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Microglia-dependent excessive synaptic pruning leads to cortical underconnectivity and behavioral abnormality
Ji Wang1, Hong-Sheng Chen1, Hou-Hong Li1
1Department of Pharmacology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan City, Hubei 430030, China.
Abstract:
Synapse loss in medial prefrontal cortex (mPFC) has been implicated in stress-related mood disorders, such as depression. However, the exact effect of synapse elimination in the depression and how it is triggered are largely unknown. Through repeated longitudinal imaging of mPFC in the living brain, we found both presynaptic and postsynaptic components were declined, together with the impairment of synapse remodeling and cross-synaptic signal transmission in the mPFC during chronic stress. Meanwhile, chronic stress also induced excessive microglia phagocytosis, leading to engulfment of excitatory synapses. Further investigation revealed that the elevated complement C3 during the stress acted as the tag of synapses to be eliminated by microglia. Besides, chronic stress induced a reduction of the connectivity between the mPFC and neighbor regions. C3 knockout mice displayed significant reduction of synaptic pruning and alleviation of disrupted functional connectivity in mPFC, resulting in more resilience to chronic stress. These results indicate that complement-mediated excessive microglia phagocytosis in adulthood induces synaptic dysfunction and cortical hypo-connectivity, leading to stress-related behavioral abnormality.
Insights
Chronic stress causes synapse loss in the medial prefrontal cortex (mPFC) by triggering microglia to engulf synapses, a process tagged by complement C3. This leads to depression-like behaviors, which can be prevented by blocking C3.
Area of Science:
- Neuroscience
- Neuroimmunology
- Molecular Psychiatry
Background:
- Synapse loss in the medial prefrontal cortex (mPFC) is linked to depression.
- The mechanisms triggering synapse elimination during stress are not fully understood.
Purpose of the Study:
- To investigate the impact of chronic stress on mPFC synapses and identify the underlying molecular mechanisms.
- To explore the role of microglia and complement C3 in stress-induced synapse loss and behavioral changes.
Main Methods:
- Longitudinal in vivo imaging of the mPFC in a chronic stress model.
- Analysis of synaptic components, microglia activity, and complement C3 levels.
- Behavioral testing in wild-type and C3 knockout mice.
Main Results:
- Chronic stress led to synapse loss, impaired remodeling, and reduced signal transmission in the mPFC.
- Microglia excessively phagocytosed excitatory synapses, facilitated by elevated complement C3.
- C3 knockout mice showed reduced synaptic pruning, preserved functional connectivity, and resilience to stress.
Conclusions:
- Elevated complement C3 drives excessive microglia phagocytosis of synapses during chronic stress.
- This process results in mPFC hypo-connectivity, synaptic dysfunction, and stress-related behavioral abnormalities.
- Targeting complement C3 may offer a therapeutic strategy for stress-related mood disorders.
