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Cited by 2Treatment of Major DepressionNeurotransmitter Receptor Influence on BehaviorStress Responses and Cortisol

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Sex differences in the modulation of anxiety- and depression-like behaviors by matrix metalloproteinase-9 expression levels in mice

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Senserrich, Júlia, Castro, Elena, Florensa-Zanuy, Eva, Díaz, Álvaro, Pazos, Ángel, Adell, Albert, Tzinia, Athina, Pilar-Cuéllar, Fuencisla·2025·Biology of Sex Differences
DOI 10.1186/s13293-025-00716-5PMC PMC12096558

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Abstract

Background: Major depressive disorder is one of the main causes of disability worldwide, but its etiopathology remains largely unknown, although several hypotheses have been proposed. Recent studies suggest a potential role for matrix metalloproteinase 9 (MMP-9) in depression, as it is overexpressed in the plasma of depressed patients and normalizes following chronic antidepressant treatment. This study aimed to characterize anxiety and depression-like behaviors in transgenic MMP-9 mice, as well as the expression of different neuroplasticity markers associated with depression, in both sexes. Methods: In this study, we characterized the behavioral phenotypes of both MMP-9 knockout and MMP-9-overexpressing male and female mice. Here, we used a battery of tests to assess anxiety (open field, light‒dark box, elevated plus maze, and novelty‒suppressed feeding tests), depressive-like (tail suspension and social interaction tests), and cognitive (T-maze) behaviors. Results: MMP-9 knockout female mice displayed increased innate anxiety (open field test), decreased behavioral despair (tail suspension test). Compared with control mice, female MMP-9 knockout mice presented increased levels of different neuroplasticity markers in the hippocampus. With respect to MMP-9-overexpressing mice, females presented decreased innate anxiety (elevated plus maze). Male MMP-9-overexpressing mice presented greater conflict-based anxiety (novelty-suppressed feeding test) than control mice did. Conclusions: MMP-9 activity modifies anxiety- and depression-like behaviors, as well as neuroplasticity markers, in female but not in male mice. These findings reinforce the sex differences in the etiopathology of depression.

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Metadata

Authors
Senserrich, J., Castro, E., Florensa-Zanuy, E., Díaz, Á., Pazos, Á., Adell, A., Tzinia, A., & Pilar-Cuéllar, F.
Affiliations
  • Universidad de Cantabria (ES)
  • National Centre of Scientific Research "Demokritos" (GR)
Corresponding author
Pilar-Cuéllar, Fuencisla
ORCID
Venue
Biology of Sex Differences
Publisher
Springer Science and Business Media LLC
Published
2025-05-22
Volume
16
Issue
1
Pages
34-34
ISSN
2042-6410 (ISSN-L)
DOI
10.1186/s13293-025-00716-5
PMC
PMC12096558
OpenAlex
W4410587990
Cited by
2
References
5
Citations by year
2026: 2
FWCI
1.12
Type
journal article
Language
en
Open access
Licence
Locations
  • Biology of Sex Differences (publishedVersion, cc-by)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DIGITAL.CSIC (Spanish National Research Council (CSIC)) (acceptedVersion, other-oa)
  • UCrea (University of Cantabria) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Ministerio de Ciencia, Innovación y Universidades (RTI2018-097534-B-I00)
  • Spanish Network for Stress Research (RED2022-134191-T)
  • Instituto de Salud Carlos III (PI19-00170)
Topics
  • Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
Keywords
MMP-9, sex differences, anxiety-like behavior, depression-like behavior, MMP-9 knockout mice, hippocampus, behavioral despair, major depressive disorder
MeSH terms
Animals, Anxiety, Behavior, Animal, Depression, Female, Hippocampus, Male, Mice, Inbred C57BL, Neuronal Plasticity, Sex Characteristics, Mice, Knockout, Matrix Metalloproteinase 9, Mice

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