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Systemic GDF11 attenuates depression-like phenotype in aged mice via stimulation of neuronal autophagy
Carine Moigneu1, Soumia Abdellaoui1,2, Mariana Ramos-Brossier2
1Perception and Memory Lab, Institut Pasteur, Université Paris Cité, CNRS UMR3571, Paris, France.
Abstract:
Cognitive decline and mood disorders increase in frequency with age. Many efforts are focused on the identification of molecules and pathways to treat these conditions. Here, we demonstrate that systemic administration of growth differentiation factor 11 (GDF11) in aged mice improves memory and alleviates senescence and depression-like symptoms in a neurogenesis-independent manner. Mechanistically, GDF11 acts directly on hippocampal neurons to enhance neuronal activity via stimulation of autophagy. Transcriptomic and biochemical analyses of these neurons reveal that GDF11 reduces the activity of mammalian target of rapamycin (mTOR), a master regulator of autophagy. Using a murine model of corticosterone-induced depression-like phenotype, we also show that GDF11 attenuates the depressive-like behavior of young mice. Analysis of sera from young adults with major depressive disorder (MDD) reveals reduced GDF11 levels. These findings identify mechanistic pathways related to GDF11 action in the brain and uncover an unknown role for GDF11 as an antidepressant candidate and biomarker.
Insights
Growth Differentiation Factor 11 (GDF11) administration in aged mice enhances memory and reduces depression-like symptoms by boosting neuronal activity and autophagy, independent of neurogenesis. GDF11 shows potential as an antidepressant and biomarker for major depressive disorder.
Area of Science:
- Neuroscience
- Molecular Biology
- Gerontology
Background:
- Aging is associated with increased cognitive decline and mood disorders.
- Identifying novel molecular targets is crucial for treating age-related neurological and psychiatric conditions.
Purpose of the Study:
- To investigate the effects of Growth Differentiation Factor 11 (GDF11) on cognitive function and mood in aged mice.
- To elucidate the underlying molecular mechanisms of GDF11 action in the brain.
- To explore GDF11's potential as a therapeutic agent and biomarker for depression.
Main Methods:
- Systemic administration of GDF11 to aged mice.
- Assessment of memory, senescence, and depression-like behaviors.
- Analysis of neurogenesis, neuronal activity, autophagy, and mammalian target of rapamycin (mTOR) signaling in hippocampal neurons.
- Transcriptomic and biochemical analyses.
- Evaluation of GDF11 in a murine model of depression and analysis of GDF11 levels in human sera from individuals with major depressive disorder (MDD).
Main Results:
- GDF11 treatment improved memory and alleviated senescence and depression-like symptoms in aged mice via a neurogenesis-independent pathway.
- GDF11 directly enhanced hippocampal neuronal activity by stimulating autophagy and reducing mTOR activity.
- GDF11 attenuated depression-like behaviors in a murine model and was found to be reduced in the sera of individuals with MDD.
Conclusions:
- GDF11 acts directly on hippocampal neurons to improve cognitive function and mood in aging.
- GDF11's mechanism involves stimulating autophagy and inhibiting mTOR signaling.
- GDF11 represents a promising therapeutic candidate for depression and a potential biomarker for MDD.
