Oligodendrocytes (OLs) express functional GABA_A receptors (GABA_ARs) that are activated by GABA released at synaptic contacts with axons or by ambient GABA in extrasynaptic domains. In both instances, the receptors’ molecular identity has not been fully defined. Furthermore, data on their structural diversity in different brain regions and information on age-dependent changes in their molecular composition are scant. This lack of knowledge has delayed access to a better understanding of the role of GABAergic signaling between neurons and OLs. Here, we used functional, and pharmacological analyses, as well as gene and protein expression of GABA_AR subunits, to explore the subunit combination that could explain the receptor functional profile expressed in OLs from the neonate rat. We found that GABA_AR composed of α3β2γ1 subunits mimicked the characteristics of the endogenous receptor when expressed heterologously in Xenopus laevis oocytes. Either α3 or γ1 subunit silencing by small interfering RNA transfection changed the GABA-response characteristics in oligodendrocyte precursor cells, indicating their participation in the endogenous receptor conformation. Thus, α3 subunit silencing shifted the mean EC₅₀ for GABA from 75.1 to 46.6 µM, whereas γ1 silencing reduced the current amplitude response by 55%. We also observed that β-carbolines differentially enhance GABA responses in oligodendroglia as compared with those in neurons. These results contribute to defining the molecular and pharmacological properties of GABA_ARs in OLs. Additionally, the identification of β-carbolines as selective enhancers of GABA_ARs in OLs may help to study the role of GABAergic signaling during myelination.

中文翻译：

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新生大鼠培养的少突胶质细胞中表达的GABAA受体含有α3和γ1亚基并具有不同的功能和药理特性

少突胶质细胞 (OLs) 表达功能性 GABA _A受体 (GABA _A Rs)，这些受体由在与轴突的突触接触处释放的 GABA 或由突触外结构域中的环境 GABA 激活。在这两种情况下，受体的分子身份尚未完全确定。此外，关于它们在不同大脑区域的结构多样性的数据和关于它们的分子组成随年龄变化的变化的信息很少。这种知识的缺乏延迟了更好地理解 GABAergic 信号在神经元和 OL 之间的作用。在这里，我们使用了功能和药理学分析，以及 GABA _{A的基因和蛋白质表达}R 亚基，探索可以解释新生大鼠 OL 中表达的受体功能谱的亚基组合。我们发现由α 3 β 2 γ 1 亚基组成的 GABA _A R在非洲爪蟾卵母细胞中异源表达时模拟了内源性受体的特征。通过小干扰 RNA 转染进行的α 3 或γ 1 亚基沉默改变了少突胶质细胞前体细胞中的 GABA 反应特征，表明它们参与了内源性受体构象。因此，α 3 亚基沉默将 GABA 的平均 EC ₅₀从 75.1 变为 46.6 µM，而γ 1 沉默将电流幅度响应降低了 55%。我们还观察到，与神经元相比， β-咔啉对少突胶质细胞中的 GABA 反应有不同的增强作用。这些结果有助于定义 OLs 中 GABA _A Rs 的分子和药理学特性。此外，鉴定β-咔啉作为 OLs 中 GABA _A Rs 的选择性增强剂可能有助于研究 GABAergic 信号在髓鞘形成过程中的作用。