Mechanisms underlying the enhancement of γ-aminobutyric acid responses in the external globus pallidus of R6/2 Huntington's disease model mice.,Journal of Neuroscience Research

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Mechanisms underlying the enhancement of γ-aminobutyric acid responses in the external globus pallidus of R6/2 Huntington's disease model mice.
Journal of Neuroscience Research ( IF 2.9 ) Pub Date : 2020-08-27 , DOI: 10.1002/jnr.24710
Joshua Barry ₁ , Theodore A Sarafian ₁ , Joseph B Watson ₁ , Carlos Cepeda ₁ , Michael S Levine ₁

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In Huntington's disease (HD), the output of striatal indirect pathway medium‐sized spiny neurons (MSNs) is altered in its target region, the external globus pallidus (GPe). In a previous study we demonstrated that selective optogenetic stimulation of indirect pathway MSNs induced prolonged decay time of γ‐aminobutyric acid (GABA) responses in GPe neurons. Here we identified the mechanism underlying this alteration. Electrophysiological recordings in slices from symptomatic R6/2 and wildtype (WT) mice were used to evaluate, primarily, the effects of GABA transporter (GAT) antagonists on responses evoked by optogenetic activation of indirect pathway MSNs. In addition, immunohistochemistry (IHC) and Western blots (WBs) were used to examine GAT‐3 expression in HD and WT mice. A GAT‐3 blocker (SNAP5114) increased decay time of GABA responses in WT and HD GPe neurons, but the effect was significantly greater in WT neurons. In contrast, a GAT‐1 antagonist (NO‐711) or a GABA_B receptor antagonist (CGP 54626) produced small increases in decay time but no differential effects between genotypes. IHC and WBs showed reduction of GAT‐3 expression in the GPe of HD mice. Thus, reduced expression or dysfunction of GAT‐3 could underlie alterations of GPe responses to GABA inputs from striatum and could be a target for therapeutic intervention.

中文翻译：

R6/2亨廷顿病模型小鼠外苍白球中γ-氨基丁酸反应增强的机制。

在亨廷顿舞蹈病 (HD) 中，纹状体间接通路中型多棘神经元 (MSN) 的输出在其靶区苍白球 (GPe) 发生改变。在之前的一项研究中，我们证明了间接途径 MSN 的选择性光遗传学刺激诱导 GPe 神经元中 γ-氨基丁酸 (GABA) 反应的衰减时间延长。在这里，我们确定了这种改变背后的机制。来自有症状的 R6/2 和野生型 (WT) 小鼠的切片中的电生理记录主要用于评估 GABA 转运蛋白 (GAT) 拮抗剂对间接途径 MSN 的光遗传学激活引起的反应的影响。此外，免疫组织化学 (IHC) 和蛋白质印迹 (WBs) 用于检查 HD 和 WT 小鼠中 GAT-3 的表达。GAT-3 阻滞剂 (SNAP5114) 增加了 WT 和 HD GPe 神经元中 GABA 反应的衰减时间，但在 WT 神经元中效果明显更大。相比之下，GAT-1 拮抗剂 (NO-711) 或 GABA_B受体拮抗剂 (CGP 54626) 使衰减时间略有增加，但基因型之间没有差异效应。IHC 和 WBs 显示 HD 小鼠 GPe 中 GAT-3 表达降低。因此，GAT-3 表达减少或功能障碍可能是 GPe 对纹状体 GABA 输入的反应改变的基础，并且可能成为治疗干预的目标。

更新日期：2020-10-04

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