Background

Ketamine elicits rapid onset antidepressant effects in patients with clinical depression through mechanisms hypothesized to involve the genesis of neocortical dendritic spines and synapses. Yet, the observed changes in dendritic spine morphology usually emerge well after ketamine clearance, raising questions about the link between rapid behavioral effects of ketamine and plasticity.

Methods

Here, we used two-photon glutamate uncaging/imaging to focally induce spinogenesis in the medial prefrontal cortex, directly interrogating baseline and ketamine-associated plasticity of deep layer pyramidal neurons in C57BL/6 mice. We combined pharmacological, genetic, optogenetic, and chemogenetic manipulations to interrogate dopaminergic mechanisms underlying ketamine-induced rapid enhancement in evoked plasticity and associated behavioral changes.

Results

We found that ketamine rapidly enhances glutamate-evoked spinogenesis in the medial prefrontal cortex, with timing that matches the onset of its behavioral efficacy and precedes changes in dendritic spine density. Ketamine increases evoked cortical spinogenesis through dopamine Drd1 receptor (Drd1) activation that requires dopamine release, compensating blunted plasticity in a learned helplessness paradigm. The enhancement in evoked spinogenesis after Drd1 activation or ketamine treatment depends on postsynaptic protein kinase A activity. Furthermore, ketamine’s behavioral effects are blocked by chemogenetic inhibition of dopamine release and mimicked by activating presynaptic dopaminergic terminals or postsynaptic Gα_s-coupled cascades in the medial prefrontal cortex.

Conclusions

Our findings highlight dopaminergic mediation of rapid enhancement in activity-dependent dendritic spinogenesis and behavioral effects induced by ketamine.

中文翻译：

---

氯胺酮通过多巴胺能机制快速增强内侧前额叶皮质中谷氨酸诱发的树突棘发生

背景

氯胺酮通过假设涉及新皮质树突棘和突触发生的机制在临床抑郁症患者中引起快速起效的抗抑郁作用。然而，在氯胺酮清除后，观察到的树突棘形态的变化通常会很好地出现，这引发了关于氯胺酮的快速行为效应与可塑性之间的联系的问题。

方法

在这里，我们使用双光子谷氨酸去壳/成像来集中诱导内侧前额叶皮层的脊髓生成，直接询问 C57BL/6 小鼠深层锥体神经元的基线和氯胺酮相关可塑性。我们结合药理学、遗传学、光遗传学和化学遗传学操作来探究氯胺酮诱导的诱发可塑性和相关行为变化快速增强的多巴胺能机制。

结果

我们发现氯胺酮可迅速增强内侧前额叶皮层中谷氨酸诱发的脊柱生成，其时间与其行为功效的开始相匹配，并且在树突棘密度变化之前。氯胺酮通过需要多巴胺释放的多巴胺 Drd1 受体 (Drd1) 激活来增加诱发的皮质脊髓生成，从而在习得性无助范式中补偿迟钝的可塑性。Drd1 激活或氯胺酮治疗后诱发的脊柱发生的增强取决于突触后蛋白激酶 A 的活性。此外，氯胺酮的行为效应被多巴胺释放的化学遗传学抑制所阻断，并通过激活内侧前额叶皮层中的突触前多巴胺能末端或突触后 Gα _{s偶联级联来模拟。}

结论

我们的研究结果强调了氯胺酮诱导的活动依赖性树突棘发生和行为效应的快速增强的多巴胺能介导。