Heterogeneous complement and microglia activation mediates stress-induced synapse loss

Area of Science:

• Neuroscience
• Immunology
• Molecular Biology

Background:

• Spatially heterogeneous synapse loss is a hallmark of neurological and psychiatric disorders, yet its mechanisms remain elusive.
• Understanding the cellular and molecular drivers of this localized neuronal damage is crucial for developing targeted therapies.

Approach:

• Investigated the role of complement activation in stress-induced synapse loss in the mouse medial prefrontal cortex (mPFC).
• Utilized single-cell RNA sequencing to identify stress-associated microglia states.
• Employed C3 knockout mice to assess the necessity of complement component 3 in mediating these effects.

Key Points:

• Spatially restricted complement activation drives heterogeneous microglia activation and synapse loss in the upper layers of the mPFC following stress.
• A stress-associated microglia state characterized by high apolipoprotein E (ApoE) expression was identified in the upper mPFC.
• Mice lacking complement component C3 were protected from stress-induced layer-specific synapse loss and ApoE-high microglia accumulation.
• C3 knockout mice exhibited resilience to stress-induced anhedonia and working memory deficits.

Conclusions:

• Complement component 3 and microglia activation are key mediators of stress-induced, layer-specific synapse loss in the mPFC.
• These findings highlight the role of region-specific complement and microglia activity in the spatially restricted patterns of synapse loss observed in brain diseases.
• Targeting complement pathways may offer a therapeutic strategy for psychiatric and neurological disorders characterized by synapse loss.