Schizophrenia-associated complement C4 impairs synaptic connectivity and decreases microglia-synapse interactions...

Area of Science:

• Neuroscience
• Immunology
• Genetics

Background:

• High-expression variants of the complement C4 gene are linked to increased schizophrenia (SZ) risk.
• Complement C4 overexpression (C4-OE) in mice mimics SZ-related phenotypes like reduced synapse density, but mechanisms are unknown.

Purpose of the Study:

• To investigate the role of microglial complement receptor 3 (CR3) in mediating the effects of C4 overexpression relevant to schizophrenia.
• To elucidate the impact of C4-OE on microglia-synapse interactions.

Main Methods:

• Utilized in vivo two-photon imaging in mouse models.
• Compared C4-overexpressing mice with CR3-deficient mice.
• Assessed synapse density, spine dynamics, microglial volume, motility, and contacts with neuronal structures.

Main Results:

• C4 overexpression altered synapse density and function, effects rescued in CR3-deficient mice.
• C4-OE reduced microglial surveilled volume, motility, and frequency of contacts with synaptic structures.
• These microglial changes were abolished in the absence of CR3.

Conclusions:

• Microglial CR3 plays a crucial role in mediating the synaptic and behavioral alterations observed in C4 overexpression models of schizophrenia.
• CR3-modulated interactions between microglia and synapses underlie C4-OE's impact on brain function relevant to SZ.