GABA interneurons are the cellular trigger for ketamine's rapid antidepressant actions
GABA interneurons are the cellular trigger for ketamine's rapid antidepressant actions
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DOI：
10.1172/jci130808
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发表时间：
2020-03-02
影响因子：
15.9
通讯作者：
Duman, Ronald S.
中科院分区：
文献类型：
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作者：
Gerhard, Danielle M.;Pothula, Santosh;Duman, Ronald S.
单次亚麻醉剂量的氯胺酮（一种 NMDA 受体 (NMDAR) 拮抗剂）可对抑郁症患者产生快速且持续的抗抑郁作用，解决了治疗情绪障碍的主要未满足需求。氯胺酮使细胞外谷氨酸和前额皮质突触形成迅速增加，但引发这种增加和氯胺酮行为作用的初始细胞触发因素尚未确定。为了解决这个问题，我们结合使用病毒 shRNA 和条件突变来对与氯胺酮作用有关的关键 NMDAR 亚基 GluN2B 进行细胞特异性敲低或删除。结果表明，氯胺酮的抗抑郁作用被 GABA (Gadl) 中间神经元以及表达生长抑素 (Sst) 或小清蛋白 (Pvalb) 的亚型的 GluN2B-NMDAR 敲低所阻断，但内侧前额叶皮层 (mPFC) 中的谷氨酸主要神经元却没有被阻断。对 GABA 亚型的进一步分析表明，Sst 中间神经元中 GluN2B 的细胞特异性敲低或缺失会阻断或阻断氯胺酮的抗抑郁作用，并揭示与 mPFC 主神经元上的兴奋性突触后电流相关的性别特异性差异。这些发现表明，GABA 中间神经元上的 GluN2B-NMDAR 是氯胺酮快速抗抑郁作用的初始细胞触发因素，并显示出对 GluN2B 调节的性别特异性适应性机制。
A single subanesthetic dose of ketamine, an NMDA receptor (NMDAR) antagonist, produces rapid and sustained antidepressant actions in depressed patients, addressing a major unmet need for the treatment of mood disorders. Ketamine produces a rapid increase in extracellular glutamate and synaptic formation in the prefrontal cortex, but the initial cellular trigger that initiates this increase and ketamine's behavioral actions has not been identified. To address this question, we used a combination of viral shRNA and conditional mutation to produce cell-specific knockdown or deletion of a key NMDAR subunit, GluN2B, implicated in the actions of ketamine. The results demonstrated that the antidepressant actions of ketamine were blocked by GluN2B-NMDAR knockdown on GABA (Gadl) interneurons, as well as subtypes expressing somatostatin (Sst) or parvalbumin (Pvalb), but not glutamate principle neurons in the medial prefrontal cortex (mPFC). Further analysis of GABA subtypes showed that cell-specific knockdown or deletion of GluN2B in Sst interneurons blocked or occluded the antidepressant actions of ketamine and revealed sex-specific differences that are associated with excitatory postsynaptic currents on mPFC principle neurons. These findings demonstrate that GluN2B-NMDARs on GABA interneurons are the initial cellular trigger for the rapid antidepressant actions of ketamine and show sex-specific adaptive mechanisms to GluN2B modulation.