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1 INSERM U583, Institut des Neurosciences de Montpellier, Groupe d'Etude des Désordres Vestibulaires, Hôpital Saint Eloi, BP74 103, 34091 Montpellier Cedex 5, France
2 Institut de Génomique Fonctionnelle, Département de Pharmacologie Moléculaire, CNRS UMR5203, 141 Rue de la Cardonille, 34094 Montpellier Cedex 5, France
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Abstract |
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(Received 4 July 2006;
accepted after revision 31 July 2006;
first published online 3 August 2006)
Corresponding authors J. Bonsacquet & C. Chabbert: INSERM U583, Institut des Neurosciences de Montpellier, Hôpital Saint Eloi, BP74 103, 80 Rue Fliche, 34091 Montpellier Cedex 5 France. Email: jbonsacquet{at}univ-montp2.frcchabbert{at}univ-montp2.fr
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Introduction |
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Here, we investigated the presence of AMPA and NMDA receptors at the calyx synapse using immunocytochemistry for the GluR2, NR1 and NR2A/B subunits of the glutamate receptors. We also developed direct electrophysiological recordings at calyx terminals in situ in the turtle vestibular epithelia. We used the loose patch configuration of the patch-clamp technique, which preserves the integrity of the calyx structure, to record the spontaneous and the evoked activities triggered by mechanical deflections of the sensory cell's hair bundles. Our results reveal that although subunits from both AMPA and NMDA receptors are present at the calyx terminal, only AMPA receptors are involved in background and mechanically evoked synaptic transmission.
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Methods |
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Immunocytochemistry
Turtle posterior cristae were fixed by immersion in paraformaldehyde, 4% in 0.1 M phosphate buffer saline (PBS, pH 7.4) at 4°C for 1 h. The samples were embedded in agarose, 4% in PBS (Invitrogen, Cergy Pontoise, France), and cut into 50 µm sections using a vibrating blade microtome (Vibratome series 1000, Technical Products International, St Louis, MO, USA) in ice-cold PBS. Free-floating sections were incubated for 1 h at 4°C in PBS containing 10% normal donkey serum and 0.3% Triton X-100. The sections were then incubated overnight at 4°C with mouse anti-GluR2 monoclonal antibodies (1: 200; Chemicon, Temecula, CA, USA), mouse anti-NMDAR1 monoclonal antibodies (1: 500; BD Biosciences Pharmingen, San Diego, CA, USA), rabbit anti-NMDAR2A/B polyclonal antibodies (1: 500; Chemicon), and rabbit antineurofilament 200 polyclonal antibodies (1: 800; Sigma, Saint Louis, MO, USA) or mouse anti-neurofilament 200 clone N52 monoclonal antibodies (1: 800; Sigma) in PBS containing 5% normal donkey serum and 0.1% Triton X-100. After rinsing with PBS, sections were incubated for 2 h at room temperature with biotinylated anti-rabbit IgG (1: 200; Jackson ImmunoResearch Laboratories, West Grove, PA, USA) or biotinylated antimouse IgG (1: 200; Jackson Laboratories), and subsequently incubated with streptavidin Alexa-Fluor 546 conjugate (1: 500; Invitrogen) for glutamate receptors subunits, and fluorescein-isothiocyanate (FITC)-conjugated antirabbit IgG (1: 300, Jackson Laboratories) or Alexa-Fluor 488 antimouse IgG (1: 1000, Invitrogen) for neurofilaments. Sections were then mounted in Fluorsave Reagent (Calbiochem, France) and observed with a Bio-Rad MRC 1024 laser scanning confocal microscope equipped with x40 and 63 objectives. The specificity of immunostaining was routinely checked by omitting the primary antibody. Controls showed no specific fluorescence when primary antibodies were omitted (data not shown).
Western blotting
Mouse and turtle brains were washed twice in ice-cold PBS and homogenized with 10–15 strokes using a glass-Teflon homogenizer in cold homogenization buffer (0.32 M sucrose, 10 mM Hepes, pH 7.4, 2 mM EDTA) containing a cocktail of protease inhibitors (Roche, France). Washed membrane pellets (P1) were obtained by a series of centrifugations. Briefly, the homogenate was centrifuged at 280 g for 20 min at 4°C, the supernatant was collected and re-centrifuged at 200 000 g for 15 min (4°C). The pellet (P1) thus obtained was resuspended in homogenization buffer and centrifuged again at 200 000 g for 15 min (4°C). P1 was resuspended in Hepes lysis buffer (50 mM Hepes, pH 7.4, 2 mM EDTA, protease inhibitors) and passed five times through a 26G needle. Protein concentration was determined and proteins were solubilized in 1% Triton X-100 for 45 min at 4°C. Membrane proteins (50 µg) were subjected to SDS-PAGE, transferred to a nitrocellulose membrane, which was then saturated overnight with 5% fat-free milk. The membrane was incubated overnight with the same primary antibodies as those used for immunocytochemistry (1: 1000), washed, and incubated for 1 h with the appropriate secondary antibodies coupled to peroxidase. Bands were visualized using SuperSignal West Pico or Femto chemiluninescent substrate (Pierce Biotechnology, Inc., Rockford, IL, USA).
Physiological recordings
Turtles were deeply anaesthetized (sodium pentobarbital, 6%) and decapitated, and a sagittal cut was made in the head. The brain was then removed and the posterior ampulla was transferred to the recording chamber. The sensory epithelium remained connected to the brainstem by the terminal branch of the eighth nerve. The ampulla was opened to access the neuroepithelium and the cupula removed in low calcium (0.1 mM) APS to preserve hair bundle integrity. Explants were anchored to a parafilm base mounted on a glass coverslip in a recording chamber filled with 2 ml of oxygenated APS. The bath was renewed at a rate of 0.5 ml min–1 at a distance from the sample to avoid any mechanical stimulation of the hair bundles. Recordings were taken at room temperature (21–23°C). Electrical activities were recorded by using the loose patch clamp configuration of the patch-clamp technique. This method was found to be well suited for overcoming difficulties of establishing stable recordings, encountered using the whole-cell mode due to the peculiar shape of the calyx terminal, which is formed by close apposition of membrane layers rather than a cylindrical cable. Recording pipettes filled with APS with an impedance of 1.5–3 M
were placed on the external membrane of the calyx terminal while maintaining a positive pressure during the approach. Seal resistances ranged between 50 and 100 M. Electrical activities were recorded and filtered at 5 or 10 kHz using an Axopatch 200B patch clamp amplifier, controlled by a 1322-A Digidata controller (Axon Instruments/Molecular Devices Corp., Union City, CA, USA). Data were sampled at 5 kHz (pCLAMP9, Axon Instruments). Frequency analysis was performed using SERF v2.62 software (http://www.bram.org/serf/serf.php). The mean frequency of the background activities was determined during 3–5 min recordings. Statistical significances were determined using Student's t test. The recordings at the calyx terminals often lasted for more than 1 h, attesting to the viability of our preparations.
Identification and pharmacology
To identify the afferent fibre under investigation, we broke the dendrite membrane at the end of the experiment, allowing Lucifer yellow contained in the recording pipette to diffuse into the terminal. Dye loading into the calyx terminal was examined using a two-photon microscope (Radiance 2000, Bio-Rad, UK). Data sampled in the present study were taken from multicalyx bearing afferents that are restricted to the central part of the hemi-crista (Brichta & Peterson, 1994). Hair bundles were deflected using a velocity controlled perfusion system (Microlab 500B/C Series Diluter, Hamilton Company, Reno, NV, USA). APS was delivered to the hair bundles through calibrated pipettes with 30 µm diameter tips placed 1 mm from the epithelium. The preparation was orientated to evoke a maximal response (usually perpendicular to the sensory epithelia) and APS was applied with a velocity between 1 and 10 µl s–1. Pharmacological agents were applied in the bath solution at the following concentrations: TTX (0.5 µM), gentamicin (100 µM), FM1-43 (5 µM), nitrendipine (15 µM), the competitive AMPA/KA receptor antagonist NBQX (1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxali-ne-7-sulphonamide) (5 µM), the specific non-competitive AMPA receptor antagonist GYKI 53784 ((–)1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-4,5-dihydro-3-methylcarbamoyl-2,3-benzodiazepine; 15 µM; Lilly Research Laboratories, USA), the selective non-competitive NMDA receptor antagonist MK-801 (5R,10S-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate; 20 µM) and the NMDA receptor antagonist D-AP5 (D-2-amino-5-phosphonopentanoate; 50 µM).
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Results |
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Several studies have shown that glutamate is the main excitatory neurotransmitter involved in synaptic transmission between the type I vestibular hair cell and the calyx terminal (Dechesne et al. 1984; Dememes et al. 1990). To identify the glutamate receptors involved in calyx neurotransmission in the turtle posterior crista, we looked for the presence of AMPA and NMDA receptors by using antibodies against the GluR2, NR1 and NR2A/B subunits. Immunoreactivity for each antibody appeared as bright spots restricted to the synaptic contact between the type I hair cells and their cognate afferent fibre (Fig. 1). Multiple bright spots were found at single calyx terminals. These observations indicated that both the AMPA and NMDA receptors were present at the calyx terminal in the turtle crista. Western blot analysis confirmed the specificity of the antibodies in the turtle. The immunoblots illustrated in Fig. 1 showed single bands that migrated for both turtle and mouse tissue with apparent molecular masses of 102, 120 and 180 kDa corresponding to GluR2, NR1 and NR2A/B subunits, respectively, in the mouse brain (Petralia & Wenthold, 1992; Petralia et al. 1994).
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We used the loose-patch configuration of the patch-clamp technique to record the electrical activities at calyx terminals from the central parts of the turtle hemi-cristae. A patch pipette inserted through the surface of the sensory epithelium was gently apposed against the external membrane of the calyx terminal in situ in a whole-mount explant (Fig. 2A and B). Most of the calyx terminals (78%; n = 31) displayed a background electrical activity (mean frequency: 16.5 ± 14 spikes s–1), while some remained silent (22%; n = 9). We were able to reversibly suppress these transient variations in the membrane voltage by the substitution of sodium by choline in the bathing medium (n = 4) and to completely remove them with 0.5 µM TTX (n = 11) (Fig. 2C). We then checked whether hair cells are involved in generating the background firing at the calyx terminal by using specific blockers of the mechano-electrical transduction (MET) channels. In less than 30 s, 100 µM of gentamicin (n = 6) or 5 µM of FM1-43 (n = 3) completely abolished the background activity recorded at calyx terminals (Fig. 2D), indicating that an influx of cations through the MET channels was required to generate the firing. Furthermore, 15 µM of nitrendipine, the L-type voltage-gated calcium channels specific blocker, reversibly blocked the background discharge of the terminals (n = 3) (Fig. 2E). Mechanical stimulation of the hair bundles of the sensory cells increased the firing frequency both in the fibres displaying background activity (n = 15) and in the silent fibres (n = 9) (Fig. 3A and B). The mechanically evoked activities were blocked by 0.5 µM TTX (n = 9) and were prevented by 100 µM gentamicin (n = 7) (Fig. 3C and D). Together, these observations confirmed that this preparation and recording method were appropriate for monitoring the electrical activity at intact calyx terminals, thus allowing access to the synaptic transmission at calyx synapses.
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We then studied the effect of selective NMDA and non-NMDA antagonists on the background and the mechanically evoked activities recorded at calyx terminals. As illustrated in Fig. 4, the non-competitive NMDA receptor antagonist MK801 (20 µM) did not significantly affect the background (Fig. 4A) nor the mechanically evoked discharge rates (Fig. 4B) (P > 0.2; n = 6). In contrast, the AMPA/KA receptor antagonist NBQX (5 µM) blocked both the background (n = 8) and the mechanically evoked (n = 12) activities (Fig. 4A and B). A similar blocking effect was observed using the specific AMPA receptor antagonist GYKI 53784 (15 µM; n = 3) (Fig. 4C). Complete recovery of the background and mechanically evoked activities was observed after 30–50 min washing with APS (not shown). Mean discharge frequencies did not significantly differ prior to GYKI application and after washing (P > 0.2; n = 3). In the three calyx terminal tested, the mechanically evoked activities always recovered before the background activities. Since NMDA receptors are present at the calyx synapse (see above), we studied their potential functionality. Perfusion of Mg2+ free APS combined with the NMDA receptor coagonist glycine (10 µM) significantly enhanced the background discharge recorded at the calyx terminal (P < 0.05; n = 8) (Fig. 4D). The complete reversion of this effect was obtained by application of NMDA receptor antagonist D-AP5 (50 µM) (n = 4). These results demonstrate that the NMDA receptors are functional. Altogether, these results show that although both AMPA and NMDA receptors are both present at calyx synapse, only AMPA receptors are involved in standard conditions in the background and mechanically evoked synaptic transmission.
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Discussion |
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We detected sodium-based action potentials within the calyx terminal. The pattern of the background activity was not different from those recorded in the turtle vestibular nerve. Their mean frequencies were very similar to those found in the non-myelinated segment below the calyx terminals in the chick crista (Yamashita & Ohmori, 1990) and in the myelinated segment proximal to Scarpa's ganglion in the turtle (Brichta & Goldberg, 2000a). Furthermore, our recordings showed that silent units are also present, as previously reported in the turtle (Brichta & Goldberg, 2000a). The recorded discharges were found to depend strictly on the hair cell activities as these were modulated when the hair bundles of the sensory cells were displaced. In addition, the discharges were completely blocked by MET channel blockers, such as gentamicin (Kroese et al. 1989) and FM1-43 (Gale et al. 2001; Meyers et al. 2003). We previously demonstrated that gentamicin had a fast blocking effect on isolated vestibular hair cells (Chabbert et al. 1994). In the present study, its effect, as that of FM1-43, is also very fast (within 30 s) suggesting a direct action on the transduction channels rather than a long-term toxic effect on the hair cells or the terminals. Therefore, we can interpret the background activity as a consequence of cation influx through a small population of MET channels that remain open at rest, as previously demonstrated both in vestibular (Corey & Hudspeth, 1983) and auditory hair cells (Crawford & Fettiplace, 1985). The inhibitory effect of nitrendipine showed for the first time that the transmitter release is mediated by the L-type calcium channel previously described in vestibular hair cells (Bao et al. 2003). Given the reduced number of type II hair cells (Jorgensen, 1974; Brichta & Peterson, 1994; Lysakowski, 1996) and the small percentage of synapses between type II hair cells and calyces in the central zone of the epithelia (less than 15%, A. Lysakowski personal communication), we can reasonably conclude that we mainly recorded afferent discharge resulting from activation of type I hair cells.
AMPA GluR2 and NMDA NR1 subunits have been previously identified at calyx synapses in mammals (Matsubara et al. 1999; Ishiyama et al. 2002). Our immunocytochemical data demonstrate that these proteins are expressed at the same location in reptiles, suggesting that such synaptic equipment is common in higher vertebrates. Beside the punctuate labelling clearly identifiable at the synapse, a slight diffuse labelling is present in the hair cell cytoplasm. Although this could be considered as non-specific labelling, it cannot be excluded that it reflects the presence of presynaptic receptors, as the NMDA receptor has been previously described at calyx synapses in the rat (Ishiyama et al. 2002) and in central nervous system (Berretta & Jones, 1996; Breukel et al. 1998) where it modulates glutamate release. In the cochlear system, AMPA receptors have been reported as the only glutamate receptors involved in quantal synaptic activity between cochlear afferents and inner hair cells (Ruel et al. 1999; Ruel et al. 2000; Glowatzki & Fuchs, 2002). The first pharmacological evidence for the involvement of non-NMDA receptors in vestibular neurotransmission was recently provided from the blocking effect of the AMPA/KA receptor blocker CNQX on the synapse activity at bouton terminals of turtle posterior crista (Holt et al. 2006). The present study further demonstrates that the AMPA receptor mediates chemical neurotransmission between type I hair cells and their cognate afferents, since GYKI 53784 has been reported to be a selective AMPA receptor antagonist (Ruel et al. 2002). The presence of the GluR2 subunit is of special interest with regard to its involvement in defining the calcium impermeability of the AMPA receptors (Hollmann et al. 1991). Whether other AMPA receptor subunits are present at the calyx terminal and how they participate in shaping the calyx synaptic activity should be investigated, as the mRNAs of five subunits (GluR2-6) of this receptor have been previously reported in the cell body of Scarpa's ganglion neurons in mammals (Niedzielski & Wenthold, 1995). The expression of the NR1 and NR2A/B subunits at the calyx terminal in the turtle raises several questions about the putative functional role of the NMDA receptor since it is not involved in either the background or the mechanically evoked activities. Conversely, in lower vertebrates, its activation is essential for the background activity, while it seems to be less involved in the mechanically evoked transmission (Soto et al. 1994). In the present study, the lack of activation cannot be interpreted as the consequence of missing subunits needed to form a functional receptor, since the combination of NR1 and NR2 subunits is sufficient to form a functional NMDA channel (for review see Nakanishi, 1992). We demonstrated the functionality of these receptors by removing the Mg2+ block which normally leads to a non-permeant ionic channel at hyperpolarized membrane potential although they bind their agonist glutamate and coagonist glycine (Mayer & Westbrook, 1987; Ascher & Nowak, 1988). It may therefore be possible that under our stimulation conditions the depolarization of the terminal is not sufficient to reach the threshold for NMDA receptor activation. Such depolarization could occur during periods of high activity giving to these receptors a significant role. In addition, we cannot exclude that the NMDA receptor may be activated under specific conditions, such as the reported excitatory efferent activation on the calyx terminals (Brichta & Goldberg, 2000b) and/or pathophysiological conditions as reported in the cochlea after excitotoxicity (Puel, 1995; d'Aldin et al. 1997). In the giant terminal calyx of Held located in the medial nucleus of the trapezoid body (MNTB), it has been shown that NMDA receptors are essential for synapse maturation, while their involvement declines with age (Bellingham et al. 1998; Joshi & Wang, 2002). Such a developmental phenomenon would explain the lack of involvement of NMDA receptors in the vestibule of mature turtles.
In a theoretical analysis, Goldberg (1996) proposed that neurotransmission at the calyx synapse may involve cooperation between conventional synaptic transmission and intercellular K+ ion accumulation. The latter may modulate the conventional transmission by depolarizing both the pre- and postsynaptic elements and by possibly activating the NMDA pathway. The present results constitute the first direct demonstration that conventional synaptic transmission occurs at the calyx synapse. The modulatory effect of the K+ fluxes on neurotransmission still remains to be demonstrated; this hypothesis seems more and more relevant regarding the recent results obtained on the bouton synapse, which confirm the major role of K+ in neurotransmission (Holt et al. 2006).
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