Rescue of GABAB and GIRK function in the lateral habenula by protein phosphatase 2A inhibition ameliorates depression-like phenotypes in mice
Rescue of GABAB and GIRK function in the lateral habenula by protein phosphatase 2A inhibition ameliorates depression-like phenotypes in mice
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DOI：
10.1038/nm.4037
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发表时间：
2016-03-01
期刊：
影响因子：
82.9
通讯作者：
Mameli, Manuel
中科院分区：
文献类型：
--
作者：
Lecca, Salvatore;Pelosi, Assunta;Mameli, Manuel
外侧缰核(LHb)编码厌恶信号，其异常活动与抑郁症状有关。然而，对LHb过度活动的细胞机制的有限了解阻碍了药物策略的发展以改善抑郁样表型。在这里，我们报告了在小鼠身上的厌恶经历，如足部电击暴露(FSE)，诱导LHb神经元过度活动和抑郁样症状。这伴随着蛋白磷酸酶2A(PP2A)活性的增加，已知的GABA(B)受体(GABA(B)R)和G蛋白门控内向整流钾(GIRK)通道表面表达的调节。相应地，FSE触发GABA(B1)和GIRK2内化，导致GABA(B)激活的GIRK介导的(GABA(B)-GIRK)电流迅速而持久地减弱。药物抑制PP2A可恢复GABA(B)-GIRK功能和神经元兴奋性。因此，抑制PP2A可以改善FSE后的抑郁样症状以及在抑郁症的习得性无助模型中的症状。因此，LHb中的GABA(B)-GIRK-GIRK可塑性代表了厌恶体验的细胞底物。此外，通过抑制PP2A逆转它可能为缓解以LHb多动为特征的疾病中的抑郁症状提供一种新的治疗方法。
The lateral habenula (LHb) encodes aversive signals, and its aberrant activity contributes to depression-like symptoms. However, a limited understanding of the cellular mechanisms underlying LHb hyperactivity has precluded the development of pharmacological strategies to ameliorate depression-like phenotypes. Here we report that an aversive experience in mice, such as foot-shock exposure (FsE), induces LHb neuronal hyperactivity and depression-like symptoms. This occurs along with increased protein phosphatase 2A (PP2A) activity, a known regulator of GABA(B) receptor (GABA(B)R) and G protein gated inwardly rectifying potassium (GIRK) channel surface expression. Accordingly, FsE triggers GABA(B1) and GIRK2 internalization, leading to rapid and persistent weakening of GABA(B)-activated GIRK-mediated (GABA(B)-GIRK) currents. Pharmacological inhibition of PP2A restores both GABA(B)-GIRK function and neuronal excitability. As a consequence, PP2A inhibition ameliorates depression-like symptoms after FsE and in a learned-helplessness model of depression. Thus, GABA(B)-GIRK-GIRK plasticity in the LHb represents a cellular substrate for aversive experience. Furthermore, its reversal by PP2A inhibition may provide a novel therapeutic approach to alleviate symptoms of depression in disorders that are characterized by LHb hyperactivity.