission might play a role in the development of irreversible neuronal injury in the course of brain ischaemia.
A1 adenosine receptors; ATP-dependent potassium channels; brain slices; electrophysiology; neuroprotection
IPSC = inhibitory postsynaptic current
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionSource of inhibitory inputs...Activation of adenosine A1...ATP-sensitive potassium channels...ConclusionsAcknowledgementsReferences |
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Oxygen and/or glucose withdrawal causes rapid depression of glutamate-mediated excitatory synaptic transmission in the brain (Rosen and Morris, 1993
; Martin et al., 1994; Zhu and Krnjevic, 1994; Congar et al., 1995; Calabresi et al., 1997). This effect is mainly caused by the inhibitory action of adenosine released in the extracellular space, and precedes the development of irreversible neuronal injury and extracellular accumulation of both excitatory and inhibitory amino acids (Van Wylen et al., 1986; Haddad and Jiang, 1993; Martin et al., 1994; Melani et al., 1999). For example, in the spinal cord, hippocampus and striatum, the inhibition of excitatory synaptic transmission is evident at the early stages of various metabolic insults, and is dependent on the stimulation of presynaptic adenosine A1 receptors by endogenous adenosine (Lloyd et al., 1988; Zhu and Krnjevic, 1993; Calabresi et al., 1997). Extracellular levels of adenosine increase rapidly during energy deprivation as a result of enhanced ATP breakdown to ADP and AMP (Berne et al., 1974; Snyder, 1985; Van Wylen et al., 1986; Greene and Haas, 1991; Zhu and Krnjevic, 1993; Ramkumar et al., 1995; Chen and Simon, 1997).
The data collected until now on the effects of energy deprivation on inhibitory synaptic transmission are conflicting. It has been shown in hippocampal and neocortical neurones that the inhibitory component of the synaptic responses is depressed by anoxia earlier than the excitatory component. Further, in these cells, as well as in the dorsolateral septal nucleus (Akasu et al., 1996), the GABA (gamma-aminobutyric acid)-mediated synaptic transmission recovered more slowly than the glutamateric synaptic responses (Hansen et al., 1982; Fujiwara et al., 1987; Cherubini et al., 1989; Ben-Ari, 1990; Krnjevic et al., 1991; Hershkowitz et al., 1993; Rosen and Morris, 1993; Zhang and Krnjevic, 1993). On the other hand, monosynaptic GABA-mediated postsynaptic potentials and currents have been found to be less affected by anoxic insults than excitatory synaptic potentials (Khazipov et al., 1993, 1995; Zhu and Krnjevic, 1994; Congar et al., 1995), and stimulation of adenosine A1 receptors, the main determinant for the ischaemia-mediated suppression of excitatory transmission, selectively attenuated the ischaemia-evoked release of excitatory amino acids, but not of GABA (Goda et al., 1998). This latter finding is consistent with other reports showing in hippocampal slices that adenosine had no effect on inhibitory terminals (Lambert and Teyler, 1991; Yoon and Rothman, 1991; Thompson et al., 1992; Khazipov et al., 1995).
Other studies, however, have shown that stimulation of adenosine receptors efficiently inhibited GABAergic transmission in several other brain areas (Uchimura and North, 1991; Ulrich and Huguenard, 1995; Wu et al., 1995; Bonci and Williams, 1996; Chen and van den Pol, 1997; Chieng and Williams, 1998; Bagley et al., 1999). This indicates that the release of GABA during an ischaemic episode can lead to the suppression of inhibitory synaptic transmission by stimulating adenosine receptors. It is also conceivable that energy deprivation interferes with the release of GABA independently of adenosine receptor stimulation through the activation of ATP-dependent potassium channels. These channels, which are activated by deprivation of energy substrates (Ashcroft, 1988; Krnjevic, 1990; Freedman and Lin, 1996) and cause neuronal inhibition (Stanford and Lacey, 1995, 1996; Lee et al., 1998), have been shown to modulate GABAergic inhibitory postsynaptic currents (IPSCs) in central GABAergic neurones (Stanford and Lacey, 1996; Calabresi et al., 1999).
In the present study we employed an electrophysiological approach in vitro to study the effects of combined oxygen and glucose deprivation on GABA-mediated IPSCs in the striatum to further investigate the possible modulatory effects of the withdrawal of energy substrates on GABAergic synaptic transmission. We found that in vitro ischaemia suppresses GABA-mediated synaptic transmission in this nucleus and that endogenous adenosine, but not ATP-dependent potassium channels, is involved in this inhibitory action.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionSource of inhibitory inputs...Activation of adenosine A1...ATP-sensitive potassium channels...ConclusionsAcknowledgementsReferences |
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Preparation and maintenance of corticostriatal slices
Adult male Wistar rats (100–250 g) were used for all experiments. All efforts were made to minimize animal suffering and to reduce the number of animals used, in accordance with the European Communities Council Directive of 24 November, 1986 (86/609/EEC). Animals were anaesthetized with halothane and killed by severing the major blood vessels in the chest. The brain was then removed and corticostriatal slices 270 µm thick were prepared from tissue blocks of the brain using a vibratome (Calabresi et al., 1997
, 1998, 1999). A single slice was transferred to a recording chamber and submerged in a continuously flowing Krebs solution (32°C; 2–3 ml/min) gassed with 95% O2 – 5% CO2. To study ischaemia in striatal neurones, slices were deprived of glucose by removing glucose totally from the perfusate and adding sucrose to balance the osmolarity. This solution was gassed with a mixture of 95% N2 – 5% CO2 instead of the normal gas mixture. Ischaemic solutions entered the recording chamber no later than 20 s after operating a three-way tap. Complete replacement of the medium in the chamber took ~90 s as determined by the speed of diffusion of a coloured solution. The composition of the control solution was: 126 NaCl, 2.5 KCl, 1.2 MgCl2, 1.2 NaH2PO4, 2.4 CaCl2, 11 glucose and 25 NaHCO3 (all in mM).
Whole-cell patch clamp recordings
Whole-cell patch clamp recordings were made with borosilicate glass pipettes (3–5 M
; 1.8 mm outside diameter) containing K+-gluconate (125 mM), NaCl (10 mM), CaCl2, (1.0 mM), MgCl2 (2.0 mM), BAPTA [1,2-bis(2-aminophenoxy)ethane-N,N,N,N-tetraacetic acid; 1 mM], HEPES [4-(2-hydroxyethyl)-1-piperazine-ethanesulphonic acid; 19 mM], guanosine triphosphate (0.3 mM) and Mg-ATP (adenosine triphosphate; 2.0 mM), adjusted to pH 7.3 with KOH. The striatum could be readily identified under low power magnification, whereas individual neurones were visualized in situ using a differential interference contrast (Nomarski) optical system. This employed an Olympus BX50WI (Japan) non-inverted microscope with x40 water immersion objective combined with an infra-red filter, a monochrome CCD camera (COHU 4912) and a PC compatible system for analysis of images and contrast enhancement (WinVision 2000; Delta Sistemi, Italy). Recording pipettes were advanced towards individual cells in the slice under positive pressure and, on contact, tight G seals were made by applying negative pressure. The membrane patch was then ruptured by suction, and membrane current and potential monitored using an Axopatch 1D patch clamp amplifier (Axon Instruments, Foster City, Calif., USA). Whole-cell access resistances measured in voltage clamp were in the range of 5–30 M prior to electronic compensation (60–80% was routinely used). For synaptic stimulation bipolar electrodes were used. These stimulating electrodes were located within striatum close to the recording electrode. IPSCs were evoked at a frequency of 0.2 Hz and at the holding potential of –40 mV. All experiments were performed in the presence of MK-801 (30 µM) and CNQX (6-cyano-7-nitroquinoxaline-2,3-dione; 10 µM) to block, respectively, NMDA (N-methyl-D-aspartate) and AMPA (
-amino-3-hydroxy-5-methyl-isoxazole-4-propionate)glutamate receptors. Membrane conductance of the recorded neurones was calculated by measuring the current drops produced from the holding potential of –40 mV by 5 mV voltage steps in hyperpolarizing direction.
Data analysis and drug applications
Quantitative data on modifications of IPSCs are expressed as a percentage of the controls, the latter representing the mean of responses recorded during a stable period (5–10 min) in control medium. Values given in the text and in the figures are mean ± standard error of changes in the respective cell populations. Wilcoxon's test or Student's t-test (for paired and unpaired observations) was used to compare the means, and ANOVA (analysis of variance) was used when multiple comparisons were made against a single control group. Drugs were applied by dissolving them in the saline to the desired final concentration. CNQX, (+)-MK-801 maleate (MK-801) and ZM-241385 were from Tocris (Bristol, UK). Bicuculline (BMI), glipizide, tolbutamide, CPT [8-(4-chlorophenylthio)adenosine] and DPCPX were from RBI (Natick, Mass., USA). Adenosine was from Sigma (St Louis, Mo., USA).
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Results |
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Intrinsic and synaptic properties of the recorded striatal neurones
Rat striatal medium spiny neurones were identified by morphological and electrophysiological criteria (n = 112). Striatal spiny neurones had significantly smaller somata than interneurones (15–25 µm versus 30–60 µm) and displayed high resting membrane potential (–87 ± 3 mV), an action potential discharge with little adaptation during depolarizing current pulses and a typical current–voltage relationship both in current- and voltage-clamp recordings (Fig. 1A and B
). These electrophysiological properties were similar to those reported previously by our group and by others for medium spiny neurones of the striatum (Kita et al., 1984; Jiang and North, 1991; Wilson and Kawaguchi, 1996; Calabresi et al., 1998).
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In our corticostriatal slice preparation, GABA-mediated IPSCs were inducible in almost all of the recorded cells (96 out of 112). GABA-mediated synaptic currents were recorded following intrastriatal stimulation in the presence of MK-801 (30 µM) and CNQX (10 µM), which blocked NMDA and AMPA glutamate receptors, respectively. These currents were completely sensitive to the GABAA receptor antagonist bicuculline (3 µM; n = 14) and were detected as outward deflections when the membrane potential of the cells was depolarized to –40 mV (Fig. 1C
). Conversely, at holding potentials close to the resting membrane potential of striatal spiny neurones (–80 mV), the bicuculline-sensitive GABAA-mediated synaptic currents were usually detected as inward events of small amplitude (~20–80 pA, not shown). In this study, therefore, all GABAA-dependent IPSCs were recorded at a holding potential of –40 mV. In this experimental condition, the amplitude of GABAA-mediated outward currents recorded from striatal spiny neurones was dependent solely on the distance between the stimulating and the recording sites (200–800 µm) and the intensity of stimulation. No change in the latency or time to peak accompanied the IPSC amplitude changes obtained by progressively grading the stimulus strength (n = 5, not shown), indicating that these IPSCs were monosynaptic events.
Effects of in vitro ischaemia on striatal GABAergic IPSCs
Combined oxygen and glucose deprivation (in vitro ischaemia) produced progressive depression of IPSCs recorded from striatal neurones. As shown in Fig. 2A, this inhibitory action started ~50 s after the onset of the ischaemic insult and led to a marked depression of the IPSC amplitude in 5 min (n = 18, p < 0.001). Approximately 3–4 min after the application of the ischaemic solution, the holding current and membrane conductance of the voltage-clamped neurones started to change and, after 5 min of ischaemia, an inward current was detected in six cells (–42 ± 8 pA), an outward current in seven cells (36 ± 6 pA) and no current in five cells. However, in vitro ischaemia (5 min) caused a significant increase in membrane conductance in all the tested neurones (13 ± 5%; P < 0.05) (Fig. 2B). This electrophysiological parameter was calculated by measuring the current drops produced from the holding potential of –40 mV by 5 mV voltage steps in the hyperpolarizing direction.
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These data are in agreement with previous reports in which the increased membrane conductance produced by ischaemia in striatal neurones was attributed to the opening of both sodium and potassium channels, leading to a reversal potential of the ischaemic current of approximately –40 mV (Calabresi et al., 1995
, 1999; Centonze et al., 2001). Both the early synaptic inhibition and the delayed membrane conductance change induced by 5 min of in vitro ischaemia were fully reversible after the ischaemic solution was washed out (Fig. 2A and B).
The ischaemic depression of striatal inhibitory transmission does not depend on changes of IPSC reversal potential or intracellular ATP concentration
A positive shift in the reversal potential of GABAA receptor-mediated postsynaptic currents has been proposed to explain the anoxia-induced depression of IPSCs in pyramidal cells (Luhmann and Heinemann, 1992; Katchman et al., 1994). To investigate whether the early depression of IPSCs observed in striatal cells was attributable to this postsynaptic effect, we compared the current–voltage relationship of striatal GABAergic IPSCs in the control condition and during in vitro ischaemia (n = 6). As shown in Fig. 3A, although a decrease in GABAA-mediated currents was found during ischaemia at all the explored membrane potentials, the polarity was reversed at approximately –67 mV in both experimental conditions. This finding indicates that a change in chloride reversal potential does not contribute substantially to the observed IPSC depression caused by ischaemia in striatal cells.
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Intracellular ATP has been shown to maintain GABAA receptor permeability in several brain cells by favouring the phosphorylation of receptor–chloride channel complexes (Gyenes et al., 1988
; Stelzer et al., 1988; Chen et al., 1990; Shirasaki et al., 1992; Chen and Wong, 1995; Akasu et al., 1996). Therefore, in a further set of experiments, we studied the effects of in vitro ischaemia on IPSC amplitude recorded from striatal neurones perfused with patch-pipette (internal) solution containing 1 mM (n = 4) or 5 mM (n = 6) ATP. The time-course and extent of IPSC depression caused by 5 min in vitro ischaemia in both experimental conditions, however, were indistinguishable from those recorded with `normal' (2 mM) ATP (n = 18), suggesting that postsynaptic ATP concentrations do not play a significant role in the early depression of GABAA-mediated synaptic transmission in the striatum (Fig. 3B).
Effects of adenosine receptor antagonists on ischaemia-induced depression of striatal GABAergic synaptic transmission
To test the possible involvement of adenosine in the ischaemia-induced depression of striatal IPSCs, we measured the effects of selective antagonists of adenosine A1 (CPT and DPCPX) and A2A (ZM-241385) receptors on the depressant effects caused by in vitro ischaemia on GABA-mediated synaptic transmission. Both CPT (1 µM; n = 6) and DPCPX (300 nM; n = 8) bath applied 7–10 min before the ischaemic solution, caused no change in the intrinsic membrane properties of the recorded striatal neurones (holding current, membrane conductance, current–voltage relationship) (not shown) but dramatically reduced the depression of the IPSCs produced by subsequent application of the ischaemic insult (P < 0.01 for both pharmacological agents) (Fig. 4A). Notably, both these adenosine A1 receptor antagonists failed to affect the ischaemia-induced increase in membrane conductance (P > 0.05) but increased per se the IPSC amplitude recorded in control medium (CPT 16 ± 4%, P < 0.01, n = 10; DPCPX 19 ± 3%, P < 0.01, n = 12) (Fig. 4B). These data are consistent with the idea that ambient adenosine exerts an inhibitory effect on GABAergic synaptic transmission, not only during energy deprivation, but also under physiological conditions. The adenosine A2A receptor antagonist ZM-241385 (1 µM; n = 6; 7–10 min bath application) failed to prevent the inhibition of GABAergic synaptic transmission produced by in vitro ischaemia (P > 0.05) (Fig. 4A). This compound also failed to affect the intrinsic properties of the recorded striatal cells (not shown) and the IPSC amplitude recorded in control medium (Fig. 4B).
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Effects of CPT and DPCPX on the electrophysiological action of exogenous adenosine
The electrophysiological data presented above suggest that, during energy deprivation, increased extracellular levels of adenosine activate A1 receptors to produce suppression of striatal GABAergic synaptic transmission. This conclusion is based upon the ability of both CPT and DPCPX, two putative A1 adenosine receptor antagonists, to prevent the inhibition of IPSCs produced by in vitro ischaemia in striatal slices. To further strengthen this idea, two new sets of experiments were performed. First, we tried to mimic the electrophysiological effects of in vitro ischaemia on GABA-mediated IPSCs through the application of adenosine in the bathing solution. Exogenous adenosine (3–300 µM; n = 9; 7–10 min), which failed per se to affect the intrinsic properties of the recorded striatal cells, potently and dose-dependently inhibited striatal IPSCs (Fig. 5A
). Secondly, we measured the effects of both CPT and DPCPX on the electrophysiological action of adenosine. As with in vitro ischaemia, preincubation of the slices (7–10 min) with both CPT (1 µM; n = 4) and DPCPX (300 nM; n = 4) significantly reduced the inhibition of IPSCs caused by 30 µM adenosine (P < 0.01 for both pharmacological agents) (Fig. 5).
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Effects of in vitro ischaemia and adenosine on paired-pulse facilitation
Since either a decreased release of neurotransmitter or a decreased postsynaptic sensitivity to GABA can be responsible for the ischaemia- and adenosine-induced inhibition of striatal IPSCs, we tried to distinguish between these possibilities through paired pulse experiments (50–100 ms interstimulus interval). We measured the IPSC2 : IPSC1 ratio before and during the application of the ischaemic medium and of adenosine. As shown in Fig. 6A
, the application of the ischaemic medium reversibly increased the magnitude of the IPSC2 : IPSC1 ratio in all of the neurones tested (n = 13, P < 0.01). Similar results were obtained with 30 µM adenosine (n = 7, P < 0.01) indicating that the depression of the striatal IPSCs caused by both in vitro ischaemia and exogenous adenosine is essentially mediated by a presynaptic mechanism (Fig. 6B) (Lupica et al., 1992; Manabe et al., 1993; Schultz et al., 1994).
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Effects of ATP-dependent potassium channels on ischaemia-induced synaptic depression
Activation of ATP-dependent potassium channels might play a role in the decrease of GABAergic synaptic transmission during energy deprivation. These channels are, in fact, activated by deprivation of energy substrates and might counteract transmitter release during in vitro ischaemia (Ashcroft, 1988
; Mourre et al., 1989; Lee et al., 1995; Freedman and Lin, 1996; Stanford and Lacey, 1996). Therefore, we tested whether incubation of a corticostriatal slice in the presence of the ATP-dependent potassium channel blockers tolbutamide and glipizide affected the ischaemia-induced depression of striatal IPSCs. Neither tolbutamide (1 mM; n = 6) nor glipizide (100 nM; n = 5) counteracted the inhibition of GABAergic synaptic transmission produced by in vitro ischaemia (Fig. 7). Both pharmacological agents also failed to affect the intrinsic properties of the recorded striatal cells and the IPSC amplitude recorded in the control medium (not shown).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionSource of inhibitory inputs...Activation of adenosine A1...ATP-sensitive potassium channels...ConclusionsAcknowledgementsReferences |
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The present study demonstrates that in vitro ischaemia produces a rapid suppression of GABA-mediated synaptic transmission in the striatum, which is caused by the stimulation of A1 receptors by endogenous adenosine. The blockade of GABA-mediated synaptic inhibition during a metabolic insult might have a deleterious effect on striatal neurones, by favouring membrane depolarization and irreversible intracellular accumulation of sodium and calcium ions, which are important determinants for neuronal death (Haddad and Jiang, 1993
; Martin et al., 1994; Lee et al., 1999). In accordance with this idea, it has been shown that the pharmacological potentiation of GABAergic synaptic transmission has neuroprotective effects in several experimental models of cerebral ischaemia (Chen Xu et al., 2000; Galeffi et al., 2000; Schwartz-Bloom et al., 2000). The enhancement of paired pulse facilitation, together with the lack of any postsynaptic action on IPSC reversal potential, holding current and membrane conductance, point to a presynaptic site for the effect of brief in vitro ischaemic insults. This is consistent with earlier reports showing that both aglycaemia and adenosine depress excitatory transmission through a presynaptic mechanism (Lupica et al., 1992; Calabresi et al., 1997). |
Source of inhibitory inputs to striatal neurones |
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TopAbstractIntroductionMethodsResultsDiscussionSource of inhibitory inputs...Activation of adenosine A1...ATP-sensitive potassium channels...ConclusionsAcknowledgementsReferences |
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GABAergic inputs to striatal neurones are essentially intrinsic, arising from GABAergic fast-spiking and parvalbumin-immunoreactive interneurones contacting striatal spiny neurones in their somatodendritic region (Wilson and Groves, 1980
; Bennet and Bolam, 1994; Yung et al., 1996; Plentz and Kitai, 1998; Koos and Tepper, 1999). Although recurrent collaterals of spiny neurones form a dense intrastriatal network (Wilson and Groves, 1980; Wickens et al., 1995; Beiser and Houk, 1998), functional studies have shown that mutual inhibitory interaction between medium spiny neurones is virtually absent (Jaeger et al., 1994). Conversely, the activation of fast-spiking interneurones can produce efficient GABA-mediated synaptic events in nearby medium spiny neurones (Plentz and Kitai, 1998; Koos and Tepper, 1999). These observations suggest that the GABAergic nerve terminals stimulated in our study to produce IPSCs were probably those of striatal GABAergic interneurones. The transmitter release from these appeared to be modulated by energy deprivation and adenosine via adenosine A1 receptors. In accordance with this idea, lesion studies have indicated that striatal adenosine A1 receptors are preferentially located in intrinsic neurones (Geiger, 1986). |
Activation of adenosine A1 receptors inhibits GABAergic inputs to striatal neurones in physiological conditions and during ischaemia |
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TopAbstractIntroductionMethodsResultsDiscussionSource of inhibitory inputs...Activation of adenosine A1...ATP-sensitive potassium channels...ConclusionsAcknowledgementsReferences |
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Extracellular levels of adenosine increase during energy substrate deprivation as a result of net breakdown of intracellular ATP to ADP and AMP (Berne et al., 1974
; Snyder, 1985; Van Wylen et al., 1986; Greene and Haas, 1991; Zhu and Krnjevic, 1993; Ramkumar et al., 1995; Chen and Simon, 1997). Adenosine, however, is also produced in physiological conditions, as indicated by its presence in the extracellular compartment of intact neural tissue at concentrations of ~1 µM (Newman and McIlwain, 1977; Zetterström et al., 1982). Compelling evidence of a tonic activation of adenosine receptors has been demonstrated in brain slices, where it was shown that application of adenosine antagonists resulted in increased synaptic efficacy in the hippocampus, ventral tegmental area, nucleus accumbens and dorsal striatum (Haas and Greene, 1988; Dunwiddie and Diao, 1994; Bonci and Williams, 1996; Calabresi et al., 1997; Harvey and Lacey, 1997; present study). Conversely, in thalamic, hypoglossal and periaqueductal grey neurones recorded from slices, no effect of endogenous adenosine was found, although these neurones responded to this transmitter applied exogenously (Umemiya and Berger, 1994; Ulrich and Huguenard, 1995; Bagley et al., 1999). These data indicate that adenosine production is not homogeneous throughout the brain and suggest that this transmitter might exert a more prominent modulatory action in specific brain areas. It should be noted, however, that in contrast to observations in acutely prepared hippocampal slices (Dunwiddie and Diao, 1994), no effect of adenosine antagonists was found in an in vitro study on hippocampal slice cultures (Thompson et al., 1992). This observation suggests caution should be exercised in the interpretation of the data presented above, as tissue damage produced in acutely prepared slices may lead to an aberrant increase in extracellular adenosine concentration, as well as a low rate of exchange between the bathing solution and the extracellular space in the centre of the slice. Other reasons that might account for the different results observed between acutely prepared slices and slice cultures are the different connectivity, and glial and/or neuronal density existing in the two experimental preparations.
A1, A2A and A3 receptors have been reported as being present in the striatum where they can mediate various physiological effects of adenosine (Fredholm, 1995; Huston et al., 1996; Ferré et al., 1997; Richardson et al., 1997). The evidence that DPCPX and CPT, but not ZM-241385, prevented both ischaemia- and adenosine-mediated IPSC depression in the striatum, however, strongly implies adenosine A1 receptors in this presynaptic action. This finding is consistent with earlier studies in other brain areas, including the ventral part of the striatum, where the inhibitory action of adenosine on GABAergic transmission is mediated by A1 receptors (Uchimura and North, 1991; Ulrich and Huguenard, 1995; Wu et al., 1995; Bonci and Williams, 1996; Chieng and Williams, 1998; Bagley et al., 1999). Conversely, in previous studies, both A1 and A2A receptors have been found to inhibit GABA transmission and release in the dorsal striatum (Concas et al., 1993; Kirk and Richardson, 1994; Kurokawa et al., 1994; Mori et al., 1996; Corsi et al., 1999; Chergui et al., 2000), indicating a complex action of different subtypes of adenosine receptors in this brain area.
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ATP-sensitive potassium channels are not involved in the ischaemic inhibition of striatal GABA-mediated synaptic transmission |
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TopAbstractIntroductionMethodsResultsDiscussionSource of inhibitory inputs...Activation of adenosine A1...ATP-sensitive potassium channels...ConclusionsAcknowledgementsReferences |
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ATP-sensitive potassium channels have been found in many types of excitable cells and are believed to provide a link between excitability and metabolic status both in peripheral tissues and in the central nervous system (Ashcroft and Ashcroft, 1990
). They are normally inhibited by physiological levels of ATP (Ashcroft, 1988), but a decrease in cytosolic ATP concentration, such as that which occurs during hypoxia and/or hypoglycaemia, opens these channels and leads to membrane hyperpolarization (Jiang and Haddad, 1991; Haddad and Jiang, 1993; Martin et al., 1994). Hyperpolarization, in turn, reduces energy consumption and preserves cytosolic high-energy phosphates (ATP, ADP and AMP). ATP-sensitive potassium channels are formed by the molecular interaction between an inwardly rectifying potassium channel subunit and a high affinity receptor for sulphonylureas (Inagaki et al., 1995a, b; Sakura et al., 1995). Interestingly, activation of sulphonylurea-sensitive potassium currents has been shown to be involved in the generation of the somatic membrane hyperpolarization of several neuronal subtypes, and also in limiting membrane depolarization of other brain cells in conditions which lower intracellular ATP levels (Jiang and Haddad, 1991; Riepe et al., 1992; Calabresi et al., 1999). In addition, ATP-sensitive potassium channels have also been demonstrated presynaptically, where they appear to be important in decreasing both excitatory and inhibitory neurotransmitter release (Mourre et al., 1989; Lee et al., 1995; Stanford and Lacey, 1996). In the striatum, however, blockers of ATP-sensitive potassium channels affected ischaemia-induced membrane potential hyperpolarization and depolarization of cholinergic interneurones and projection cells, respectively, whereas neither aglycaemic depression of glutamate-mediated transmission (Calabresi et al., 1997), nor ischaemia-mediated inhibition of GABAergic inputs (present study) were sensitive to these blockers. These data are consistent with the idea that striatal neurones express ATP-sensitive potassium channels in their somatodendritic region, but not at the presynaptic level of either excitatory or inhibitory nerve terminals (Schwanstecher and Panten, 1994; Schwanstecher and Bassen, 1997; Lee et al., 1998). |
Conclusions |
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TopAbstractIntroductionMethodsResultsDiscussionSource of inhibitory inputs...Activation of adenosine A1...ATP-sensitive potassium channels...ConclusionsAcknowledgementsReferences |
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Certain brain areas and also specific neuronal subtypes express particularly high sensitivity to ischaemia. The striatum is one of the most vulnerable structures of the brain and, among striatal cells, medium spiny projection cells are precociously damaged in course of energy deprivation. Although the reasons for such cell-type specific vulnerability are still largely unknown, the precocious depression of inhibitory synaptic transmission might play a significant role in the development of those pathological events, eventually leading to ischaemic striatal neurone death.
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Acknowledgements |
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TopAbstractIntroductionMethodsResultsDiscussionSource of inhibitory inputs...Activation of adenosine A1...ATP-sensitive potassium channels...ConclusionsAcknowledgementsReferences |
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We thank Mr Massimo Tolu for technical assistance. This work was supported by the following grants: BIOMED (BMH4–97–2215) and Ministero della Sanità (Progetto strategico per la malattia di Alzheimer) to P.C., MURST-CNR (legge 95/95) to G.B and MURST (Cofin 2000) to A.P.
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Received January 19, 2001. Revised April 4, 2001. Accepted April 30, 2001.
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