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Abstract：
Signaling at nerve cell synapses is a key determinant of proper brain function, and synaptic defects-or synaptopathies-are at the basis of many neurological and psychiatric disorders. Collybistin (CB), a brain-specific guanine nucleotide exchange factor, is essential for the formation of γ-aminobutyric acidergic (GABAergic) postsynapses in defined regions of the mammalian forebrain, including the hippocampus and basolateral amygdala. This process depends on a direct interaction of CB with the scaffolding protein gephyrin, which leads to the redistribution of gephyrin into submembranous clusters at nascent inhibitory synapses. Strikingly, synaptic clustering of gephyrin and GABAA type A receptors (GABAARs) in several brain regions, including the cerebral cortex and certain thalamic areas, is unperturbed in CB-deficient mice, indicating that the formation of a substantial subset of inhibitory postsynapses must be controlled by gephyrin-interacting proteins other than CB. Previous studies indicated that the α3 subunit of GABAARs (GABAAR-α3) binds directly and with high affinity to gephyrin. Here, we provide evidence (i) that a homooligomeric GABAAR-α3A343W mutant induces the formation of submembranous gephyrin clusters independently of CB in COS-7 cells, (ii) that gephyrin clustering is unaltered in the neuronal subpopulations endogenously expressing the GABAAR-α3 in CB-deficient brains, and (iii) that exogenous expression of GABAAR-α3 partially rescues impaired gephyrin clustering in CB-deficient hippocampal neurons. Our results identify an important role of GABAAR-α3 in promoting gephyrin-mediated and CB-independent formation of inhibitory postsynapses.
摘要：
神经细胞突触信号是正常脑功能的关键决定因素，和突触缺陷-或突触病理学-是许多神经和精神疾病的基础。Collybistin(CB),大脑特异性鸟嘌呤核苷酸交换因子，对于哺乳动物前脑特定区域的γ-氨基丁酸能（GABA能）突触后的形成至关重要，包括海马体和基底外侧杏仁核。这个过程取决于CB与支架蛋白gephyrin的直接相互作用，这导致gephyrin在新生的抑制性突触处重新分布到膜下簇中。引人注目的是，gephyrin和GABAAA型受体（GABAAR）在几个大脑区域的突触聚集，包括大脑皮层和某些丘脑区域，在CB缺乏的小鼠中不受干扰，这表明抑制性突触后的大量子集的形成必须由除CB之外的gephyrin相互作用蛋白控制。先前的研究表明，GABAAR的α3亚基（GABAAR-α3）直接结合并与gephyrin高亲和力。这里,我们提供了证据（i）在COS-7细胞中，同源寡聚GABAAR-α3A343W突变体诱导了独立于CB的亚膜gephyrin簇的形成，（ii）在CB缺陷的大脑中内源性表达GABAAR-α3的神经元亚群中，gephyrin聚类没有改变，和（iii）GABAAR-α3的外源表达部分挽救了CB缺陷的海马神经元中的gephyrin聚类受损。我们的结果确定了GABAAR-α3在促进gephyrin介导的和不依赖CB的抑制性突触后形成中的重要作用。
