Sex Differences in the Modulation of Anxiety- and Depression-like Behaviors by Matrix Metalloproteinase-9 Expression Levels in Mice

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 withdepression, 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‒suppressedfeeding tests), depressive-like (tail suspension and social interaction tests), and cognitive (T-maze) behaviors. Results: MMP-9 knockout female mice displayed increasedinnate anxiety (open field test), decreasedbehavioral despair (tail suspension test), and increased sociability (social interaction test). This increased sociability was also observed in male MMP-9 knockout mice. 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 decreasedinnate anxiety (elevated plus maze and light‒dark box). Male MMP-9-overexpressing mice presented greaterconflict-based anxiety (novelty-suppressed feeding test) and lower working memory (T-maze) than control mice did. These male mice presented a reduction in mTOR pathway activation and increased PSD95 hippocampal levels. Conclusions: MMP-9 levels may have a sex-dependent impact on the anxious/depressive-like phenotype, as well as on neuroplasticity markers in the hippocampus. These findings reinforce the sex differences in the etiopathology of depression.