A synaptic substrate for ketamine-mediated amelioration of stress-induced anhedonia

总结 抑郁症是世界范围内发病率和死亡率的主要原因，预计将成为第二大原因。 到2030年成为残疾的主要原因。尽管这些结果表明，迫切需要解决抑郁症作为一个 公共卫生优先考虑减少疾病负担和残疾，目前的抑郁症药物治疗需要 长期给药（如果不是数月，也是数周）以改善临床，并且它们通常与高 无答复率。相反，最近的临床证据表明，单次亚麻醉剂量的氯胺酮 在70%的耐药患者中诱导了强大而快速的（几小时内）抗抑郁作用。 值得注意的是，氯胺酮是第一种速效抗抑郁药，对主要精神分裂症的难治性症状有效。 抑郁症，如快感缺乏症。快感缺乏，定义为减少的乐趣，或兴趣， 以前有益的活动通常是由暴露于慢性压力而促成的，它非常适合于 在实验室动物中进行研究。 尽管氯胺酮的主要分子靶点仍在争论中，但文献中存在广泛共识， AMPAR的激活以及由从头蛋白质合成依赖性 氯胺酮改善应激诱导的快感缺失的能力需要一种机制。不过，少校 技术障碍阻碍了这种机制的回路和突触水平的解剖。因此，我们认为， 了解详细的电路和突触机制，并建立氯胺酮之间的因果关系- 诱发的AMPAR介导的突触可塑性和特定的行为结果对于设计新的和 更安全的治疗目标。在这里，我们将通过使用电生理学，光遗传学和最近的 开发的技术提供了前所未有的机会，以阻止AMPAR以及从头蛋白质 在特定的基因细胞内合成。因此，将检验以下假设：（一）增加 AMPAR介导的D1-MSNs上的突触传递介导氯胺酮的抗快感缺失作用，（ii） mPFC->NAc输入对于氯胺酮介导的应激诱导的快感缺失的改善是必要的，以及（iii） 氯胺酮诱导的D1-MSNs从头蛋白质合成依赖性可塑性驱动氯胺酮介导的 改善应激诱导的快感缺失。总之，这些研究的结果将增加我们对 氯胺酮的作用机制，并可能导致新的潜在目标，以治疗压力引起的 快感缺乏

SUMMARY Depression is a leading cause of morbidity and mortality worldwide and it is projected to become the second leading cause of disability by 2030. Despite these results indicate the urgent need to address depression as a public-health priority to reduce disease burden and disability, current pharmacotherapies for depression require prolonged administration (weeks if not months) for clinical improvement and they are often associated with high non-response rate. In contrast, recent clinical evidence has shown that a single sub-anesthetic dose of ketamine induces a robust and rapid (within matter of hours) antidepressant effect in 70% of treatment-resistant patients. Notably, ketamine is the first rapid-acting antidepressant with efficacy for treatment-resistant symptoms of major depression disorder such as anhedonia. Anhedonia, defined as diminished pleasure from, or interest in, previously rewarding activities is commonly precipitated by exposure to chronic stress and it is well suited to study in laboratory animals. Whereas ketamine’s primary molecular target is under debate, there is broad consensus in the literature that activation of the AMPAR as well as induction of synaptogenesis driven by de novo protein synthesis-dependent mechanisms are required for ketamine’s ability to ameliorate stress-induced anhedonia. Nevertheless, major technical barriers have hindered a circuit and synaptic-level dissection of such mechanisms. Therefore, understanding the detailed circuit and synaptic mechanisms and establishing a causal link between ketamine- evoked AMPAR-mediated synaptic plasticity and specific behavioral outcomes is crucial for designing novel and safer therapeutic targets. Here, we will tackle this question by using electrophysiology, optogenetics and recently developed technologies that offer the unprecedented opportunity to block AMPAR as well as de novo protein synthesis within genetically specified cells. Accordingly, the following hypotheses will be tested: (i) increased AMPAR-mediated synaptic transmission on D1-MSNs mediates the anti-anhedonic effects of ketamine, (ii) mPFC->NAc input is necessary for ketamine-mediated amelioration of stress-induced anhedonia, and (iii) ketamine-induced de novo protein synthesis-dependent plasticity in D1-MSNs drives ketamine-mediated amelioration of stress-induced anhedonia. Altogether, results from these studies will increase our understanding of the mechanisms of action of ketamine and might lead to new potential targets to treat stress-induced anhedonia.