GABA interneurons mediate the rapid antidepressant-like effects of scopolamine
GABA interneurons mediate the rapid antidepressant-like effects of scopolamine
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DOI：
10.1172/jci85033
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发表时间：
2016-07-01
影响因子：
15.9
通讯作者：
Duman, Ronald S.
中科院分区：
文献类型：
--
作者：
Wohleb, Eric S.;Wu, Min;Duman, Ronald S.
重度抑郁症（MDD）是一种反复发作的精神疾病，会造成严重的健康和社会经济负担。临床报告显示，东莨菪碱是一种非选择性的毒蕈碱乙酰胆碱受体拮抗剂，对MOD患者产生快速的抗抑郁作用。临床前模型表明，这种快速的抗抑郁作用可以通过阻断m1型毒蕈碱乙酰胆碱受体（M1-AChR）来重现；然而，对东莨菪碱活性依赖性突触和行为反应的细胞机制尚未确定。在这里，我们证明了东莨菪碱的抗抑郁样作用是由内侧前额叶皮层（mPFC）的GABA中间神经元介导的。mPFC中GABAergic （GAD67(+)）和glutamergic （CaMKII+）的中间神经元均表达M1-AChR。在小鼠实验中，病毒介导的在mPFC中特异性敲除gaba能神经元中的M1-AChR，而不是谷氨酸能神经元中的M1-AChR，减弱了东莨菪碱的抗抑郁样作用。免疫组织学和电生理学结果显示，mPFC中生长抑素（SST）中间神经元表达M1-AChR的水平高于小白蛋白中间神经元。此外，mPFC中SST中间神经元中M1-AChR的下调表明，东莨菪碱的快速抗抑郁样作用需要这些神经元中M1-AChR的表达。这些数据表明，mPFC中的SST中间神经元是开发速效抗抑郁药物的有希望的药理学靶点。
Major depressive disorder (MDD) is a recurring psychiatric illness that causes substantial health and socioeconomic burdens. Clinical reports have revealed that scopolamine, a nonselective muscarinic acetylcholine receptor antagonist, produces rapid antidepressant effects in individuals with MOD. Preclinical models suggest that these rapid antidepressant effects can be recapitulated with blockade of M1-type muscarinic acetylcholine receptors (M1-AChR); however, the cellular mechanisms underlying activity-dependent synaptic and behavioral responses to scopolamine have not been determined. Here, we demonstrate that the antidepressant-like effects of scopolamine are mediated by GABA interneurons in the medial prefrontal cortex (mPFC). Both GABAergic (GAD67(+)) interneurons and glutamatergic (CaMKII+) interneurons in the mPFC expressed M1-AChR. In mice, viral-mediated knockdown of M1-AChR specifically in GABAergic neurons, but not glutamatergic neurons, in the mPFC attenuated the antidepressant-like effects of scopolamine. Immunohistology and electrophysiology showed that somatostatin (SST) interneurons in the mPFC express M1-AChR at higher levels than parvalbumin interneurons. Moreover, knockdown of M1-AChR in SST interneurons in the mPFC demonstrated that M1-AChR expression in these neurons is required for the rapid antidepressant-like effects of scopolamine. These data indicate that SST interneurons in the mPFC are a promising pharmacological target for developing rapid-acting antidepressant therapies.