Glutamate transporter studies reveal the pruning of metabotropic glutamate receptors and absence of AMPA receptor desensitization at mature calyx of Held synapses.
Glutamate transporter studies reveal the pruning of metabotropic glutamate receptors and absence of AMPA receptor desensitization at mature calyx of Held synapses.
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DOI：
10.1523/jneurosci.1848-05.2005
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发表时间：
2005-09-14
期刊：
影响因子：
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通讯作者：
von Gersdorff H
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文献类型：
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作者：
Renden R;Taschenberger H;Puente N;Rusakov DA;Duvoisin R;Wang LY;Lehre KP;von Gersdorff H
我们检查了谷氨酸转运蛋白阻断对 Held 突触花萼的影响。在未成熟突触中[定义为出生后第 8 天 (P8) 至 P10 大鼠]，转运蛋白阻断会导致 NMDA 受体的强直激活，并强烈抑制 AMPA 受体介导的 EPSC 振幅。 EPSC 抑制被代谢型谷氨酸受体 (mGluR) 拮抗剂 [1 μm LY341495 (2S-2-amino-2-(1S,2S-2-carboxycycloprop-1-yl)-3-(xanth-9-yl)propanoic Acid)] 阻断，表明静息谷氨酸浓度升高会特异性激活 II 组和 III 组 mGluR。使用 mGluR 亚型特异性激动剂和拮抗剂，我们确定增加的谷氨酸会激活突触前 mGluR2/3 和 mGluR8 受体，但不会激活 mGluR4，尽管该受体存在。令人惊讶的是，在老年动物（P16-P18）中，转运蛋白阻断对 EPSC 振幅没有影响，因为大鼠和小鼠中 II/III 组 mGluR 激活的发育下调。与其他 CNS 突触相反，我们观察到转运蛋白阻断对 EPSC 衰减动力学没有影响，尽管谷氨酸转运蛋白在 P9 和 P17 附近的胶质细胞过程中表达很强。最后，使用低亲和力 AMPA 受体拮抗剂（γ-d-谷氨酰甘氨酸），我们发现脱敏发生在 P8-P10，但在 P16-P18 不存在，即使在高频（100-300 Hz）刺激过程中也是如此。我们认为扩散和转运蛋白激活不足以清除未成熟肾盏突触释放的谷氨酸，导致显着脱敏。因此，mGluRs 可能在未成熟的花萼中表达，以帮助限制谷氨酸的释放。在更成熟的花萼中，由于高度有孔的突触末端形态，存在小得多的扩散屏障，因此避免了 AMPA 受体脱敏，并且不需要 mGluR 介导的抑制。
We examined the effect of glutamate transporter blockade at the calyx of Held synapse. In immature synapses [defined as postnatal day 8 (P8) to P10 rats], transporter blockade causes tonic activation of NMDA receptors and strong inhibition of the AMPA receptor-mediated EPSC amplitude. EPSC inhibition was blocked with a metabotropic glutamate receptor (mGluR) antagonist [1 μm LY341495 (2S-2-amino-2-(1S,2S-2-carboxycycloprop-1-yl)-3-(xanth-9-yl)propanoic acid)], suggesting that elevated resting glutamate concentration specifically activates group II and group III mGluRs. Using mGluR subtype-specific agonists and antagonists, we determined that increased glutamate activates presynaptic mGluR2/3 and mGluR8 receptors but not mGluR4, although this receptor is present. Surprisingly, in older animals (P16–P18), transporter blockade had no effect on EPSC amplitude because of a developmental downregulation of group II/III mGluR activation in rats and mice. In contrast to other CNS synapses, we observed no effect of transporter blockade on EPSC decay kinetics, although expression of glutamate transporters was strong in nearby glial processes at both P9 and P17. Finally, using a low-affinity AMPA receptor antagonist (γ-d-glutamylglycine), we show that desensitization occurs at P8–P10 but is absent at P16–P18, even during trains of high-frequency (100–300 Hz) stimulation. We suggest that diffusion and transporter activation are insufficient to clear synaptically released glutamate at immature calyces, resulting in significant desensitization. Thus, mGluRs may be expressed in the immature calyx to help limit glutamate release. In the more mature calyx, there is a far smaller diffusional barrier attributable to the highly fenestrated synaptic terminal morphology, so AMPA receptor desensitization is avoided and mGluR-mediated inhibition is not necessary.