波兰科学院Monika Bijata课题组研究出慢性5-HT7R激活驱动抑郁表型和突触功能障碍。相关论文于2026年2月3日发表在《中国药理学报》杂志上。

研究团队研究了以选择性激动剂AGH-194为主题的5-HT7受体（5-HT7R）慢性和急性激活对雄性小鼠的影响。行为评估显示，慢性AGH-194在新颖性抑制喂养试验（NSFT）、女性尿液嗅吸试验（FUST）和新物体定位试验（NOLT）中诱导抑郁样效应。急性注射后，仅在NSFT中观察到抑郁样作用。在分子水平上，AGH-194通过5-HT7R-Gαs信号依赖机制激活基质金属蛋白酶9 （MMP-9）。急性治疗诱导短暂激活，而慢性治疗导致酶活性延长，并伴有海马α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体（AMPAR）的GluA1亚基表达减少。在细胞水平上，急性而非慢性AGH-194治疗诱导海马CA1和齿状回（DG）区域向更年轻的树突棘形态转变，同时DG的树突棘密度增加。

电生理记录显示，急性给药AGH-194通过增加CA1的群体峰幅来增强海马的兴奋性。慢性AGH-194处理进一步调节了短期可塑性，增加了CA1的群体峰值和细胞外场电位对脉冲比（PS-PPR和EPSP-PPR），同时增强了EPSP斜率的最大振幅。这些发现提供了新的证据，表明慢性5-HT7R激活可以诱导雄性小鼠的抑郁样行为，可能是通过MMP-9的持续激活和突触可塑性的改变。了解选择性5-HT7R刺激的分子和电生理后果可能有助于深入了解可能导致SSRI诱导的副作用的受体特异性机制，从而有助于改进抗抑郁药物策略的发展。

据了解，选择性血清素再摄取抑制剂（SSRIs）通常以治疗抑郁症为主题，但其慢性主题与抑郁症的副作用和残留症状有关。SSRIs诱导的两种效应都是由血清素受体依赖的信号通路介导的，但这些效应的分子机制尚不清楚。

附：英文原文

Title: Chronic 5-HT7R activation drives depressive phenotypes and synaptic dysfunction

Author: Pochwat, Bartomiej, Masternak, Julia, Bobula, Bartosz, Bijata, Krystian, Chrucicka-Smaga, Barbara, Turek, Justyna, Hogendorf, Adam, Walczak, Maria, Smolik, Magdalena, Worch, Remigiusz, Kusek, Magdalena, Bojarski, Andrzej J., Tokarski, Krzysztof, Szewczyk, Bernadeta, Bijata, Monika

Issue&Volume: 2026-02-03

Abstract: Selective serotonin reuptake inhibitors (SSRIs) are commonly used to treat depression, but their chronic use is associated with side effects and residual symptoms of depression. Both effects induced by SSRIs are mediated by serotonin receptor-dependent signaling pathways, yet the molecular mechanisms underlying these effects remain unclear. Here, we investigated the impact of chronic and acute activation of the 5-HT7 receptor (5-HT7R) using the selective agonist AGH-194 in male mice. Behavioral assessment revealed that chronic AGH-194 administration induced depressive-like effects in the novelty suppressed feeding test (NSFT), female urine sniffing test (FUST), and novel object location test (NOLT). After acute injection, depressive-like effects were observed only in NSFT. At the molecular level, AGH-194 administration activated matrix metalloproteinase 9 (MMP-9) through a 5-HT7R-Gαs signaling-dependent mechanism. Acute treatment induced transient activation, while chronic treatment led to prolonged enzymatic activity, accompanied by a reduction in the expression of the GluA1 subunit of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) in the hippocampus. At the cellular level, acute but not chronic AGH-194 treatment induced a shift toward more juvenile dendritic spine morphology in the CA1 and dentate gyrus (DG) regions of the hippocampus, along with an increase in dendritic spine density in DG. Electrophysiological recordings demonstrated that acute AGH-194 administration enhanced hippocampal excitability by increasing population spike amplitude in CA1. Chronic AGH-194 treatment further modulated short-term plasticity, increasing both population spike and extracellular field potential paired-pulse ratios (PS-PPR and EPSP-PPR) in CA1, while also enhancing the maximum EPSP slope amplitude. These findings provide novel evidence that chronic 5-HT7R activation can induce depressive-like behaviors in male mice, potentially through sustained MMP-9 activation and alterations in synaptic plasticity. Understanding the molecular and electrophysiological consequences of selective 5-HT7R stimulation may provide insights into receptor-specific mechanisms that could contribute to SSRI-induced side effects, thereby contributing to the development of improved antidepressant strategies.

DOI: 10.1038/s41401-025-01722-4

Source: https://www.nature.com/articles/s41401-025-01722-4