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NEUROSCIENCE |
1 Inserm, UMR S603, Paris, 75006 and Université Paris Descartes, UFR Biomédicale, Paris, 75006 France
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(Received 25 October 2006;
accepted after revision 18 December 2006;
first published online 21 December 2006)
Corresponding author E. Audinat: Neurophysiology and New Microscopies, Inserm U603, Université Paris Descartes, 45 rue des Saints Pères, 75006 Paris, France. Email: etienne.audinat{at}univ-paris5.fr
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Methods |
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All experiments followed European Union and institutional guidelines for the care and use of laboratory animals (Council directive 86/609EEC). Fourteen- to 29-day-old Wistar rats were either anaesthetized with an intraperitoneal injection of a mixture of ketamine (65 mg kg–1) and xylazine (14 mg kg–1) or humanely killed by cervical dislocation and decapitated. Transverse hippocampal slices (400 µm) were cut in an oxygenated ice-cold solution containing (mM): 235 sucrose, 2.5 KCl, 1.25 NaH2PO4, 0.5 CaCl2, 7 MgCl2, 20 glucose, 26 NaHCO3, 5 pyruvate. They were incubated at 34°C for 30 min and then maintained at room temperature for 0.5–4 h in an oxygenated physiological solution containing (mM): 126 NaCl, 2.5 KCl, 1.25 NaH2PO4, 2 CaCl2, 1 MgCl2, 20 glucose, 26 NaHCO3, 5 pyruvate. Finally the slices were transferred into a recording chamber perfused at 2.5 ml min–1 with the same solution. Recordings were performed at room temperature except during some experiments performed at 35°C as indicated in the Results section.
For experiments aiming at inhibiting the vacuolar H+-ATPase the slices were incubated for 2.5 h at 34°C in the physiological solution containing 4 µM of bafilomycin A1; the control slices were from the same rat and were incubated in the same conditions but without bafilomycin A1. The same procedure was followed for experiments aiming at inhibiting the glutmamine synthase with L-methionine sulfoximine (MSO; 5 mM) except that the incubation time varied from 1 to 3 h.
Electrophysiology
Pyramidal neurons from the subiculum or the CA1 regions were visually identified by means of infrared videomicroscopy. Whole-cell recordings were performed at a holding potential of +40 mV with an intracellular solution containing (mM): 100 caesium gluconate, 10 TEACl, 4 NaCl, 1 MgCl2, 10 Hepes, 10 BAPTA, 5 phosphocreatine, 2 ATP, 0.3 GTP; the pH was adjusted to 7.3 with CsOH. For recordings performed at –60 mV the intracellular solution contained (mM): 130 potassium gluconate, 10 Hepes, 4 NaCl, 1 MgCl2, 10 phosphocreatine, 4 ATP, 0.3 GTP, 0.2 EGTA; and the pH was adjusted to 7.3. With these intracellular solutions patch pipettes had a resistance of 3–5 M
. All potentials were corrected for a junction potential of –10 mV.
The current–voltage relationship of the tonic current was obtained by subtracting the mean of three current responses to a voltage ramp from +40 to –80 mV recorded in the presence of D-AP5 (50 µM) to that recorded just before the application of the antagonist. In experiments aimed at studying evoked synaptic currents, a surgical cut was made between CA3 and CA1. Evoked EPSCs recorded at +40 mV in the presence of 100 µM picrotoxin and 10 µM NBQX were elicited by a monopolar electrode placed in a patch pipette filled with the extracellular solution and positioned in the stratum radiatum. Short (100 µs) current pulses were delivered at a rate of 0.1 Hz and stimulus intensity was adjusted to maintain the EPSC amplitude in the range 50–150 pA.
Data collection and analysis
Membrane currents were recorded using an Axopatch 200B (Axon Instruments) amplifier. They were filtered at 2–5 kH, digitized at 5–20 kHz with a 1322A Digidata (Axon Instruments). Series resistance was not compensated but was regularly monitored throughout the experiment using a –1 mV step and recordings showing unstable (> 20%) series resistance were rejected. Acquisitions and off-line analysis were performed using pClamp9 softwares (Axon Instruments). The amplitude of the synaptic currents was determined by measuring the difference between the mean of the current during 5 ms just before stimulation artefacts and the mean of the current during a 5 ms period around the peak of the EPSCs. When the effects of a drug on the synaptic and on the tonic NMDAR-mediated currents had to be compared, responses were normalized to the amplitude of the currents blocked by a saturating concentration of D-AP5 or MK801. The effect of MK801 on synaptic current was determined by comparing the mean amplitude of the 10 last EPSCs in control conditions to the amplitude of the first EPSC after stimulation resumption.
For evaluating statistical differences between two samples Student's t test was performed; when more than two samples were compared an ANOVA test was used, followed by Dunnett's or Tukey tests. Differences were considered to be significant if P < 0.05. Values are given as mean ± S.E.M., and n refers to the number of cells.
Drugs
Tetrodotoxin (TTX) was purchased from Latoxan (Valence, France). Sarcosine, picrotoxin and L-methionine sulfoximine (MSO) were purchased from Sigma. [±]-cis-1-[Phenanthren-2yl-carbonyl]piperazine-2,3-dicarboxylic acid (PPDA) was a generous gift from D. T. Monaghan. This competitive antagonist of NMDARs has a slightly better affinity for NMDAR2C- or 2D-containing receptors (Lozovaya et al. 2004; Feng et al. 2004). [(R)-[(S)-1-(4-Bromo-phenyl)-ethylamino] - (2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl)-methyl]-phosphonic acid (NVP-AAM077) was a generous gift from Novartis. At a concentration of 0.1 µM this compound is selective for NMDAR2A-containing NMDARs (Auberson et al. 2002; Liu et al. 2004; Berberich et al. 2005). (2S)-2-Amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-(xanth-9-yl) propanoic acid (LY341495), 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[F]quinoxaline-7-sulphonamine disodium salt (NBQX disodium salt), 7-chloro-4-hydroxyquinoline-2-carboxilic acid (7-chlorokynurenic acid), D-(–)-2-amino-5-phosphonopentanoic acid (D-AP5), (5S,10R)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK801), D-serine, 6-chloro-3,4-dihydro-3 - (5-norbornen-2-yl) - 2H-1,2,4-benzothiazidianzine-7-sulphonamide-1,1-dioxide (cyclothiazide), DL-threo-
-benzyloxyaspartic acid (TBOA), 2S,3S,4R - 2 - carboxy - 4 - isopropyl - 3 - pyrrolidineacetic acid (DHK, dihydrokainic acid), bafilomycin A1 and 2-(4-benzylpiperidino) - 1 - (4 - hydroxyphenyl) - 1 - propanol hemitartrate (ifenprodil hemitartrate) were purchased from Tocris Cookson (Bristol, UK).
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Results |
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We recorded pyramidal cells of the CA1 and subiculum regions in acute slices of the rat hippocampus. At a holding potential of +40 mV and in the presence of extracellular Mg2+, TTX (0.5–1 µM) and picrotoxin (100 µM), application of a saturating concentration of the NMDAR antagonist D-AP5 (50 µM) blocked a tonic current that had a mean amplitude of 50.8 ± 13.4 pA (n = 12, Fig. 1A). Application of two other NMDAR blockers, MK801 (40 µM) and 7-Cl-KYN (10 µM), revealed a tonic current comparable to that observed with D-AP5 (respectively 53.2 ± 8.3 pA, n = 23 and 65.3 ± 17.7 pA, n = 5, Fig. 1C). This pharmacological profile suggests that the tonic current results from the activation of NMDARs by ambient glutamate rather than from spontaneous openings of these channels. Indeed, competitive antagonists, such as D-AP5, are less efficient at reducing single-channel currents due to spontaneous openings than ligand-activated currents (Turecek et al. 1997). The tonic current reversed at +5.18 ± 4.43 mV (n = 6) and showed the expected inward rectification of NMDA channels at membrane potentials between –80 and –30 mV (Fig. 1B). Near resting membrane potential, the tonic current was barely detectable whereas it reached –27.6 ± 6.46 pA at –30 mV (n = 6). Neither NBQX (40 µM, n = 5), which blocks both AMPA and kainate ionotropic receptors, nor LY341495 (100 µM, n = 4), a non-selective antagonist at all glutamate metabotropic receptors, decreased the amplitude of the tonic current. Since AMPARs could be fully desensitized by prolonged applications of glutamate we also reduced desensitization of these receptors by applying cyclothiazide (100 µM). However, neither cyclothiazide alone nor NBQX applied in the presence of cyclothiazide (n = 4) had any effect on the holding current of pyramidal cells (Fig. 1C). These results indicate that NMDARs were the only glutamate receptor type contributing to the tonic current recorded in pyramidal cells.
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We next asked whether ambient glutamate concentration was dependent upon neuronal activity. We therefore compared the amplitude and the pharmacological profile of the tonic current in control slices and in slices pre-treated with bafilomycin A1, an inhibitor of the vacuolar H+-ATPases. This pump establishes the proton gradient across vesicular membrane which drives transmitter uptake into synaptic vesicles (Drose & Altendorf, 1997). Pre-treatment of the slices for 2.5 h at 34°C with 4 µM bafilomycin A1 (see Methods) totally abolishes spontaneous synaptic currents as well as those evoked by raising extracellular potassium concentration (Fig. 4A). In these conditions, bath application of TBOA (100 µM) still induced an increase of the tonic current which did not differ from that induced in control slices (Fig. 4B and C). Moreover, the effect of NBQX and MK801 on the TBOA-induced current did not differ between control and bafylomycin-treated slices (Fig. 4C). Importantly, as described for control slices, application of MK801 significantly reduced the holding current revealing the presence of a NMDAR-mediated tonic current in bafylomycin A1-pre-treated slices (Fig. 4C). At a holding potential of +40 mV, the average amplitude of this basal tonic current was 65.19 ± 20.99 pA (n = 9), a value not significantly different from that of the tonic current recorded in control slices (50.34 ± 11.74 pA; n = 9). Therefore, the amplitude of the basal and TBOA-induced currents mediated by NMDARs was not dependent upon vesicular release of glutamate.
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Extrasynaptic NMDA receptors mediate tonic current
Pharmacological and physiological studies of GABAA receptors mediating the tonic inhibition of cerebellar and hippocampal neurons have provided evidence that these receptors are extra-synaptic and have a subunit composition which differs from that of synaptic GABAA receptors (Semyanov et al. 2004; Farrant & Nusser, 2005). We thus compared the effects of different subunit-selective NMDAR antagonists on the synaptic and tonic currents recorded in CA1 pyramidal neurons. However, the results obtained with PPDA (a NMDAR2C- and D-preferring antagonist), ifenprodil (a NMDAR2B antagonist) and NVP-AAM077 (a NMDAR2A antagonist; see Methods) did not reveal clear different pharmacological profile between synaptic and tonic currents (Fig. 5). PPDA inhibited more the tonic than the synaptic currents (62.7 ± 4.2%, n = 18 versus 42.3 ± 3.7%, n = 7, respectively; P = 0.0092). The larger percentage block of the tonic current by this competitive antagonist could result from a more important contribution of NMDAR2D subunits to this current or from a lower concentration of the glutamate mediating the tonic current relative to that responsible for the synaptic currents. Ifenprodil left unaffected the amplitude of both tonic and synaptic currents (4.5 ± 13.3%, n = 19; 5.6 ± 8.9%, n = 12, respectively). NVP-AAM077, the NMDAR2A-preferring antagonist, inhibits tonic and synaptic currents in the same proportions (37.0 ± 6.77, n = 10; 26.1 ± 6.37%, n = 8, respectively; P = 0.2647).
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Discussion |
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The amplitude of the NMDAR-mediated tonic conductance recorded in our experiments (
1 nS) falls in between those reported by Sah and co-workers (5 nS; Sah et al. 1989) and by Cavelier and Attwell (0.15 nS; Cavelier & Attwell, 2005) in CA1 pyramidal cells. These variations may originate partly from differences in the thickness of the slices (400 µm in our case; 225 µm for Cavelier & Attwell; mostly 400 µm for Sah et al. who also tested 100 µm thick slices) and from the depth at which the neurons were recorded. Sah et al. (1989) observed that the tonic current measured in thin slices was smaller than in thick slices and that the current recorded near the surface of thick slices was similar to that recorded in thin slices. Another difference between the experimental conditions of these studies is the age of the animals: Cavelier & Attwell (2005) used young rats (P11 to P13) whereas we used animals between P14 and P29 but most of our recordings were obtained around P18 (the age of the animals used by Sah et al. was not specified). In this context, it is worth noting that the expression of glutamate transporters is not completed before P20 (Kugler & Schleyer, 2004) and that the total concentration of glutamate as determined in vivo by means of NMR spectroscopy doubles between P14 and P21 (and stabilizes thereafter) in the hippocampus (Tkac et al. 2003).
By comparing the amplitude of the tonic current with that of the response induced by a saturating concentration of agonist and using the dose–response curve for NMDARs obtained from cultured neurons (Hill coefficient, nH, of 1.5 and EC50 of 2.3 µM; Patneau & Mayer, 1990), Cavelier & Attwell (2005) estimated an ambient glutamate concentration of 27–33 nM at 25°C, and 77–89 nM at 35°C. Using the value of the tonic current recorded in our experiments and following the same reasoning (for the details of the procedure see the Appendix in Cavelier & Attwell, 2005), we estimated the extracellular concentration of glutamate to reach 83–87 nM at 25°C. These values are far below those reported in vivo by glutamate-sensitive microelectrode array and microdialysis experiments which measured low micromolar (2 µM) concentrations of extracellular glutamate (Baker et al. 2002; Montiel et al. 2005). This important built up of ambient glutamate concentration in vivo may be a consequence of the higher synaptic activity observed in vivo than in vitro (Pare et al. 1998). In keeping with this hypothesis, extracellular glutamate measured with glutamate-sensitive electrodes is highly dependent on neuronal action potential propagation (Day et al. 2006). However, microdialysis measurements in vivo led to a different picture in which the ambient glutamate is not dependent on action potential activity (Baker et al. 2002). Therefore, the relative contribution of neuronal activity-dependent and -independent mechanisms in establishing the level of ambient glutamate in vivo remains unclear, while in the in vitro slice preparation the tonic current induced by ambient glutamate is totally independent of neuronal activity (see Results). Finally, it is difficult to ascertain that extracellular glutamate is not artefactually low in the slice preparation or that it is artefactually high when measured in vivo with large probes that might damage the tissue and compromise the integrity of the blood–brain barrier (Westergren et al. 1995; see also Cavelier et al. 2005).
Nevertheless, both in in vivo (Day et al. 2006) and in vitro experiments (Jabaudon et al. 1999; Angulo et al. 2004; Cavelier & Attwell, 2005; see also Arnth-Jensen et al. 2002), TBOA increases the concentration of ambient glutamate, indicating that the sodium-dependent glutamate uptake plays an important role in controlling the functional consequences of the tonic release of glutamate. The amplitude of the tonic current recorded in the presence of TBOA was nearly four times larger than in control conditions. This would correspond (see above) to an extracellular glutamate concentration of 300 nM. Although still low, this concentration appeared to be sufficient to activate some AMPARs. This relatively high affinity of AMPARs expressed by pyramidal neurons compares favourably with that of GluR1 homomeric receptors expressed in oocytes which start to be activated with glutamate concentrations as low as 100 nM (Dawson et al. 1990; Sakimura et al. 1990). When glutamate uptake is not inhibited, however, neither NBQX nor cyclothiazide have any effect on the tonic current, confirming that the ambient glutamate concentration is below 100 nM in the slices.
The activation of NMDARs requires the presence of two co-agonists, glutamate and glycine or D-serine (Johnson & Ascher, 1987; Mothet et al. 2000). Although manipulating the ambient glutamate concentration with inhibitors of the glutamate uptake readily modulates the tonic current, inhibitors of glycine uptake or applications of exogenous D-serine or glycine do not increase the amplitude of the tonic current. The saturation of the glycine sites of the NMDARs mediating the tonic current might have pointed to a difference between these receptors and those mediating synaptic responses. Indeed, Martina et al. (2003) have shown that the NMDA component of the synaptic responses evoked by the Schaffer collateral stimulation in rat hippocampal slices is potentiated by adding exogenous D-serine. However, in our recording conditions D-serine failed to increase the amplitude of NMDAR-mediated Schaffer collateral EPSCs. The reason of this discrepancy is not clear but our results are in good agreement with those of Ballard et al. (2002) and Scimemi et al. (2004) who also reported that saturating concentrations of D-serine do not increase the amplitude of the synaptic and extra-synaptic NMDAR-mediated responses in mouse CA1 pyramidal neurons.
Pyramidal neurons of CA1 express NR1, NR2A, NR2B and NR2D subunits of the NMDARs (Monyer et al. 1994; Thompson et al. 2002). Our results with NVP-AAM077 and PPDA show that the NMDARs mediating the tonic and the synaptic currents most probably contain NR2A and NR2D subunits. The higher percentage block of the tonic current by PPDA may indicate that NR2D-containing NMDARs contribute more to the tonic current than to the synaptic responses. However, the results obtained with this competitive antagonist may also simply reflect the difference in the glutamate concentrations mediating the tonic and the synaptic currents. Finally, it is difficult to exclude totally a contribution of NR2B subunits to NMDARs mediating the tonic current on the ground of the observation that ifenprodil does not inhibit this current. Indeed, the selectivity of this ‘subunit-selective’ antagonist is not known for all types of NMDARs and the effects of ifenprodil depend also on the glutamate concentration (Neyton & Paoletti, 2006). Thus, our results do not support a difference in the subunit composition of the NMDARs mediating the synaptic and the tonic currents although the experiments with MK801 point toward an extra-synaptic localization of the receptors activated by ambient glutamate.
The tonic current studied here shares many common features with slow transient currents recorded in the same neurons and resulting from a release of glutamate by astrocytes. In particular, both types of currents are mediated by the activation of NMDARs and are independent of neuronal vesicular release (Angulo et al. 2004; Fellin et al. 2004; Perea & Araque, 2005). These similarities suggest that the glutamate originates in both cases from the same source, i.e. astroglial cells. In keeping with this hypothesis, inhibition of the astrocyte-specific enzyme glutamine synthetase (Norenberg & Martinez-Hernandez, 1979), which converts glutamate into glutamine (Ottersen et al. 1992), increases the tonic current observed upon inhibition of glutamate transporters by TBOA, both in acute slices (our present results and Cavelier et al. 2005) and in organotypic cultures (Jabaudon et al. 1999) of the hippocampus. In addition, a similar tonic current mediated by NMDARs has been observed in CA1 pyramidal cells when astrocytic purinergic receptors are activated (Fellin et al. 2006).
Our results are in keeping with the idea that ambient glutamate predominantly originates from glial cells and tonically activates extrasynaptic NMDARs but the physiological role of this ambient glutamate remains unclear. The magnesium block of NMDARs near resting membrane potential implies that the tonic current will operate only at depolarizing potentials. Sah and co-workers showed that blocking the tonic current reduces the action potential firing frequency and the functional coupling between dendritic and somatic compartments of CA1 neurons (Sah et al. 1989). However, in our experimental conditions, i.e. with a 5–10 times smaller tonic current, bath application of D-AP5 failed to significantly change the action potential discharge of CA1 neurons (see Supplementary Fig. 1). Further experiments are therefore needed to test whether the level of ambient glutamate reported here or by Cavelier & Attwell (2005) finely tunes dendritic processing of synaptic inputs. Finally, it has been shown that activation of extrasynaptic receptors can selectively trigger cell death (Hardingham et al. 2002). Our results showing that ambient glutamate primarily originates from astrocytes and targets extrasynaptic NMDARs therefore suggest that astrocytes play a pivotal role in many excitotoxicity-related pathologies.
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Acknowledgements |
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Author's present address
M. Galante: Pharmacologie de la Synapse, UMR CNRS 8619, Université Paris Sud, Orsay, France.
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