Key Laboratory of Developmental Genes and Human Diseases, MOE, Department of Histology and Embryology, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, PR China.
Department of Pharmacy, The Affiliated Jiangyin Hospital, School of Medicine, Southeast University, Jiangyin, Jiangsu 214400, PR China.
Theranostics. 2022 May 1;12(8):3656-3675. doi: 10.7150/thno.70370. eCollection 2022.
Adult hippocampal neurogenesis and synaptic plasticity are necessary for the behavioral response to the selective serotonin reuptake inhibitor (SSRI) fluoxetine, but the molecular mechanisms underlying these effects are only partially understood. Anxiety and depressive-like behaviors in mice were developed by chronic mild stress (CMS) or chronic corticosterone (CORT) treatment. Pharmacological and genetic approaches were used to investigate the role of the neuronal nitric oxide synthase (nNOS)-carboxy-terminal PDZ ligand of nNOS (CAPON) interaction in behavioral and neuroplasticity effects of serotoninergic system. Molecular biological and morphological studies were performed to examine the mechanisms underlying the behavioral effects of nNOS-CAPON interaction that modulated by 5-HT1A receptor (5-HT1AR). Fluoxetine prevented chronic stress-induced nNOS-CAPON upregulation and coupling in the dentate gyrus (DG), and promoting nNOS-CAPON association weakened the anxiolytic and antidepressant effects of fluoxetine in stressed mice. The chronic fluoxetine elevated 5-HT and 5HT1AR agonist 8-OH-DPAT decreased the expression and binding of nNOS with CAPON, whereas 5-HT1AR antagonist NAN-190 had the opposite effects. Importantly, augmenting nNOS-CAPON binding neutralized 8-OH-DPAT-upregulated spine density of DG granule cells and well-characterized synaptic-related proteins, including brain-derived neurotrophic factor (BDNF) and phosphorylation of extracellular signal regulated kinase (ERK), cAMP-response element binding protein (CREB), and synapsin in the DG and abolished the anxiolytic and antidepressant-like effects of 8-OH-DPAT. In contrast, dissociation of nNOS from CAPON rescued the effects of NAN-190 on behavior and neuroplasticity. Taken together, our results indicated that fluoxetine modifies mood behaviors and hippocampal neuroplasticity by disrupting the nNOS-CAPON interaction that links postsynaptic 5-HT1AR activation.
成年海马神经发生和突触可塑性是对选择性 5-羟色胺再摄取抑制剂 (SSRI) 氟西汀产生行为反应所必需的，但这些效应的分子机制仅部分被理解。慢性轻度应激 (CMS) 或慢性皮质酮 (CORT) 处理会导致小鼠出现焦虑和抑郁样行为。使用药理学和遗传学方法来研究神经元型一氧化氮合酶 (nNOS)-nNOS 羧基末端 PDZ 配体 (CAPON) 相互作用在 5-羟色胺能系统的行为和神经可塑性效应中的作用。进行分子生物学和形态学研究，以检查调节 5-HT1A 受体 (5-HT1AR) 的 nNOS-CAPON 相互作用的行为效应的机制。氟西汀可防止慢性应激诱导的齿状回 (DG) 中 nNOS-CAPON 的上调和偶联，并促进 nNOS-CAPON 关联减弱应激小鼠中氟西汀的抗焦虑和抗抑郁作用。慢性氟西汀升高 5-HT 和 5-HT1AR 激动剂 8-OH-DPAT 会降低 nNOS 与 CAPON 的表达和结合，而 5-HT1AR 拮抗剂 NAN-190 则具有相反的作用。重要的是，增强 nNOS-CAPON 结合可使 8-OH-DPAT 上调的 DG 颗粒细胞的棘密度以及公认的突触相关蛋白，包括脑源性神经营养因子 (BDNF) 和细胞外信号调节激酶 (ERK)、cAMP 反应元件结合蛋白 (CREB) 和突触素的磷酸化正常化，并且消除 8-OH-DPAT 的抗焦虑和抗抑郁样作用。相反，将 nNOS 从 CAPON 中解离出来可挽救 NAN-190 对行为和神经可塑性的作用。总的来说，我们的结果表明，氟西汀通过破坏与突触后 5-HT1AR 激活相关的 nNOS-CAPON 相互作用来调节情绪行为和海马神经可塑性。
