Postsynaptic GABAB receptor signalling enhances LTD in mouse cerebellar Purkinje cells
Postsynaptic GABAB receptor signalling enhances LTD in mouse cerebellar Purkinje cells
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DOI：
10.1113/jphysiol.2007.141010
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发表时间：
2007-12-01
影响因子：
5.5
通讯作者：
Kano, Masanobu
中科院分区：
文献类型：
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作者：
Kamikubo, Yuji;Tabata, Toshihide;Kano, Masanobu
小脑平行纤维浦肯野细胞突触兴奋性传递的长期抑制（LTD）是突触可塑性的一种形式，对小脑运动学习至关重要。在这些突触的突触后膜周围，B 型 γ-氨基丁酸受体 (GABA(B)R)（一种抑制性递质 GABA 的 G(i/o) 蛋白偶联受体）集中存在，并与 1 型代谢型谷氨酸受体 (mGluR1) 密切相关，后者的信号传导是诱导 LTD 的关键因素。我们发现，在培养的浦肯野细胞中，GABA(B)R 激活增强了谷氨酸诱发电流 (LTDglu) 的 LTD，从而增加了抑郁的程度。据报道，平行的纤维浦肯野细胞突触接收从邻近 GABA 能中间神经元的突触末端溢出的微摩尔水平的 GABA。这一水平的 GABA 能够增强 LTDglu。我们的药理学分析表明，G(i/o) 蛋白的 β γ 亚基而非 α 亚基介导 GABA(B)R 介导的 LTDglu 增强。 G(i/o) 蛋白激活足以增强 LTDglu。在这方面，LTDglu 增强明显不同于先前报道的 GABA(B)R 介导的 mGluR1 耦合慢兴奋性突触后电位的增强。仅在 LTDglu 诱导期应用巴氯芬就足以增强 LTDglu，表明 GABA(B)R 信号传导可能调节 LTDglu 诱导的机制。巴氯芬以 G(i/o) 蛋白依赖性方式增强细胞内储存的 mGluR1 偶联 Ca2+ 释放。因此，GABA(B)R 介导的 LTDglu 增强可能是由于 mGluR1 信号传导增强所致。此外，GABA(B)R 的药理学抑制降低了小脑切片中平行纤维浦肯野细胞突触处的 LTD 强度。这些发现证明了一种促进小脑运动学习的新机制。
Long-term depression (LTD) of excitatory transmission at cerebellar parallel fibre-Purkinje cell synapses is a form of synaptic plasticity crucial for cerebellar motor learning. Around the postsynaptic membrane of these synapses, B-type gamma-aminobutyric acid receptor (GABA(B)R), a G(i/o) protein-coupled receptor for the inhibitory transmitter GABA is concentrated and closely associated with type-1 metabotropic glutamate receptors (mGluR1) whose signalling is a key factor for inducing LTD. We found that in cultured Purkinje cells, GABA(B)R activation enhanced LTD of a glutamate-evoked current (LTDglu), increasing the magnitude of depression. It has been reported that parallel fibre-Purkinje cell synapses receive a micromolar level of GABA spilt over from the synaptic terminals of the neighbouring GABAergic interneurons. This level of GABA was able to enhance LTDglu. Our pharmacological analyses revealed that the beta gamma subunits but not the alpha subunit of G(i/o) protein mediated GABA(B)R-mediated LTDglu enhancement. G(i/o) protein activation was sufficient to enhance LTDglu. In this respect, LTDglu enhancement is clearly distinguished from the previously reported GABA(B)R-mediated augmentation of an mGluR1-coupled slow excitatory postsynaptic potential. Baclofen application for only the induction period of LTDglu was sufficient to enhance LTDglu, suggesting that GABA(B)R signalling may modulate mechanisms underlying LTDglu induction. Baclofen augmented mGluR1-coupled Ca2+ release from the intracellular stores in a G(i/o) protein-dependent manner. Therefore, GABA(B)R-mediated LTDglu enhancement is likely to result from augmentation of mGluR1 signalling. Furthermore, pharmacological inhibition of GABA(B)R reduced the magnitude of LTD at parallel fibre-Purkinje cell synapses in cerebellar slices. These findings demonstrate a novel mechanism that would facilitate cerebellar motor learning.