ADIPONECTIN ELICITS RAPID-ANTIDEPRESSANT EFFECTS IN CHRONICALLY STRESSED MICE IN ASSOCIATION WITH INCREASED GLUTAMATERGIC ACTIVITY IN THE MPFC
Authors: Formolo *Douglas Affonso , Cheng Tong , Yau Suk-Yu 
Published: February 2025

Abstract

Background
Depression is a pervasive disease and a worldwide health challenge 1. First-line antidepressants have a delayed therapeutic onset and low remission rates 2,3, while rapid-acting antidepressants (e.g., ketamine) have psychomimetic side effects that hinder their widespread use 4. Adiponectin is an adipocyte-related hormone that has been implicated in depression 5 and is shown to elicit rapid antidepressant effects in pre-clinical studies 6. Despite its promise as a target in depression treatment 7–9, adiponectin antidepressant properties have not been tested in animal models of depression and the mechanisms behind its antidepressant effects remain largely elusive.

Objectives
Test and characterize the rapid antidepressant effects of central adiponectin administration in a mouse model of depression.

Methods
Six-week-old mice were exposed to chronic unpredictable stress (CUS) for 21 days once daily to induce depression, whereas controls were briefly handled for the same period. On the 14th day, animals were implanted with intracerebroventricular cannulas. On the 22nd day, one cohort of CUS and control mice received a single infusion of globular adiponectin (1 mg) or vehicle (PBS) and were tested on the open field test (OFT) to examine locomotor activity and anxiety-like behavior, followed by the forced swim test (FST) to examine behavioral despair 30 min post-infusion. Mice then received a second infusion of adiponectin or vehicle 2 h before euthanasia for immunohistochemical analysis. Another cohort of animals was tested on the splash test (ST) for motivation-like behavior, followed by the sucrose preference test (SPT) for anhedonia-like behavior.

Results
Two-way ANOVA with Tukey post-hoc test indicated that adiponectin treatment reversed the CUS-induced increase in behavioral despair and anhedonia-like behavior, with no significant effects observed in motivation- or anxiety-like behaviors. Locomotor activity was not affected. Immunohistochemical analysis of brain slices from stressed mice showed increased expression of c-Fos in the anterior cingulate cortex (ACC) and prelimbic (PL) subregion of the medial prefrontal cortex (mPFC) in adiponectin-treated when compared to vehicle- treated mice, suggesting an acute increase in mPFC neuronal activation in response to adiponectin treatment. Moreover, the level of c-Fos expression in the ACC and PL subregions presented strong negative correlations with the immobility time in the FST, indicating that increased mPFC activity in response to adiponectin treatment is associated with improvements in depression-like behavior in stressed mice. Co-labeling analysis demonstrated that approximately 83% of c-Fos positive cells in the mPFC were CaMKII positive in adiponectin-treated mice (versus ~58% in vehicle-treated mice), suggesting the rapid antidepressant effects of adiponectin were associated with increased mPFC glutamatergic activity.

Conclusion
Adiponectin elicits rapid antidepressant effects, which is associated with increased glutamatergic activity in the mPFC of stressed mice. Such findings suggest the central adiponectin signaling system is a potential target for the rapid relief of depression symptoms.

References
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