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RAPID REPORT |
2 glutamate receptor to regulate synaptic plasticity and motor coordination
1 Department of Physiology, School of Medicine, Keio University, Tokyo 160-8582, Japan
2 Department of Anatomy, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan
3 Department of Neurophysiology, Gunma University Graduate School of Medicine, Maebashi 371-8511, Japan
4 SORST, Japan Science and Technology Agency, Kawaguchi 332-0012, Japan
5 Department of Molecular Neurobiology and Pharmacology, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan
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Abstract |
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2 glutamate receptor (GluR2) plays a crucial role in cerebellar functions; mice with a disrupted GluR2 gene (GluR2–/–) display impaired synapse formation and abrogated long-term depression (LTD). However, the mechanisms by which GluR2 functions have remained unclear. Because a GluR2 mutation in lurcher mice causes channel activities characterized by Ca2+ permeability, GluR2 was previously suggested to serve as a Ca2+-permeable channel in Purkinje cells. To test this hypothesis, we introduced a GluR2 transgene, which had a mutation (Gln618Arg) in the putative channel pore, into GluR2–/– mice. Interestingly, the mutant transgene rescued the major functional and morphological abnormalities of GluR2–/– Purkinje cells, such as enhanced paired-pulse facilitation, impaired LTD at parallel fibre synapses, and sustained innervation by multiple climbing fibres. These results indicate that the conserved glutamine residue in the channel pore, which is crucial for all Ca2+-permeable glutamate receptors, is not essential for the function of GluR2.
(Received 20 December 2006;
accepted after revision 18 January 2007;
first published online 25 January 2007)
Corresponding author M. Yuzaki: Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. Email: myuzaki{at}sc.itc.keio.ac.jp
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Introduction |
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-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, kainate receptors, N-methyl-D-aspartate (NMDA) receptors, and glutamate receptors (Hollmann & Heinemann, 1994). The 2 glutamate receptor (GluR2), which is predominantly expressed on the postsynaptic sites of parallel fibre (PF)–Purkinje cell synapses, plays a crucial role in cerebellar functions: mutant mice with a disrupted GluR2 gene (GluR2–/– mice) display impaired formation of PF–Purkinje cell synapses (Kurihara et al. 1997; Lalouette et al. 2001). In addition, long-term depression (LTD), a form of synaptic plasticity thought to underlie motor coordination and information storage in the cerebellum (Ito, 1989), is completely abrogated at these synapses in GluR2–/– mice (Kashiwabuchi et al. 1995). Despite its importance, the mechanisms by which GluR2 participates in cerebellar functions have remained elusive (Yuzaki, 2004).
A fundamental unanswered question is whether GluR2 functions as an ion channel. Support for GluR2 channel activity has come from studies on spontaneously occurring ataxic mutant lurcher mice. A point mutation at the end of the third transmembrane region causes the constitutive activation of mutant GluR2 channels in lurcher (GluR2Lc) (Zuo et al. 1997). When a similar point mutation was introduced in the corresponding region of AMPA and kainate receptors, these mutant iGluRs showed constitutive channel activation that reflected the corresponding wild-type properties (Kohda et al. 2000). GluR2Lc exhibited a rectified current–voltage relationship, was sensitive to a polyamine antagonist, and showed moderate Ca2+ permeability (Kohda et al. 2000; Wollmuth et al. 2000). In addition, similar to wild-type AMPA receptors, the Ca2+ permeability of GluR2Lc was abolished by the substitution of glutamine with arginine at the putative channel pore region (the Q/R/N site; Fig. 1A and B). Furthermore, endogenous GluR2 contains glutamine at the Q/R/N site (Kohda et al. 2000) and exists mainly as a homomeric receptor in vivo (Mayat et al. 1995; Kohda et al. 2003). These findings suggest that endogenous GluR2 may form a Ca2+-permeable channel. On the other hand, PF-evoked excitatory postsynaptic currents (EPSCs) were completely blocked by AMPA receptor antagonists in wild-type cerebellum (Kano & Kato, 1987). In addition, amplitudes and kinetics of miniature EPSCs, as well as those of AMPA-evoked currents, are normal in Purkinje cells lacking GluR2 (Jeromin et al. 1996; Yawata et al. 2006). Therefore, GluR2 is unlikely to mediate normal synaptic transmission; however, it may still function as a Ca2+-permeable channel under certain conditions.
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2 was suggested to serve as a Ca2+-permeable channel during LTD-inducing stimulation (Wollmuth et al. 2000). Because comparison of Ca2+ levels between wild-type and GluR2–/– Purkinje cell spines during LTD could be complicated by morphological abnormalities associated with GluR2–/– synapses (Kurihara et al. 1997; Lalouette et al. 2001), we did not rely on Ca2+ imaging, but instead we generated mice that express a mutant GluR2 transgene, in which arginine replaces the glutamine at the Q/R/N site (TgQ/R), onto a GluR2–/– background. We hypothesized that, unlike the wild-type GluR2 transgene (Tgwt) (Hirai et al. 2005), TgQ/R would not rescue the abnormal phenotypes of GluR2–/– mice if GluR2 functions as a Ca2+-permeable channel. |
Methods |
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A mutant GluR2 transgene (TgQ/R), in which arginine replaced the glutamine at position 618, was inserted into the BamH I site of pL7
AUG (Fig. 1 in online Supplemental material) and was injected into fertilized eggs (Hirai et al. 2005). Ten TgQ/R founders were bred onto a GluR2–/– background (termed as GluR2–/–/TgQ/R), as previously described (Hirai et al. 2005). Homozygous transgenic lines were established and confirmed by backcrossing with wild-type mice. All procedures relating to the care and treatment of the animals were carried out according to NIH guidelines.
Immunoblotting
Mice were decapitated after anaesthetization with tribromoethanol. Whole cerebella were homogenized in lysis buffer (50 mM NaF, 1% NP-40, 20 mM EDTA, 0.1% SDS, 50 mM Tris-HCl, pH 8.0) containing a protease inhibitor cocktail (Calbiochem, San Diego, CA, USA), and the homogenates were analysed using immunoblotting with anti-GluR2-specific antibody (Chemicon, Temecula, CA, USA) and enhanced chemiluminescence (Amersham, Piscataway, NJ, USA), as previously described (Hirai et al. 2005). The fluorescence intensities were quantified using an image analyser (LAS-3000; Fujifilm, Tokyo, Japan).
Immunohistochemistry
Under deep anaesthesia with tribromoethanol, adult mice (over 4 weeks old) were perfused transcardially with 4% paraformaldehyde in 0.1 m sodium phosphate buffer (pH 7.4), and processed into paraffin sections (5 µm) using a sliding microtome (SM2000R; Leica Microsystems, Nussloch, Germany). Sagittal sections were immunostained with anti-GluR2 antibody followed by incubation with a Cy3-conjugated secondary antibody (Jackson ImmunoResearch, West Grove, PA, USA). Images were captured using a fluorescence microscope (AX-70; Olympus, Tokyo, Japan) or a confocal laser scanning microscope (Fluoview; Olympus).
Behavioural tasks
Restoration of ataxic phenotypes of GluR2–/– mice was analysed by the footprint patterns and the rotor-rod test as previously described (Hirai et al. 2005) (see Supplemental material).
Electrophysiology
Sagittal or coronal cerebellar slices (200 µm thick) were prepared from GluR2–/– and transgenic mice (postnatal days 22–46) as previously described (Hirai et al. 2005) (see Supplemental material). To induce LTD, PF-EPSCs were recorded successively at a frequency of 0.1 Hz from Purkinje cells clamped at –80 mV. After stable PF-EPSCs were observed for at least 15 min, a conjunctive stimulation composed of 30 single PF stimuli together with 200 ms depolarizing pulses from a holding potential of –60 to +20 mV was applied. Access resistances were monitored every 10 s by measuring the peak currents in response to 2 mV, 50 ms hyperpolarizing steps throughout the experiments; the measurements were discarded if the resistance changed by more than 20% of its original value.
Data analysis and statistics
Results are reported as the mean ± S.E.M., and the statistical significance was defined at P < 0.05, as determined using the Mann–Whitney U test, unless stated otherwise.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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2 transgene (Tgwt) and obtained a transgenic ‘rescue’ line called GluR2–/–/Tgwt by breeding transgenic mice onto a GluR2–/– background (Hirai et al. 2005). Similarly, to examine the putative role of Ca2+ influx through GluR2 channels, we generated GluR2–/–/TgQ/R lines that express GluR2 transgenes, which contained arginine instead of glutamine at the Q/R/N site. We confirmed that transgenes were properly inserted into the genome by sequencing the genomic DNA (Fig. 1C). Immunohistochemical analysis with anti-GluR2 antibody showed the Purkinje cell-specific expression of Tgwt and TgQ/R (Fig. 1D). Although the expression levels of TgQ/R protein were approximately 10% of those of endo-genous GluR2 protein in wild-type cerebellum and approximately half of those of Tgwt protein (Fig. 1E), GluR2–/–/TgQ/R mice exhibited no ataxia and could walk along a straight line (Fig. 1F). In addition, like wild-type and GluR2–/–/Tgwt mice, the GluR2–/–/TgQ/R mice performed normally on the rotor-rod task at 20 r.p.m. (Fig. 1G), indicating that TgQ/R could rescue the motor discoordination of GluR2–/– mice.
Paired-pulse facilitation (PPF) is a short-term plasticity that reflects changes in presynaptic transmitter release probability (Zucker & Regehr, 2002). As reported earlier (Kashiwabuchi et al. 1995), the ratio of PPF at an interpulse interval of 50 ms was elevated in GluR2–/– Purkinje cells (Fig. 2; 2.38 ± 0.07, n
= 15), a finding indicating that the lack of GluR2 at postsynaptic sites reduced the probability of glutamate release at presynaptic PF terminals. Interestingly, Purkinje cells from GluR2–/–/TgQ/R as well as GluR2–/–/Tgwt mice displayed PPF ratios (1.65 ± 0.06, n
= 21; 1.73 ± 0.04, n
= 20, respectively) that were significantly smaller than that of GluR2–/– mice (P < 0.001) and comparable to that of wild-type mice (1.81 ± 0.04, n
= 7; Kondo et al. 2005). These results indicate that the reduced release probability of PFs in GluR2–/– mice was restored by the expression of TgQ/R as well as the expression of Tgwt.
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2 was proposed to regulate the number of postsynaptic AMPA receptors at PF–Purkinje cell synapses (Hirai et al. 2003) and thus was thought to play essential roles in LTD induction (Kashiwabuchi et al. 1995). Indeed, no LTD was induced by conjunctive stimulation of PFs with the depolarization of GluR2–/– Purkinje cells (Fig. 3A and D; 101 ± 4% at t
= 30 min, n
= 6 from 4 mice). In contrast, LTD was effectively induced in GluR2–/–/Tgwt Purkinje cells (Fig. 4B and D; 68 ± 6% at t
= 30 min, n
= 6 from 4 mice). Similarly, robust LTD was induced in GluR2–/–/TgQ/R Purkinje cells (Fig. 3C and D; 74 ± 3% at t
= 30 min, n
= 7 from 5 mice); the reduction of EPSC amplitudes was similar to that in GluR2–/–/Tgwt Purkinje cells (P
= 0.57) and significantly larger than that in GluR2–/– mice (P < 0.005). Therefore, TgQ/R was as effective as Tgwt in restoring blunted LTD in GluR2–/– mice.
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2 is proposed to play crucial roles not only in functional synaptic plasticity, such as PPF and LTD, but also in synapse formation and its maintenance (Yuzaki, 2004). The number of PF–Purkinje cell synapses is markedly reduced in GluR2–/– cerebella, whereas the total spine density does not differ significantly from that in wild-type cerebella; as a result, many spines are ‘naked’ ones that lack presynaptic contact (Kurihara et al. 1997; Lalouette et al. 2001). Serial electron microscopic analysis (Supplemental Fig. 2) revealed a significantly reduced number of naked spines in GluR2–/–/TgQ/R cerebella (12 ± 6%; 300 total spines counted in 3 mice; P < 0.04), compared to that in GluR2–/– mice (40 ± 2%; 300 total spines counted in 3 mice). However, the percentage of naked spines was still higher, although not statistically significant, in GluR2–/–/TgQ/R cerebella than in GluR2–/–/Tgwt cerebella (0.3 ± 0.3%; 300 total spines counted in 3 mice; P > 0.05). In addition to the loss of PF synapses, the remaining PF–Purkinje cell synapses in GluR2–/– mice frequently show another specific abnormality: the length of the postsynaptic density (PSD) does not equal that of the opposing presynaptic active zone (Lalouette et al. 2001). Serial electron microscopic analysis (Supplemental Fig. 2) revealed that the occurrence of mismatching between the PSD and the active zone at PF synapses was reduced in GluR2–/–/TgQ/R cerebella (5 ± 2%), compared to that in GluR2–/– cerebella (29 ± 6%; 300 spines counted in 3 representative mice from each line; P < 0.01). However, it was still higher than that in GluR2–/–/Tgwt cerebella (0.5 ± 0.4%; P < 0.02). These results indicate that abnormal PF–Purkinje cell synaptogenesis in GluR2–/– cerebella was partially restored by TgQ/R.
Immature Purkinje cells are innervated by multiple CFs that originate from the inferior olive of the medulla. By the end of the third postnatal week during development, approximately 90% of the redundant CFs are eliminated (Kashiwabuchi et al. 1995; Hashimoto et al. 2001). Because a single CF has a single threshold for excitation, increasing the stimulus intensity normally elicits CF-evoked EPSCs in an all-or-none manner. Single CF-EPSCs were elicited in only 40% of the Purkinje cells from postnatal day 22–46 GluR2–/– mice (Fig. 4), a result confirming the crucial role of GluR2 in the elimination process of CFs (Hashimoto et al. 2001). In contrast, over 80% of the Purkinje cells from GluR2–/–/TgQ/R as well as GluR2–/–/Tgwt mice showed a relationship of one CF to one Purkinje cell (Fig. 4), a percentage comparable to that of wild-type mice (Hashimoto et al. 2001). These results indicate that, like Tgwt, TgQ/R restored the normal process of CF synapse elimination in GluR2–/– mice.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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2 transgene, which contained arginine at the Q/R/N site, rescued functional and morphological abnormalities of the GluR2–/– cerebellum, such as enhanced PPF at PF–Purkinje cell synapses (Fig. 2), abrogated LTD at PF–Purkinje cell synapses (Fig. 3), and sustained innervation of Purkinje cells by multiple CFs (Fig. 4). Although the contribution of each phenotype is unclear, gross motor discoordination of GluR2–/– mice was also restored by TgQ/R (Fig. 1). These results indicate that the residue at the Q/R/N site, whether it is glutamine or arginine, is not essential for GluR2 to regulate these functions in the cerebellum.
The residue at the Q/R/N site plays crucial roles in determining the Ca2+ permeability of AMPA, kainate and NMDA receptors (Hollmann & Heinemann, 1994); Ca2+ permeability is highly reduced when arginine is present at the Q/R/N site of one of the subunits that constitute the channel complex (Burnashev et al. 1992a,b). Similarly, GluR2Lc channels showed moderate Ca2+ permeability, a characteristic that was lost when the glutamine residue at its putative Q/R/N site was replaced with arginine (Kohda et al. 2000; Wollmuth et al. 2000). Therefore, although the role of the Q/R/N site in wild-type GluR2 is unclear, TgQ/R protein is unlikely to function as a Ca2+-permeable channel in vivo.
Morphological abnormalities at PF–Purkinje cell synapses in GluR2–/– mice were also restored by TgQ/R, but this effect was incomplete compared with that induced by Tgwt (Supplemental Fig. 2). Although we cannot rule out the possibility that incomplete rescue by TgQ/R reflects a partial dependency of PF synaptic integrity on the Q/R/N site of GluR2 transgenes, it is more likely to be caused by the lower expression levels of TgQ/R proteins (Fig. 1E) than by Tgwt proteins. Indeed, hemizygous GluR2–/–/Tgwt mice, which expressed levels of transgene proteins that were almost the same as those of homozygous GluR2–/–/TgQ/R mice, also displayed a partial recovery of abnormal PF synapses (data not shown). Interestingly, the major abnormal phenotypes of the GluR2–/– mice, such as poor motor performance (as assessed using the rotor-rod test), sustained innervation of Purkinje cells by multiple CFs, and abrogated LTD, were completely restored in the rescue lines when the expression levels of the transgenes were higher than approximately 10% of that of endogenous GluR2 in wild-type mice (Yuzaki, 2005). Such a dosage effect of the transgenes may reflect distinct mechanisms by which GluR2 regulates each phenotype, or it may simply indicate the sensitivity of each assay. To address this issue more clearly, new rescue lines that express higher levels of TgQ/R are necessary. Nevertheless, it would be safe to say that the residue at the Q/R/N site is not crucial for GluR2 to perform most of its functions in the cerebellum.
Receptor complexes composed of homomeric iGluR subunits containing arginine at the Q/R/N site not only show a very low Ca2+ permeability but also have an extremely low single-channel conductance. For example, the single-channel conductance of arginine-containing homomeric iGluRs is approximately 300 fS for GluR2 (Swanson et al. 1997), 200 fS for GluR5, and 225 fS for GluR6 receptors (Swanson et al. 1996). In addition, the surface expression of AMPA receptors is reduced when arginine is present at the Q/R/N site (Greger et al. 2002). Indeed, GluR2Lc, in which arginine replaces glutamine at the Q/R/N site, exhibits smaller constitutive currents than the original GluR2Lc in heterologous cells (Kohda et al. 2000; Wollmuth et al. 2000). Thus, GluR2 may not even function as an ion channel in vivo. On the other hand, the roles of GluR2 in regulating the number of postsynaptic AMPA receptors (Hirai et al. 2003) and the synaptic integrity at PF–Purkinje cell synapses (Yuzaki, 2004) suggest that GluR2 may function by modulating an intracellular signalling pathway, possibly through its C-terminal intracellular domain, to which several adaptor proteins bind (Yuzaki, 2004). Therefore, GluR2 signalling is unique in that, although it belongs to the iGluR family, it is unlikely to be activated by glutamate (Hirai et al. 2005) and unlikely to function as an ion channel. Further studies are warranted to decipher the GluR2 signalling mechanism.
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Footnotes |
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