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Neuroscience Programme, International School for Advanced Studies, Trieste, Italy
Submitted 2 May 2004; accepted in final form 9 July 2005
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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-aminobutyric acid type A (GABAA) receptors with bicuculline. All these effects were prevented by DPCPX, indicating the involvement of inhibitory A1 receptors. In contrast, GABAergic synaptic events were not changed by adenosine. Consistent with the endogenous role of adenosine on network activity, DPCPX per se increased the frequency of GDPs, interictal bursts, and spontaneous glutamatergic synaptic events recorded from GABAergic interneurons. Moreover, the adenosine transport inhibitor NBTI and the adenosine deaminase blocker EHNA decreased the frequency of GDPs, thus providing further evidence that endogenous adenosine exerts a powerful control on GDP generation. We conclude that, in the neonatal rat hippocampus, the inhibitory action of adenosine on GDPs arises from the negative control of glutamatergic, but not GABAergic, inputs. |
INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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). GDPs are characterized by recurrent membrane depolarizations with superimposed fast action potentials. They occur at the frequency of 0.03–0.3 Hz and can be detected both in vitro (Ben-Ari et al. 1989) and in vivo (Leinekugel et al. 2002). GDPs are generated by the synergistic action of glutamate and -aminobutyric acid (GABA) (Bolea et al. 1999). Early in postnatal life, GABA depolarizes and excites postsynaptic cells (Ben-Ari 2002; Ben-Ari et al. 1997; Cherubini et al. 1991) due to high intracellular [Cl–], which results mainly from the unbalance of two Cl– cotransporter systems, the NKCCl and KCC2 that enhance and lower intracellular [Cl–], respectively (Payne et al. 2003; Rivera et al. 1999). The depolarizing action of GABA during GDPs results in calcium influx through the activation of voltage-dependent calcium channels and N-methyl-D-aspartate (NMDA) receptors (Leinekugel et al. 1997). Thus GDPs acting as coincidence detector signals for enhancing synaptic efficacy (Kasyanov et al. 2004) may contribute to the functional and structural refinement of the hippocampal network.
In previous studies from our and other laboratories it was shown that GDPs are regulated by a number of neurotransmitter receptors and modulators localized on pre- and postsynaptic sites of principal cells and interneurons (Avignone and Cherubini 1999; Gaiarsa et al. 1991; Maggi et al. 2001; McLean et al. 1996; Strata et al. 1995; Xie et al. 1994). In turn, neurotransmitters release can be regulated by activity dependent processes like GDPs. Consistent with this, in a recent study (Safiulina et al. 2005) we demonstrated that adenosine triphosphate (ATP), a widely distributed neurotransmitter and neuromodulator (Burnstock 2004), which regulates network activity by ionotropic P2X and metabotropic P2Y receptors, can be released during GDPs. Because ATP is hydrolyzed to adenosine by ectonucleotidases (Cunha et al. 1998; Dunwiddie et al. 1997) the possibility that this neurotransmitter also regulates frequency of GDPs by activation of adenosine receptors by its breakdown product adenosine cannot be ruled out.
In the hippocampus adenosine has been shown to act on pre- and postsynaptic A1 receptors to inhibit glutamate release (Lupica et al. 1992; Wu and Saggau 1994; Yoon and Rothman 1991) and to enhance potassium conductance (Greene and Haas 1985), respectively. Altogether these effects would produce a reduction in cell excitability and firing rate (for a review see Ribeiro et al. 2003b). Here we demonstrate that, during the first week of postnatal life, endogenous adenosine, by activating A1 receptors localized mainly on glutamatergic terminals projecting to principal cells or interneurons, regulates the occurrence of GDPs.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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Experiments were performed on hippocampal slices obtained from postnatal (P) P2–P6 Wistar rats (P0 was taken as the day of birth) as previously described (Maggi et al. 2001). The procedure was in accordance with the European Community Council Directive of 24 November 1986 (86/609EEC) and was approved by the local authority veterinary service. Animals were decapitated after being anesthetized with an intraperitoneal injection of urethane (2 g/kg). After decapitation the brain was removed from the skull and placed in ice-cold artificial cerebrospinal fluid (ACSF) containing (in mM): NaCl, 130; KCl, 3.5; NaH2PO4, 1.2; NaHCO3, 25; MgCl2, 1.3; CaCl2, 2, glucose, 25; saturated with 95% O2-5% CO2 (pH 7.3–7.4). Hippocampal slices (500 µm thick) were cut with a vibratome and incubated at room temperature (22–25°C) in oxygenated ACSF. Registrations of activity were performed from an individual slice in a submerged chamber continuously perfused at 33–34°C with oxygenated ACSF at a rate of 2–3 ml/min.
Patch-clamp whole cell recordings
Electrophysiological experiments were performed from CA3 pyramidal cells and from GABAergic interneurons localized on stratum radiatum using the whole cell configuration of the patch-clamp technique in current-clamp mode. Neurons were visualized using infrared Nomarski optics on an upright microscope (Leica DMLFS, Wetzlar, Germany). GDPs and spontaneous (action potential–dependent and –independent) ongoing synaptic potentials (sPSPs), were recorded from a holding potential of –70 ± 5 mV with a standard patch-clamp amplifier (Axoclamp 2B, Axon Instruments; Foster City, CA). Patch electrodes, pulled from borosilicate glass capillaries (Hilgenberg, Malsfeld, Germany), had a resistance of 5–7 M
when filled with an intracellular solution containing (in mM): KCl, 140; MgCl2, 1; NaCl, 1; EGTA, 1; HEPES, 2; and K2ATP, 2; the pH was adjusted to 7.3 with KOH.
The whole cell capacitance was fully compensated and the series resistance (10–20 M) was compensated at 75–80%. The stability of the patch was checked by repetitively monitoring the input and series resistance during the experiment. Cells exhibiting 15–20% changes were excluded from the analysis. Membrane input resistance was measured during recordings from the amplitude of the electrotonic potentials (300-ms duration) evoked by passing hyperpolarizing current steps of 100–200 pA across the cell membrane.
Drugs
All substances were prepared as 1,000 x concentrated stock solutions. ATP, adenosine, picrotoxin, and 6-[(4-nitrobenzyl)thio]-9-
-D-ribofuranosylpurine (NBTI) were purchased from Sigma. Bicuculline methochloride, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX), 6,7-dinitroquinoxaline-2,3-dione (DNQX), and erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA) hydrochloride were purchased from Tocris Cookson. DPCPX and picrotoxin were dissolved in ethanol (final concentration of ethanol in solution 0.02%); NBTI and DNQX were dissolved in dimethylsulfoxide (DMSO). Control experiments using a solution containing 2.5/1,000 of DMSO did not affect GDPs or sPSPs. Stock solutions were stored at –20°C. The substances to be tested were dissolved at their final concentrations in extracellular solution just before the recording session. All substances were applied through a three-way tap system. Bath volume exchange was completed within 1.5 min.
Data acquisition and analysis
Data were transferred to a computer after digitization with an A/D converter (Digidata 1200, Axon Instruments). Data were sampled at 20 kHz and filtered with a cutoff frequency of 1 kHz. Acquisition and analysis were performed with Clampex 7 (Axon Instruments).
The analysis of sPSPs was performed with Mini Analysis Program (Synaptosoft, Decatur, GA). General principles and details on the analysis of synaptic currents can be found elsewhere (Jo et al. 1998; Poisbeau et al. 1996).
The cumulative amplitude and interevent plots obtained for cell in controls and after drug application were compared using the Kolmogorov–Smirnov (KS) test.
For each cell, the mean GDPs frequency was calculated in control conditions and during drug application (starting 3 min after the onset of drug perfusion). Statistical comparisons were made between mean values (control vs. drug treatment). The numerical data are given as means ± SE and compared using the Student’s t-test. The differences were considered significant when P was <0.05.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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In CA3 pyramidal cells ATP reduces the frequency of GDPs by P2 receptors and its breakdown product adenosine
Because the breakdown of ATP in the extracellular space is one important source of adenosine (Ribeiro et al. 2003b) in a first set of experiments we tested the effects of ATP on GDPs. As shown in Fig. 1A, bath application of ATP (50 µM) reversibly blocked GDPs, an effect that was associated with an increase in frequency of sPSPs. At lower concentrations (2 µM) ATP induced a reduction of frequency of GDPs from 0.06 ± 0.004 to 0.009 ± 0.001 Hz (n = 4, P < 0.01). The effect of ATP on the frequency of GDPs was dose dependent with an EC50 of 0.78 µM (Fig. 1C). In eight out of 14 cells, ATP (50 µM) induced a membrane hyperpolarization (4.6 ± 0.8 mV) associated with an increase in membrane conductance (9 ± 1%). When ATP (50 µM) was applied in the presence of a high concentration of DPCPX (10 µM), which blocks adenosine receptors (Khakh et al. 2003), it produced a biphasic effect: an initial increase followed by a persistent decrease in frequency of GDPs (Fig. 1B; see also Safiulina et al. 2005). The depressant effect was concentration dependent with an EC50 value of 16.2 µM (Fig. 1C). Thus at the concentration of 50 µM the reduction in frequency of GDPs produced by ATP was 43 ± 1.5%. Comparison of the two curves of Fig. 1C suggests a strong adenosine effect. Interestingly, in 10 µM DPCPX ATP (50 µM) was still able to up-regulate the frequency of sPSPs recorded from principal cells, indicating that this effect was adenosine independent (the frequency of sPSPs was 10.9 ± 0.9 and 10.8 ± 2.8 Hz in the presence of ATP and ATP + DPCPX, respectively; n = 4). Moreover, it should be stressed that in the presence of DPCPX, the effects of ATP on GDPs were never associated with changes in membrane potential and resistance, suggesting that the latter were probably mediated by postsynaptic A1 adenosine receptors. These data strongly suggest that endogenous ATP may also regulate the activity of GDPs by its breakdown product adenosine acting on A1 receptor subtypes.
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To further explore this issue, adenosine was directly applied to hippocampal slices at concentrations ranging from 0.1 to 10 µM. As shown in Fig. 2A, adenosine (10 µM) completely blocked GDPs. This effect was reversible 2–3 min after adenosine was washed out. At a lower concentration (0.5 µM) adenosine reduced the frequency of GDPs from 0.06 ± 0.004 to 0.03 ± 0.002 Hz without modifying their shape (the area under GDPs was 15.9 ± 1.4 and 16.3 ± 2.2 mV s–1 before and during adenosine application, respectively; P > 0.05). The effect of adenosine on GDPs was dose dependent (the EC50 value was 0.52 µM; Fig. 2C). The closed circle in Fig. 2C represents the ratio between the frequency of GDPs obtained in control conditions and that achieved in the presence of a saturating concentration of DPCPX (100 nM; see Fig. 3) when the action of endogenous adenosine is neutralized. This value corresponds to the inhibitory effect of endogenous adenosine on the frequency of GDPs. In four out of seven cells, adenosine (10 µM) produced a membrane hyperpolarization (4.3 ± 0.3 mV) that was associated with an increase in membrane conductance (8 ± 1%). In contrast with ATP, adenosine did not modify the frequency of sPSPs that at P2–P6 are mainly GABAA mediated (Hosokawa et al. 1994). In keeping with this, adenosine (10 µM) also failed to modify the frequency of GABAA-mediated sPSPs when applied in the presence of the 
-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptor antagonist DNQX (10 µM). In DNQX, the frequency of sPSPs was 5.7 ± 1.5 and 6.0 ± 1.7 Hz (n = 3, P > 0.05) before and during adenosine application, respectively. The effects of exogenously applied adenosine on GDPs, membrane potential, and conductance were prevented by 100 nM of DPCPX (n = 4, Fig. 2B), which at this concentration selectively blocks A1 receptors (Giniatullin and Sokolova 1998; Ralevic and Burnstock 1998).
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To further evaluate the contribution of endogenous adenosine to the generation of GDPs we increased the extracellular level of endogenous adenosine by applying in the bath NBTI, which inhibits adenosine transport (de Mendonça and Ribeiro 1994; Fredholm et al. 1994; Ribeiro et al. 2003a,b), or EHNA that blocks adenosine deaminase, the enzyme that converts adenosine into the inactive metabolite inosine (Ribeiro et al. 2003a,b). NBTI, at the concentration of 20 µM, significantly decreased the frequency of GDPs from 0.07 ± 0.004 to 0.045 ± 0.002 Hz (n = 5, P < 0.01; Fig. 4, A and C), in the absence of any change in GDP amplitude or shape. This effect was prevented by DPCPX (100 nM; n = 3), implying that it was mediated by adenosine acting on A1 receptor subtypes (Fig. 4A). Similar results were obtained with EHNA (10 µM). The adenosine deaminase inhibitor reduced the frequency of GDPs was from 0.07 ± 0.002 to 0.003 ± 0.002 Hz (n = 3, P < 0.001; Fig. 4, B and C). As for NBTI, the effect of EHNA was prevented by DPCPX (100 nM; n = 4; Fig. 4B). These data further support the idea that endogenous adenosine contributes to control the generation of GDPs.
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GDPs are generated by the synergistic action of glutamate and GABA acting on AMPA and GABAA receptors, respectively (Bolea et al. 1999). Therefore they are readily blocked either by DNQX or bicuculline (Ben-Ari et al. 1989; Bolea et al. 1999).
In agreement with a previous report (Safiulina et al. 2005) DPCPX did not modify the frequency or amplitude of sPSPs in principal cells (the frequency of sPSPs was 5.5 ± 0.7 and 5.4 ± 0.9 Hz, whereas the amplitude was 3.9 ± 0.4 and 3.8 ± 0.5 mV before and during DPCPX, respectively; n = 3). In our experimental conditions (symmetrical chloride solutions) sPSPs recorded at –60 mV from principal cells can be attributed to the action of GABA and glutamate acting on GABAA and AMPA/kainate receptors, respectively. Therefore to see whether endogenous adenosine regulates glutamate release into principal cells we blocked GABAA receptors with picrotoxin. However, in keeping with the late development of glutamatergic connections (Ben-Ari et al. 1989; Hennou et al. 2002; Hosokawa et al. 1994; Tyzio et al. 1999) in the presence of picrotoxin (100 µM) glutamatergic events were merely detectable, suggesting that during the first postnatal week, spontaneous activity of principal cells is mainly explained by GABA acting on GABAA receptors. DPCPX applied in the presence of DNQX (10 µM) failed to modify spontaneous GABAA-mediated synaptic activity (the frequency of spontaneous events was 4.7 ± 0.8 and 4.8 ± 0.9 Hz in the presence or absence of 100 nM DPCPX; n = 3; P > 0.05; data not shown). These data suggest that, in control conditions, endogenous adenosine exerts its action on GDPs through glutamatergic terminals localized downstream of principal cells.
Endogenous adenosine affects the glutamatergic drive to GABAergic interneurons
To identify at the network level where the action of adenosine originated from, in additional experiments (n = 12) direct recordings from GABAergic interneurons were performed. Interneurons were localized on stratum radiatum, in close vicinity to stratum lucidum. They had a resting membrane potential ranging from –44 to –70 mV (on average –54.7 ± 2.4 mV) and input resistance ranging from 129 to 400 M (on average 293 ± 23 M). They discharged at high frequency (63 ± 7 Hz) in response to long depolarizing current pulses (100 pA, 400 ms; see also Safiulina et al. 2005). In these cells, GABAergic and glutamatergic activities were studied in isolation in the presence of bicuculline (20 µM) and DNQX (20 µM), respectively. DPCPX, even at high concentration (10 µM), did not modify the frequency or the amplitude of GABAergic sPSPs recorded in the presence of DNQX. In three interneurons the frequency of sPSPs was 8.5 ± 1.3 and 8.2 ± 1.2 Hz, whereas the amplitude of sPSPs was 5.9 ± 0.9 and 4.8 ± 0.4 mV, in control and in the presence of DPCPX, respectively (P > 0.05).
In contrast, DPCPX (100 nM) significantly increased the frequency (but not the amplitude) of glutamatergic sPSPs recorded in the presence of bicuculline (10 µM) from 2.5 ± 0.01 to 3.7 ± 0.3 Hz; (n = 3; P < 0.05; Fig. 5, A, B, and E).
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Endogenous adenosine affects the release of glutamate from recurrent collaterals of CA3 principal cells
In a recent work it has been shown that a prolonged exposure of hippocampal slices from P2–P6 rats to GABAA antagonists produces low-frequency interictal-like discharges that involve recurrent glutamatergic collaterals (Khazipov et al. 2004). To see whether endogenous adenosine can modulate interictal activity generated by glutamatergic recurrent collaterals in the absence of GABAA-mediated inhibition, bicuculline (20 µM) was applied for 10–15 min. In these conditions, interictal events developed at 0.02 ± 0.004 Hz (n = 9). Further application of DPCPX (100 nM) increased the frequency of interictal bursts from 0.027 ± 0.001 to 0.04 ± 0.01 Hz (P < 0.05; n = 3; Fig. 6, B and C). In spite of their increase in frequency, the shape and the area under GDPs was unchanged (9.4 ± 2.1 and 7.1 ± 1.2 mV s–1, P > 0.05 before and during DPCPX application). This indicates that A1 receptors localized on recurrent glutamatergic collaterals are involved in adenosine action. Furthermore, application of adenosine (10 µM; n = 3) completely blocked bicuculline-induced interictal bursts, an effect that was associated with a membrane hyperpolarization (5.5 ± 0.5 mV; Fig. 6A) and an increase in input conductance (8 ± 2%, P < 0.05).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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GDPs represent a hallmark of developmental networks (Ben-Ari 2002), which, as already mentioned, are generated by the neurotransmitter GABA (that at early stages of development is depolarizing and excitatory) and to a lesser extent by the excitatory transmitter glutamate (Ben-Ari et al. 1989). Our data suggest that GDPs could be completely blocked by low micromolar concentrations of adenosine, which specifically switches off only glutamatergic inputs, indicating a key role of the latter in the induction of GDPs.
The transient expression of GDPs suggests that these membrane oscillations exert a functional role for only a limited period of time during postnatal development, acting as coincident detection signals for increasing synaptic efficacy (Kasyanov et al. 2004). Coincidence detection would provide a combinatorial code by which to achieve outcome that cannot be generated by isolated stimuli (Spitzer 2004). Therefore early membrane oscillations such as GDPs may be crucial for setting the appropriate synaptic connections that lead to the establishment of the adult hippocampal circuit. A number of neurotransmitters and neuromodulators whose extracellular levels are maintained in an activity-dependent manner regulate network activity. Recently, we have demonstrated that ATP down-regulates GDPs and differently affects the release of glutamate and GABA within the CA3 network (Safiulina et al. 2005). In turn, GDPs would control the concentration of endogenous ATP at synapses. In the present experiments DPCPX-sensitive changes in ATP-induced reduction of the frequency of GDPs demonstrate that this nucleotide exerts its action not only through P2 but also by P1 receptors activated by the ATP breakdown product adenosine (Cunha et al. 1998; Dunwiddie et al. 1997). Interestingly, ATP also induced an increase of sPSPs that was unrelated to the activation of adenosine receptors because it persisted in the presence of DPCPX. In accord with a previous report (Safiulina et al. 2005) ATP-induced increase in the frequency of sPSPs was demonstrated to be dependent on the activation of presynaptic P2Y1 receptors present on GABAergic terminals.
Another potential source of endogenous adenosine is cyclic AMP (cAMP), which can be released from neurons and converted by extracellular phosphodiesterases into AMP and thereafter by an ecto-5'-nucleotidase to adenosine. Evidence that this pathway is functional in the hippocampus has been provided (Dunwiddie et al. 1997). In particular, early in postnatal development, cAMP can be produced after activation of metabotropic glutamate receptors by endogenously released glutamate (Strata et al. 1995). cAMP can exert opposite effects on GDPs: it may up-regulate the frequency of GDPs by directly enhancing GABA release from presynaptic nerve terminals (Strata et al. 1995) and/or may depress GDPs by indirectly interfering with glutamate release after having been converted into adenosine. However, to reach a significant level, multiple cells must release cAMP over a prolonged period of time (Brundege et al. 1997).
On the basis of their molecular structures four different adenosine P1 receptors have been characterized: A1, A2A, A2B, and A3 (Ralevic and Burnstock 1998). These receptors, which belong to the G-protein–coupled receptor family, are differentially distributed in the CNS where they exert different physiological functions. In the hippocampus, in situ hybridization and RT-PCR experiments have demonstrated that, whereas mRNA for A1 receptors is highly expressed, that for A2B and A3 receptors is below the detection level (Dixon et al. 1996). Moreover, immunocytochemical experiments have demonstrated the presence of A1 receptors on both pre- and postsynaptic sites (Ribeiro et al. 2003b).
Although at least in the cerebral cortex of immature animals [3H] DPCPX binding sites represent only 23% of those found in the adult brain, the present results clearly show that in the hippocampus A1 receptors are present and already functional during the first week of postnatal life. However, our data suggest a prevailing action of adenosine on presynaptic A1 receptors. First adenosine reduced the frequency but not the amplitude or the shape of GDPs and sPSPs. Second, on the majority of the cases adenosine did not alter the passive membrane properties of the patched neurons. Adenosine-induced changes in membrane potential and input conductance were only rarely observed and, when present, they were produced by relatively high concentrations of adenosine, which completely blocked GDPs. This is in line with a previous study from the CA3 region of the immature hippocampus, which has shown a differential ontogenesis of pre- versus postsynaptic GABAB, serotonin, and adenosine G-coupled receptors that control the same potassium and/or calcium channels (Gaiarsa et al. 1995). The delayed maturation of postsynaptic responses to adenosine may involve lack of postsynaptic receptors, absence of G-proteins, or uncoupling between G-proteins and effectors.
In keeping with previous reports obtained from cultured neurons (Yoon and Rothman 1991) or adult animals (Lupica et al. 1992), the present data clearly show that in the immature hippocampus adenosine affected only glutamatergic synaptic transmission, as suggested by the reduction in frequency of AMPA/kainate-mediated sPSPs in GABAergic interneurons. Therefore by modulating the glutamatergic drive to GABAergic interneurons adenosine exerts a powerful control on the generation of GDPs. Endogenously released adenosine also produced a strong inhibitory effect on recurrent glutamatergic synapses in the CA3 area, thought to be critical for generating bursting activity (Miles and Wong 1983), as indicated by the reduction of bicuculline-induced interictal discharges. In line with the powerful anticonvulsant action of purinoceptor agonists (Dunwiddie 1999), a potent inhibitory role of adenosine on bicuculline-induced bursting activity in adult hippocampal slices has been described (Ault and Wang 1986). As for adenosine-induced down-regulation of AMPA/kainate sPSPs, adenosine-induced depression of interictal discharges observed after block of GABAA-mediated inhibition can be attributed to a reduction of calcium entry through a decrease or an increase in calcium and potassium conductances present on glutamatergic nerve terminals, respectively (Trussell and Jackson 1987).
The concentration of endogenous adenosine produced during GDPs is unknown. However, the high sensitivity of GDPs to submicromolar concentrations of exogenous adenosine (IC50 = 0.52 µM) together with the strong facilitatory effect of DPCPX suggests that the concentration of endogenous adenosine is probably in the range of the IC50 value and perhaps could be increased during large depolarizations such as GDPs. In keeping with this, raising the extracellular concentration of adenosine with the adenosine transport inhibitor NBTI or with the adenosine deaminase blocker EHNA (Ribeiro et al. 2003b) induced a reduction in frequency of GDPs, thus providing further evidence that endogenous adenosine exerts a powerful control on the generation of GDPs.
In previous work, using a biochemical assay we noticed that the concentration of ATP present in the extracellular space diminished significantly in the presence of TTX, implying that ATP was released in an activity-dependent manner. Because adenosine is formed as the breakdown product of ATP from nerves, this implies that the adenosine concentration is crucially linked to the ongoing neuronal activity. Thus an increase in the frequency of GDPs may lead to the production of ATP and adenosine, which in turn may exert a negative feedback on GDPs by high-affinity presynaptic A1 receptors.
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GRANTS |
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ACKNOWLEDGMENTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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FOOTNOTES |
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Address for reprint requests and other correspondence: E. Cherubini, Neuroscience Programme, International School for Advanced Studies, Via Beirut 2-4, 34014 Trieste, Italy (E-mail: cher{at}sissa.it)
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REFERENCES |
|---|
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
|---|
Avignone E and Cherubini E. Muscarinic receptor modulation of GABA-mediated giant depolarizing potentials in the neonatal rat hippocampus. J Physiol 518: 97–107, 1999.
Ben-Ari Y. Excitatory actions of GABA during development: the nature of the nurture. Nat Rev Neurosci 3: 728–739, 2002.[CrossRef][ISI][Medline]
Ben-Ari Y, Cherubini E, Corradetti R, and Gaiarsa JL. Giant synaptic potentials in immature rat CA3 hippocampal neurones. J Physiol 416: 303–325, 1989.
Ben-Ari Y, Khazipov R, Leinekugel X, Caillard O, and Gaiarsa JL. GABAA, NMDA and AMPA receptors: a developmentally regulated "ménage à trois. " Trends Neurosci 20: 523–529, 1997.[CrossRef][ISI][Medline]
Bolea S, Avignone E, Berretta N, Sanchez-Andres JV, and Cherubini E. Glutamate controls the induction of GABA-mediated giant depolarizing potentials through AMPA receptors in neonatal rat hippocampal slices. J Neurophysiol 81: 2095–2102, 1999.
Brundege JM, Diao L, Proctor WR, and Dunwiddie TV. The role of cyclic AMP as a precursor of extracellular adenosine in the rat hippocampus. Neuropharmacology 36: 1201–1210, 1997.[CrossRef][ISI][Medline]
Burnstock G. Introduction: P2 receptors. Curr Top Med Chem. 4: 793–803, 2004.[CrossRef][ISI][Medline]
Cherubini E, Gaiarsa JL, and Ben-Ari Y. GABA: an excitatory transmitter in early postnatal life. Trends Neurosci 14: 515–519, 1991.[CrossRef][ISI][Medline]
Cunha RA, Sebastião AM, and Ribeiro JA. Inhibition by ATP of hippocampal synaptic transmission requires localized extracellular catabolism by ecto-nucleotidases into adenosine and channeling to adenosine A1 receptors. J Neurosci 18: 1987–1995, 1998.
de Mendonça A and Ribeiro JA. Endogenous adenosine modulates long-term potentiation in the hippocampus. Neuroscience 62: 385–390, 1994.[CrossRef][ISI][Medline]
Dixon AK, Gubitz AK, Sirinathsinghji DJ, Richardson PJ, and Freeman TC. Tissue distribution of adenosine receptor mRNAs in the rat. Br J Pharmacol 118: 1461–1468, 1996.[ISI][Medline]
Dunwiddie TV. Adenosine and suppression of seizures. Adv Neurol 79: 1001–1010, 1999.[Medline]
Dunwiddie TV, Diao L, and Proctor WR. Adenine nucleotides undergo rapid, quantitative conversion to adenosine in the extracellular space in rat hippocampus. J Neurosci 17: 7673–7682, 1997.
Fredholm BB, Lindstrom K, and Wallman-Johansson A. Propentofylline and other adenosine transport inhibitors increase the efflux of adenosine following electrical or metabolic stimulation of rat hippocampal slices. J Neurochem 62: 563–573, 1994.[ISI][Medline]
Gaiarsa JL, Corradetti R, Cherubini E, and Ben-Ari Y. Modulation of GABA-mediated synaptic potentials by glutamatergic agonists in neonatal CA3 rat hippocampal neurons. Eur J Neurosci 3: 301–309, 1991.[CrossRef][ISI][Medline]
Gaiarsa JL, Tseeb V, and Ben-Ari Y. Postnatal development of pre- and postsynaptic GABAB-mediated inhibitions in the CA3 hippocampal region of the rat. J Neurophysiol 73: 246–255, 1995.
Giniatullin RA and Sokolova EM. ATP and adenosine inhibit transmitter release at the frog neuromuscular junction through distinct presynaptic receptors. Br J Pharmacol 124: 839–844, 1998.[CrossRef][ISI][Medline]
Greene RW and Haas HL. Adenosine actions on CA1 pyramidal neurones in rat hippocampal slices. J Physiol 366: 119–127, 1985.
Hennou S, Khalilov I, Diabira D, Ben-Ari Y, and Gozlan H. Early sequential formation of functional GABA(A) and glutamatergic synapses on CA1 interneurons of the rat foetal hippocampus. Eur J Neurosci 16: 197–208, 2002.[CrossRef][ISI][Medline]
Hosokawa Y, Sciancalepore M, Stratta F, Martina M, and Cherubini E. Developmental changes in spontaneous GABAA-mediated synaptic events in rat hippocampal CA3 neurons. Eur J Neurosci 6: 805–813, 1994.[CrossRef][ISI][Medline]
Jo YH, Stoeckel ME, and Schlichter R. Electrophysiological properties of cultured neonatal rat dorsal horn neurons containing GABA and met-enkephalin-like immunoreactivity. J Neurophysiol 79: 1583–1586, 1998.
Kasyanov AM, Safiulina VF, Voronin LL, and Cherubini E. GABA-mediated giant depolarizing potentials as coincidence detectors for enhancing synaptic efficacy in the developing hippocampus. Proc Natl Acad Sci USA 101: 3967–3972, 2004.
Khakh BS, Gittermann D, Cockayne DA, and Jones A. ATP modulation of excitatory synapses onto interneurons. J Neurosci 23: 7426–7437, 2003.
Khazipov R, Khalilov I, Tyzio R, Morozova E, Ben-Ari Y, and Holmes GL.Developmental changes in GABAergic actions and seizure susceptibility in the rat hippocampus. Eur J Neurosci 19: 590–600, 2004.[CrossRef][ISI][Medline]
Leinekugel X, Khazipov R, Cannon R, Hirase H, Ben-Ari Y, and Buzsaki G. Correlated bursts of activity in the neonatal hippocampus in vivo. Science 296: 2049–2052, 2002.
Leinekugel X, Medina I, Khalilov I, Ben-Ari Y, and Khazipov R. Ca2+ oscillations mediated by the synergistic excitatory actions of GABAA and NMDA receptors in the neonatal hippocampus. Neuron 18: 243–255, 1997.[CrossRef][ISI][Medline]
Lupica CR, Proctor WR, and Dunwiddie TV. Presynaptic inhibition of excitatory synaptic transmission by adenosine in rat hippocampus: analysis of unitary EPSP variance measured by whole-cell recording. J Neurosci 12: 3753–3764, 1992.[Abstract]
Maggi L, Sher E, and Cherubini E. Regulation of GABA release by nicotinic acetylcholine receptors in the neonatal rat hippocampus. J Physiol 536: 89–100, 2001.
McLean HA, Caillard O, Khazipov R, Ben-Ari Y, and Gaiarsa JL. Spontaneous release of GABA activates GABAB receptors and controls network activity in the neonatal rat hippocampus. J Neurophysiol 76: 1036–1046, 1996.
Miles R and Wong RK. Single neurones can initiate synchronized population discharge in the hippocampus. Nature 306: 371–373, 1983.[CrossRef][Medline]
Payne JA, Rivera C, Voipio J, and Kaila K. Cation-chloride co-transporters in neuronal communication, development and trauma. Trends Neurosci 26: 199–206, 2003.[CrossRef][ISI][Medline]
Poisbeau P, Rene F, Egles C, Felix JM, Feltz P, and Schlichter R. Characterization of functional GABAergic synapses formed between rat hypothalamic neurons and pituitary intermediate lobe cells in coculture: Ca2+ dependence of spontaneous IPSCs. J Neurosci 16: 4835–4845, 1996.
Ralevic V and Burnstock G. Receptors for purines and pyrimidines. Pharmacol Rev 50: 413–492, 1998.
Ribeiro JA, Lobo MG, and Sebastiao AM. Endogenous adenosine modulation of 22Na uptake by rat brain synaptosomes. Neurochem Res 28: 1591–1595, 2003a.[CrossRef][ISI][Medline]
Ribeiro JA, Sebastiao AM, and de Mendonça A. Adenosine receptors in the nervous system: pathophysiological implications. Prog Neurobiol 68: 377–392, 2003b.[CrossRef][ISI]
Rivera C, Voipio J, Payne JA, Ruusuvuori E, Lahtinen H, Lamsa K, Pirvola U, Saarma M, and Kaila K. The K+/Cl– co-transporter KCC2 renders GABA hyperpolarizing during neuronal maturation. Nature 397: 251–255, 1999.[CrossRef][Medline]
Safiulina VF, Kasyanov AM, Sokolova EM, Cherubini E, and Giniatullin RA. ATP contributes to the generation of network-driven giant depolarizing potentials in the neonatal rat hippocampus. J Physiol 565: 981–992, 2005.
Spitzer NC. Coincidence detection enhances appropriate wiring of the nervous system. Proc Natl Acad Sci USA 101: 5311–5312, 2004.
Strata F, Sciancalepore M, and Cherubini E. Cyclic AMP-dependent modulation of giant depolarizing potentials by metabotropic glutamate receptors in the rat hippocampus. J Physiol 489: 115–125, 1995.
Trussell LO and Jackson MB. Dependence of an adenosine-activated potassium current on a GTP-binding protein in mammalian central neurons. J Neurosci 7: 3306–3316, 1987.[Abstract]
Tyzio R, Represa A, Jorquera I, Ben-Ari Y, Gozlan H, and Aniksztejn L. The establishment of GABAergic and glutamatergic synapses on CA1 pyramidal neurons is sequential and correlates with the development of the apical dendrite. J Neurosci 19: 10372–10382, 1999.
Wu LG and Saggau P. Adenosine inhibits evoked synaptic transmission primarily by reducing presynaptic calcium influx in area CA1 of hippocampus. Neuron 12: 1139–1148, 1994.[CrossRef][ISI][Medline]
Xie X, Hider RC, and Smart TG. Modulation of GABA-mediated synaptic transmission by endogenous zinc in the immature rat hippocampus in vitro. J Physiol 478: 75–86, 1994.
Yoon KW and Rothman SM. Adenosine inhibits excitatory but not inhibitory synaptic transmission in the hippocampus. J Neurosci 11: 1375–1380, 1991.[Abstract]
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