Disinhibition of somatostatin-positive GABAergic interneurons results in an anxiolytic and antidepressant-like brain state.
Disinhibition of somatostatin-positive GABAergic interneurons results in an anxiolytic and antidepressant-like brain state.
复制标题
DOI：
10.1038/mp.2016.188
复制
发表时间：
2017-06
影响因子：
11
通讯作者：
Luscher B
中科院分区：
文献类型：
--
作者：
Fuchs T;Jefferson SJ;Hooper A;Yee PH;Maguire J;Luscher B
重度抑郁症（MDD）与γ-氨基丁酸（GABA）浓度降低相关，通过抗抑郁治疗使其正常化。此外，GABAA受体突变小鼠的抑郁样表型可以通过常规抗抑郁药物治疗以及亚麻醉剂量的氯胺酮逆转。因此，GABA能缺陷可能导致抑郁症，而抗抑郁药治疗可能会增强GABA能突触传递。在这里，我们测试的假设，持续增强GABA能传输单独是足以引起抗抑郁症样的行为，使用GABA能中间神经元的去抑制。我们关注生长抑素阳性（SST+）GABA能中间神经元，因为有证据表明它们的功能在MDD中受到损害。为了解除SST+中间神经元的抑制，我们选择性地灭活这些神经元中GABAA受体的γ2亚基基因（SSTCre：γ2f/f小鼠）。抑制性突触输入的丧失导致SST+中间神经元的兴奋性增加。反过来，SST+神经元的锥体细胞靶点显示自发抑制性突触后电流的频率增加。SSTCre：γ2f/f小鼠的行为在许多行为测试中模仿了抗焦虑和抗抑郁药物的作用，而不影响空间学习和记忆依赖性任务的表现。最后，SSTCre：γ2f/f小鼠的脑提取物显示真核延伸因子eEF 2的磷酸化降低，这让人想起氯胺酮的作用。重要的是，这些效应的发生没有改变哺乳动物雷帕霉素靶点途径的活性，也不涉及SST表达的改变。然而，它们与eEF 2激酶的Ca 2 +/钙调蛋白依赖性自身磷酸化减少有关，该激酶控制eEF 2作为其单一靶标的活性。因此，增强从SST+中间神经元到锥体细胞的GABA能抑制性突触输入以及突触兴奋：抑制比的相应慢性降低代表了抗抑郁药治疗的新策略，其再现了快速作用的抗抑郁药的行为和生化终点。
Major depressive disorder (MDD) is associated with reduced concentrations of γ-aminobutyric acid (GABA) that are normalized by antidepressant therapies. Moreover, depressive-like phenotypes of GABAA receptor mutant mice can be reversed by treatment with conventional antidepressants drugs, as well as by subanesthetic doses of ketamine. Thus GABAergic deficits may causally contribute to depressive disorders, while antidepressant therapies may enhance GABAergic synaptic transmission. Here we tested the hypothesis that sustained enhancement of GABAergic transmission alone is sufficient to elicit antidepressant-like behavior, using disinhibition of GABAergic interneurons. We focused on somatostatin-positive (SST+) GABAergic interneurons because of evidence that their function is compromised in MDD. To disinhibit SST+ interneurons, we inactivated the γ2 subunit gene of GABAA receptors selectively in these neurons (SSTCre:γ2f/f mice). Loss of inhibitory synaptic input resulted in increased excitability of SST+ interneurons. In turn, pyramidal cell targets of SST+ neurons showed an increased frequency of spontaneous inhibitory postsynaptic currents. The behavior of SSTCre:γ2f/f mice mimicked the effects of anxiolytic and antidepressant drugs in a number of behavioral tests, without affecting performance in a spatial learning- and memory-dependent task. Finally, brain extracts of SSTCre:γ2f/f mice showed decreased phosphorylation of the eukaryotic elongation factor eEF2, reminiscent of the effects of ketamine. Importantly, these effects occurred without altered activity of the mammalian target of rapamycin pathway nor did they involve altered expression of SST. However, they were associated with reduced Ca2+/calmodulin-dependent auto-phosphorylation of eEF2 kinase, which controls the activity of eEF2 as its single target. Thus enhancing GABAergic inhibitory synaptic inputs from SST+ interneurons to pyramidal cells and corresponding chronic reductions in the synaptic excitation:inhibition ratio represents a novel strategy for antidepressant therapies that reproduces behavioral and biochemical end points of rapidly acting antidepressants.