Department of Psychiatry, Yale University School of Medicine, 34 Park Street, New Haven, CT, 06519, USA.
Mol Psychiatry. 2021 Jul;26(7):3277-3291. doi: 10.1038/s41380-020-00916-y. Epub 2020 Oct 17.
Major depressive disorder (MDD) is associated with alterations of GABAergic interneurons, notably somatostatin (Sst) as well as parvalbumin (Pvalb), in cortical brain areas. In addition, the antidepressant effects of rapid-acting drugs are thought to occur via inhibition of GABA interneurons. However, the impact of these interneuron subtypes in affective behaviors as well as in the effects of rapid-acting antidepressants remains to be determined. Here, we used a Cre-dependent DREADD-chemogenetic approach to determine if inhibition of GABA interneurons in the mPFC of male mice is sufficient to produce antidepressant actions, and conversely if activation of these interneurons blocks the rapid and sustained antidepressant effects of scopolamine, a nonselective acetylcholine muscarinic receptor antagonist. Chemogenetic inhibition of all GABA interneurons (Gad1+), as well as Sst+ and Pvalb+ subtypes in the mPFC produced dose and time-dependent antidepressant effects in the forced swim and novelty suppressed feeding tests, and increased synaptic plasticity. In contrast, stimulation of Gad1, Sst, or Pvalb interneurons in mPFC abolished the effects of scopolamine and prevented scopolamine induction of synaptic plasticity. The results demonstrate that transient inhibition of GABA interneurons promotes synaptic plasticity that underlies rapid antidepressant responses.
重度抑郁症（MDD）与皮质脑区中 GABA 能中间神经元的改变有关，特别是生长抑素（Sst）和 P 型钙通道蛋白（Pvalb）。此外，快速作用药物的抗抑郁作用被认为是通过抑制 GABA 中间神经元发生的。然而，这些中间神经元亚型在情感行为中的影响以及快速作用抗抑郁药的作用仍有待确定。在这里，我们使用 Cre 依赖性 DREADD 化学遗传学方法来确定抑制雄性小鼠 mPFC 中的 GABA 能中间神经元是否足以产生抗抑郁作用，反之亦然，即这些中间神经元的激活是否会阻止东莨菪碱（一种非选择性乙酰胆碱毒蕈碱受体拮抗剂）的快速和持续的抗抑郁作用。mPFC 中所有 GABA 能中间神经元（Gad1+）、Sst+和 Pvalb+亚型的化学遗传抑制在强迫游泳和新异物体抑制摄食试验中产生了剂量和时间依赖性的抗抑郁作用，并增加了突触可塑性。相反，mPFC 中 Gad1、Sst 或 Pvalb 中间神经元的刺激消除了东莨菪碱的作用，并防止了东莨菪碱诱导的突触可塑性。结果表明，GABA 能中间神经元的短暂抑制促进了快速抗抑郁反应所依赖的突触可塑性。
