Selective localization of collybistin at a subset of inhibitory synapses in brain circuits
Selective localization of collybistin at a subset of inhibitory synapses in brain circuits
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DOI：
10.1002/cne.22702
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发表时间：
2012-01-01
影响因子：
2.5
通讯作者：
Sassoe-Pognetto, Marco
中科院分区：
文献类型：
--
作者：
Patrizi, Annarita;Viltono, Laura;Sassoe-Pognetto, Marco
Collybistin 是一种大脑特异性鸟嘌呤核苷酸交换因子 (GEF)，对于 gephyrin 和 γ-氨基丁酸 A 受体 (GABAAR) 在抑制性突触特定子集的突触后积累至关重要。由于缺乏有关这种蛋白质在脑回路中突触定位的信息，我们对考利比斯汀的体内功能的理解受到了阻碍。在这里，我们通过使用针对不同分子域产生的抗体来描述内源性 Collybistin 的亚细胞定位，这些分子域应该识别大多数内源性 Collybistin 亚型。我们发现，collybistin 与 gephyrin 和 GABAAR 在突触点中形成共簇，并在突触发育早期被招募到突触后特化。值得注意的是，collybistin 仅存在于 gephyrin 阳性突触的子集中，在不同的大脑区域具有可变的共定位值。此外，collybistin 与含有 a1、a2 或 a3 亚基的 GABAAR 共定位，反对与特定 GABAAR 亚型的选择性关联。令人惊讶的是，我们发现 collybistin 仅在浦肯野细胞中短暂表达，这表明在这些小脑神经元中，collybistin 在突触后特化的初始组装过程中发挥着选择性作用。这些数据揭示了 GABA 能突触组织的显着异质性，并为解释人类 X 连锁智力障碍和小鼠基因敲除模型中 Collybistin 基因破坏所引起的可变效应提供了解剖学基础。 J.Comp。 Neurol.，2012 年。(c) 2011 年 Wiley 期刊公司。
Collybistin is a brain-specific guanine nucleotide exchange factor (GEF) that is crucial for the postsynaptic accumulation of gephyrin and ?-aminobutyric acid A receptors (GABAARs) at a specific subset of inhibitory synapses. Our understanding of the in vivo function of collybistin has been hampered by lack of information about the synaptic localization of this protein in brain circuits. Here we describe the subcellular localization of endogenous collybistin by using antibodies raised against distinct molecular domains that should recognize the majority of endogenous collybistin isoforms. We show that collybistin co-clusters with gephyrin and GABAARs in synaptic puncta and is recruited to postsynaptic specializations early during synapse development. Notably, collybistin is present in only a subset of gephyrin-positive synapses, with variable co-localization values in different brain regions. Moreover, collybistin co-localizes with GABAARs containing the a1, a2, or a3 subunits, arguing against a selective association with specific GABAAR subtypes. Surprisingly, we found that collybistin is expressed only transiently in Purkinje cells, suggesting that in these cerebellar neurons collybistin plays a selective role during the initial assembly of postsynaptic specializations. These data reveal a remarkable heterogeneity in the organization of GABAergic synapses and provide an anatomical basis for interpreting the variable effects caused by disruption of the collybistin gene in human X-linked intellectual disability and mouse knockout models. J. Comp. Neurol., 2012. (c) 2011 Wiley Periodicals, Inc.