The GABAB1a Isoform Mediates Heterosynaptic Depression at Hippocampal Mossy Fiber Synapses
The GABAB1a Isoform Mediates Heterosynaptic Depression at Hippocampal Mossy Fiber Synapses
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DOI：
10.1523/jneurosci.3697-08.2009
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发表时间：
2009-02-04
影响因子：
5.3
通讯作者：
Bettler, Bernhard
中科院分区：
文献类型：
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作者：
Guetg, Nicole;Seddik, Riad;Bettler, Bernhard
GABA(B) 受体亚型基于亚基亚型 GABA(B1a) 和 GABA(B1b)，它们与 GABA(B2) 亚基结合形成药理学上难以区分的 GABAB(1a,2) 和 GABA(B(1b,2)) 受体。对选择性表达 GABA(B1a) 或 GABA(B1b) 亚基的小鼠进行的研究表明，谷氨酸能末端的 GABA(B(1a, 2)) 受体比 GABA(B(1b, 2)) 受体更丰富。因此，发现当通过外源应用激动剂巴氯芬最大程度地激活时，GABA(B(1a，2))受体比GABA(B(1b，2))受体更有效地抑制谷氨酸释放。在这里，我们结合遗传、超微结构和电生理学方法来分析 GABA(B(1a, 2)) 和 GABA(B(1b, 2)) 受体在多大程度上抑制生理激活反应中的谷氨酸释放。我们首先表明，在海马苔藓纤维 (MF)-CA3 锥体神经元突触中，突触前位点存在的 GABAB1a 蛋白多于 GABAB1b 蛋白，这与其他谷氨酸能突触的发现一致。当巴氯芬浓度 >= 1 μM 时，GABA(B(1a, 2)) 和 GABA(B(1b, 2)) 受体均有助于谷氨酸释放的突触前抑制。然而，在较低浓度的巴氯芬下，选择性 GABA(B(1a, 2)) 受体有助于突触前抑制。值得注意的是，只有 GABA(B(1a, 2)) 受体响应突触释放的 GABA 而抑制谷氨酸释放。具体来说，我们证明选择性 GABA(B(1a, 2)) 受体介导 MF 传输的异突触抑制，这是一种涉及通过突触前 GABA(B) 受体对谷氨酸释放的跨突触抑制的生理现象。我们的数据表明，MF 末端 GABA(B1a) 和 GABA(B1b) 蛋白水平的差异足以在生理条件下产生严格的 GABA(B1a) 特异性效应。这证实了 GABA(B1a) 和 GABA(B1b) 蛋白的差异亚细胞定位具有监管相关性。
GABA(B) receptor subtypes are based on the subunit isoforms GABA(B1a) and GABA(B1b), which associate with GABA(B2) subunits to form pharmacologically indistinguishable GABAB(1a,2) and GABA(B(1b,2)) receptors. Studies with mice selectively expressing GABA(B1a) or GABA(B1b) subunits revealed that GABA(B(1a, 2)) receptors are more abundant than GABA(B(1b, 2)) receptors at glutamatergic terminals. Accordingly, it was found that GABA(B(1a, 2)) receptors are more efficient than GABA(B(1b, 2)) receptors in inhibiting glutamate release when maximally activated by exogenous application of the agonist baclofen. Here, we used a combination of genetic, ultrastructural and electrophysiological approaches to analyze to what extent GABA(B(1a, 2)) and GABA(B(1b, 2)) receptors inhibit glutamate release in response to physiological activation. We first show that at hippocampal mossy fiber (MF)-CA3 pyramidal neuron synapses more GABAB1a than GABAB1b protein is present at presynaptic sites, consistent with the findings at other glutamatergic synapses. In the presence of baclofen at concentrations >= 1 mu M, both GABA(B(1a, 2)) and GABA(B(1b, 2)) receptors contribute to presynaptic inhibition of glutamate release. However, at lower concentrations of baclofen, selectively GABA(B(1a, 2)) receptors contribute to presynaptic inhibition. Remarkably, exclusively GABA(B(1a, 2)) receptors inhibit glutamate release in response to synaptically released GABA. Specifically, we demonstrate that selectively GABA(B(1a, 2)) receptors mediate heterosynaptic depression of MF transmission, a physiological phenomenon involving transsynaptic inhibition of glutamate release via presynaptic GABA(B) receptors. Our data demonstrate that the difference in GABA(B1a) and GABA(B1b) protein levels at MF terminals is sufficient to produce a strictly GABA(B1a)-specific effect under physiological conditions. This consolidates that the differential subcellular localization of the GABA(B1a) and GABA(B1b) proteins is of regulatory relevance.