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Altered microglia morphology and higher resilience to stress-induced depression-like behavior in CX3CR1-deficient
Sabine Hellwig1, Simone Brioschi1, Sandra Dieni1
1Department of Psychiatry and Psychotherapy, University Hospital Freiburg, Freiburg, Germany.
Abstract:
Microglia are suggested to be involved in several neuropsychiatric diseases. Indeed changes in microglia morphology have been reported in different mouse models of depression. A crucial regulatory system for microglia function is the well-defined CX3C axis. Thus, we aimed to clarify the role of microglia and CX3CR1 in depressive behavior by subjecting CX3CR1-deficient mice to a particular chronic despair model (CDM) paradigm known to exhibit face validity to major depressive disorder. In wild-type mice we observed the development of chronic depressive-like behavior after 5days of repetitive swim stress. 3D-reconstructions of Iba-1-labeled microglia in the dentate molecular layer revealed that behavioral effects were associated with changes in microglia morphology towards a state of hyper-ramification. Chronic treatment with the anti-depressant venlafaxine ameliorated depression-like behavior and restored microglia morphology. In contrast, CX3CR1 deficient mice showed a clear resistance to either (i) stress-induced depressive-like behavior, (ii) changes in microglia morphology and (iii) antidepressant treatment. Our data point towards a role of hyper-ramified microglia in the etiology of chronic depression. The lack of effects in CX3CR1 deficient mice suggests that microglia hyper-ramification is controlled by neuron-microglia signaling via the CX3C axis. However, it remains to be elucidated how hyper-ramified microglia contribute to depressive-like behavior.
Insights
Microglia morphology changes, specifically hyper-ramification, are linked to chronic depression. The CX3C axis regulates this, as CX3CR1-deficient mice showed resistance to depression-like behaviors and morphological changes.
Area of Science:
- Neuroscience
- Immunology
- Psychiatry
Background:
- Microglia, the brain's immune cells, are implicated in neuropsychiatric disorders.
- Alterations in microglia morphology are observed in depression models.
- The CX3C axis is a key regulator of microglia function.
Purpose of the Study:
- To investigate the role of microglia and CX3CR1 in depressive behavior.
- To examine the impact of CX3CR1 deficiency on depression models.
- To understand the CX3C axis's involvement in depression-related microglia changes.
Main Methods:
- Utilized a chronic despair model (CDM) in wild-type and CX3CR1-deficient mice.
- Assessed depressive-like behavior following repetitive swim stress.
- Analyzed microglia morphology using 3D reconstructions of Iba-1 staining.
- Evaluated the effects of venlafaxine treatment.
Main Results:
- Wild-type mice developed depressive-like behavior associated with microglia hyper-ramification.
- Venlafaxine treatment improved behavior and restored microglia morphology in wild-type mice.
- CX3CR1-deficient mice exhibited resistance to stress-induced depression, morphological changes, and antidepressant effects.
Conclusions:
- Microglia hyper-ramification plays a role in the etiology of chronic depression.
- Neuron-microglia signaling via the CX3C axis controls microglia hyper-ramification.
- Further research is needed to elucidate the precise contribution of hyper-ramified microglia to depressive behavior.
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