Epitranscriptomic mechanisms of the antidepressant response to ketamine in human neurons

人类神经元抗抑郁反应的表观转录组机制

• 批准号: 10607430
• 负责人: BENJAMIN SICILIANO
• 金额: $ 4.77万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-22 至 2026-04-21
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10607430
• 关键词: Acute; Adjuvant Therapy; American; Anesthetics; Animal Model; Antidepressive Agents; Apoptotic; Autopsy; Behavioral; Biological; Brain; Brain-Derived Neurotrophic Factor; Bypass; Cell Line; Cells; Chronic; Clinical; DNA Modification Process; Data Set; Development; Diagnosis; Electrophysiology (science); Epigenetic Process; Genes; Genetic; Genetic Transcription; Glutamates; Glycogen Synthase Kinase 3; Hippocampus; Hour; Human; Image; Immunoprecipitation; Induced pluripotent stem cell derived neurons; Investigation; Ketamine; Major Depressive Disorder; Mediating; Mental Depression; Metalloproteases; Methylation; Microelectrodes; Modification; Molecular; Mus; N-Methyl-D-Aspartate Receptors; Nerve Growth Factors; Neurons; Obesity; Pathogenesis; Patients; Pharmacotherapy; Phosphorylation; Positioning Attribute; Prediction of Response to Therapy; Process; Proteins; Proteomics; RNA; RNA methylation; Reader; Regulation; Reporting; Risk; Signal Transduction; Single Nucleotide Polymorphism; Site; Stress; Structure; Testing; Therapeutic; Therapeutic Effect; Tissues; Transcription Process; Transcriptional Regulation; Translation Process Protein; Translations; Treatment Efficacy; Up-Regulation; antagonist; antidepressant effect; brain-derived neurotrophic factor precursor; demethylation; depressed patient; design; dosage; epitranscriptome; epitranscriptomics; fat mass and obesity-associated protein; functional outcomes; genome wide association study; induced pluripotent stem cell; insight; monoamine; multiple omics; neuronal growth; neurotrophic factor; novel; novel therapeutics; patch clamp; pharmacologic; postsynaptic; presynaptic; prevent; protein expression; reduce symptoms; response; restoration; side effect; synaptogenesis; transcriptome sequencing; transcriptomics; treatment-resistant depression

PROJECT SUMMARY Despite acutely enhancing monoamine function, chronic administration of monoamine antidepressants is required for clinical response, suggesting that adaptations downstream of enhanced monoaminergic signaling are central to their therapeutic efficacy. One such downstream adaption is the epigenetic upregulation of brain- derived neurotrophic factor (BDNF), a key protein in the neurotrophic process. This is in line with the neurotrophic hypothesis of depression, which posits that insufficient neuronal growth contributes to the pathogenesis of MDD, as evidenced by reduced hippocampal volume in the postmortem brains of depressed patients, and thus the restoration of neurotrophy is central to the efficacy of antidepressants. In addition to requiring chronic treatment, traditional antidepressants drugs are also ineffective in a significant proportion of depressed patients and produce a wide variety of undesirable side effects. On the other hand, ketamine, a N-methyl-D-aspartate receptor (NMDAR) antagonist and anesthetic, a single dosage of which has been shown to relieve symptoms in less than an hour and for at least one week in patients who failed to response to at least two typical antidepressants. Unlike traditional antidepressants, ketamine appears to promote BDNF-mediated neurotrophy rapidly and directly but optimizing this anesthetic for antidepressant application and designing novel drugs its image requires further elucidation of its targets and the mechanisms underlying its therapeutic effects. We hypothesize that rather than rather than indirectly altering neurotrophic genes, as with chronic administration of typical antidepressants, ketamine bypasses this prolonged process of transcriptional regulation and instead induces RNA modifications that rapidly upregulates the translation of neurotrophic proteins. stress-induced changes in levels of N6,2’-O-dimethyladenosine (m6A), the most abundant RNA modification, have been observed in MDD patients and single-nucleotide polymorphisms in the m6A demethylase, fat mass and obesity associated protein (FTO), are associated with increased risk of MDD. Furthermore, inhibition of glycogen synthase kinase 3 (GSK- 3), which ketamine does through NMDAR antagonism, increases FTO concentrations which promotes conversion of the pro-apoptotic proBDNF to BDNF through demethylation of matrix metalloprotease 9 (MMP- 9). Taken together, these findings present a plausible epitranscriptomic mechanism for the rapid neurotrophic and antidepressant effects of ketamine. Because m6A methylation varies between species, and the methylation sites of relevant genes, such as MMP-9, differ between mice and humans, we will use human induced pluripotent stem cell (hiPSC)-derived cortical glutamatergic neurons to delineate the effects of ketamine on the epitranscriptome, m6A machinery, as well as neuronal structure and function. The successful completion of these aims will elucidate the mechanisms underlying the rapid and robust antidepressant effects of ketamine thus enabling the identification and optimization of novel antidepressants.

项目摘要 尽管急性增强了单胺功能，但慢性施用单胺抗抑郁药 临床反应是必需的，这表明在增强的单胺能信号传导下游适应 是他们的治疗效率的核心。这样的下游适应是大脑的表观遗传上调 衍生的神经营养因子（BDNF），这是神经营养过程中的关键蛋白。这符合神经营养 抑郁的假设认为，神经元的生长不足有助于MDD的发病机理 如抑郁症患者的后大脑的海马体积减少所证明的那样，因此 神经营养的恢复是抗抑郁药效率的核心。除了需要慢性治疗， 传统的抗抑郁药在相当一部分抑郁症患者中也无效 产生各种不良的副作用。另一方面，氯胺酮，N-甲基-D-天冬氨酸接收器 （NMDAR）拮抗剂和麻醉剂，其单一剂量已被证明可以挽救小于小于 一个小时，至少有一个星期的患者对至少两种典型的抗抑郁药反应。 与传统抗抑郁药不同，氯胺酮似乎会迅速促进BDNF介导的神经营养 直接但可以优化这种麻醉剂，以用于抗抑郁药的应用和设计新型药物的图像需要 进一步阐明其靶标及其治疗作用的机制。我们假设这一点 而不是与典型的长期给药那样间接改变神经营养基因 抗抑郁药，氯胺酮绕过这种长期的转录调节过程，而是诱导 RNA修饰迅速上调了神经营养蛋白的翻译。压力诱导的变化 在MDD中观察到了最丰富的RNA修饰的N6,2'-O-二甲基二胺（M6A）的水平 M6A脱甲基酶，脂肪质量和肥胖蛋白的患者和单核苷酸多态性 （FTO），与MDD风险增加有关。此外，抑制糖原合酶激酶3（GSK- 3）氯胺酮通过NMDAR拮抗作用，增加了促进的FTO浓度 通过基质金属蛋白酶9（MMP-- 9）。综上所述，这些发现提出了快速神经营养性的合理的表演机制 和氯胺酮的抗抑郁作用。因为物种和甲基化之间的M6a甲基化品种 相关基因的位点，例如MMP-9，小鼠和人之间的不同，我们将使用人类诱导的多能 干细胞（HIPSC）衍生的皮质谷氨酸能神经元描述氯胺酮对 同意组，M6A机械以及神经元结构和功能。这些成功完成 目的将阐明氯胺酮快速且稳健的抗抑郁作用的基础机制。 实现新型抗抑郁药的鉴定和优化。