mGluR1‐mediated facilitation of long‐term potentiation at inhibitory synapses on a cerebellar Purkinje neuron
mGluR1‐mediated facilitation of long‐term potentiation at inhibitory synapses on a cerebellar Purkinje neuron
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DOI：
10.1111/j.1460-9568.2008.06063.x
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发表时间：
2008-02
影响因子：
3.4
通讯作者：
Y. Sugiyama;Shin-ya Kawaguchi;T. Hirano
中科院分区：
文献类型：
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作者：
Y. Sugiyama;Shin-ya Kawaguchi;T. Hirano
兴奋性突触的突触可塑性已得到广泛研究，而 GABA 能抑制性突触的可塑性研究却很有限。在大鼠小脑皮质中，浦肯野神经元 (PN) 的突触后去极化会诱导 GABAA 受体 (GABAAR) 反应性的长期增强（称为反弹增强；RP）。 RP 的诱导需要增加细胞内 Ca2+ 浓度，从而激活 Ca2+/钙调蛋白依赖性蛋白激酶 II (CaMKII)。我们之前报道过，GABAB 受体 (GABABR) 激活与去极化相结合，通过下调 cAMP 依赖性蛋白激酶 A (PKA) 活性，促进蛋白磷酸酶 1 (PP-1) 介导的 CaMKII 抑制，从而抑制 RP 诱导。在这里，我们研究了 1 型代谢型谷氨酸受体 (mGluR1) 在 RP 调节中的作用。通过对 GABA 的电流反应或从原代培养物或小脑切片中的 PN 记录的微型抑制性突触后电流的幅度来监测 RP。拮抗剂 7(羟基亚氨基)环丙[b]色烯-1a-羧酸乙酯 (CPCCOEt) 对 mGluR1 的抑制可阻止 RP 诱导，而 RP 诱导可通过激活腺苷酸环化酶或抑制 PP-1 来消除。此外，mGluR1 抑制会损害去极化诱导的 CaMKII 激活。相比之下，激动剂 (R,S)3,5-二羟基苯基甘氨酸 (DHPG) 激活 mGluR1 可以使 RP 诱导免受 GABABR 激活的抑制。 PKA 的抑制或 PP-1 活性的促进都会损害救援。此外，mGluR1 激活抵消了 GABABR 介导的 CaMKII 抑制。综上所述，这些结果表明 mGluR1 活性抵消了 GABABR 活性，并通过 PKA 激活、PP-1 下调和 CaMKII 上调促进 RP 诱导。
Synaptic plasticity has been studied extensively at excitatory synapses, whereas studies on plasticity at GABAergic inhibitory synapses have been limited. In the rat cerebellar cortex, postsynaptic depolarization of a Purkinje neuron (PN) induces long‐term potentiation of GABAA receptor (GABAAR) responsiveness (termed rebound potentiation; RP). Induction of RP requires an increase in intracellular Ca2+ concentration and resultant activation of Ca2+/calmodulin‐dependent protein kinase II (CaMKII). We previously reported that GABAB receptor (GABABR) activation coupled with depolarization suppresses RP induction by facilitating protein phosphatase 1 (PP‐1)‐mediated inhibition of CaMKII through down‐regulation of cAMP‐dependent protein kinase A (PKA) activity. Here, we examined the involvement of metabotropic glutamate receptor type 1 (mGluR1) in RP regulation. RP was monitored with the amplitudes of either the current responses to GABA or miniature inhibitory postsynaptic currents recorded from a PN in a primary culture or in a cerebellar slice. Inhibition of mGluR1 by an antagonist, 7(hydroxyimino)cyclopropa[b]chromen‐1a‐carboxylate‐ethyl‐ester (CPCCOEt), prevented RP induction, which was abolished either by activation of adenylyl cyclase or by inhibition of PP‐1. Furthermore, mGluR1 inhibition impaired depolarization‐induced CaMKII activation. By contrast, activation of mGluR1 by the agonist (R,S)3,5‐dihydroxyphenylglycine (DHPG) rescued RP induction from its suppression by GABABR activation. The rescue was impaired either by inhibition of PKA or by facilitation of PP‐1 activity. In addition, mGluR1 activation counteracted the GABABR‐mediated CaMKII inhibition. Taken together, these results suggest that mGluR1 activity counteracts GABABR activity and contributes to RP induction through PKA activation, down‐regulation of PP‐1 and up‐regulation of CaMKII.