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Chronic 5-HT7R activation drives depressive phenotypes and synaptic dysfunction

Acta Pharmacologica Sinica (2026)Cite this article

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.

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Fig. 1: Specific and dose-dependent activation of 5-HT7R mediated Gαs signaling by AGH-194.
Fig. 2: Time-dependent activation of MMP-9 and the role of Gαs in AGH-194-induced MMP-9 signaling.
Fig. 3: Behavioral effects of acute and chronic AGH-194 treatment.
Fig. 4: Activation of 5-HT7R with AGH-194 leads to dendritic spine elongation in the CA1 and DG subregion of the hippocampus.
Fig. 5: Chronic activation of 5-HT7R with AGH-194 does not alter dendritic spine morphology or density in the CA1 and DG subregions of the hippocampus.
Fig. 6: Chronic AGH-194 administration reduces hippocampal expression of total GluA1.
Fig. 7: Electrophysiological effects of single AGH-194 administration on PS (a-e) and EPSP (f-j) recorded in the hippocampal CA1 area.
Fig. 8: Electrophysiological effects of repeated AGH-194 administration on PS (a-e) and EPSP (f-j) recorded in the hippocampal CA1 area.

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All data supporting the findings of this study are available within the article or are available from the corresponding author upon reasonable request.

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Acknowledgements

This work was supported by grants from National Science Centre (UMO- 2019/35/D/NZ4/02042). In addition, the functional characterization of AGH-194 was funded by the National Science Centre, Poland (2024/55/D/NZ7/02178). The pharmacokinetic study was supported by grant OPUS 2017/25/B/NZ7/02929 from the Polish National Science Centre. Some of the experiments were carried out with equipment cofinanced by the qLife Priority Research Area under the program. “Excellence Initiative—Research University” at Jagiellonian University.

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Authors and Affiliations

  1. Nencki Institute of Experimental Biology, Polish Academy of Sciences, 02-093, Warsaw, Poland

    Bartłomiej Pochwat, Julia Masternak, Krystian Bijata, Remigiusz Worch & Monika Bijata

  2. Maj Institute of Pharmacology, Polish Academy of Sciences, 31-343, Cracow, Poland

    Bartłomiej Pochwat, Bartosz Bobula, Barbara Chruścicka-Smaga, Justyna Turek, Adam Hogendorf, Magdalena Kusek, Andrzej J. Bojarski, Krzysztof Tokarski & Bernadeta Szewczyk

  3. Department of Toxicology, Jagiellonian University Medical College, Kraków, 30-688, Poland

    Maria Walczak & Magdalena Smolik

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  1. Bartłomiej Pochwat
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Contributions

BP conceptualized the study, performed behavioral experiments, Western blot analyses, and contributed to data interpretation; he also wrote the first draft of the manuscript and participated in its editing. JM conducted behavioral experiments, performed AAV-based manipulations, and analyzed dendritic spine morphology. BB, MK, and KT were responsible for electrophysiological recordings and data analysis. BCS carried out in vitro assays. RW performed statistical analyses. AH provided resources (AGH-194), AJB provided resources (AGH-194). MW and MS performed pharmacokinetic study. BS and JT contributed to behavioral analysis and supervised tissue collection. KB conducted biochemical experiments. MB conceptualized the study, acquired funding, supervised the project, and was responsible for writing and editing the first draft of the manuscript.

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Correspondence to Bartłomiej Pochwat or Monika Bijata.

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Pochwat, B., Masternak, J., Bobula, B. et al. Chronic 5-HT7R activation drives depressive phenotypes and synaptic dysfunction. Acta Pharmacol Sin (2026). https://doi.org/10.1038/s41401-025-01722-4

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