Microglia mediate memory dysfunction via excitatory synaptic elimination in a fracture surgery mouse model.

Area of Science:

• Neuroscience
• Immunology
• Molecular Biology

Background:

• Postoperative cognitive dysfunction (POCD) is a common complication following surgery, with unclear underlying neural mechanisms.
• Surgical stress activates glial cells and causes neuronal hypoexcitability, contributing to POCD.
• The role of neuron-glia interactions in POCD pathology requires further elucidation.

Purpose of the Study:

• To investigate the neural mechanisms of POCD by examining neuron-glia crosstalk.
• To identify specific molecular pathways involved in surgery-induced cognitive deficits.

Main Methods:

• Integrated transcriptomics and proteomics analyses in a mouse model of POCD.
• Immunohistochemical analysis to detect complement C3 localization.
• Genetic knockout of C3ar1 and inhibition of p-STAT3 signaling.

Main Results:

• Surgery activated complement cascades and microglial phagocytotic pathways in the POCD mouse model.
• Increased complement C3 associated with presynaptic elements led to reduced excitatory synapses and impaired synaptic transmission.
• Genetic knockout of C3ar1 or p-STAT3 inhibition prevented neuronal hypoexcitability and alleviated memory deficits.

Conclusions:

• The complement C3a-C3aR signaling pathway, coupled with p-STAT3, plays a critical role in POCD pathogenesis.
• Targeting the C3aR and p-STAT3 signaling pathways offers potential therapeutic strategies for mitigating POCD.