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Genetically Predicted Brain C4A Expression Is Associated With TSPO and Hippocampal Morphology.

Tania Da Silva1, Elisa Guma2, Sina Hafizi3

  • 1Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.

Biological Psychiatry
|August 30, 2021
PubMed
Summary

Higher complement C4A expression links to brain changes and microglial activity in humans. This study reveals lower C4A in those at high risk for psychosis, suggesting a role in schizophrenia development.

Keywords:
C4AHippocampal morphologyMicroglial functionTranslocator protein

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Area of Science:

  • Neuroscience
  • Immunology
  • Genetics

Background:

  • Alterations in complement C4A are implicated in schizophrenia pathophysiology.
  • C4A's role in microglia-mediated synapse elimination is known in preclinical models but unconfirmed in humans.
  • The impact of C4A on human brain morphology remains unclear.

Purpose of the Study:

  • To investigate the association between genetically predicted brain C4A expression and microglial activity in living humans.
  • To examine the relationship between C4A expression and hippocampal morphology.
  • To explore C4A expression in individuals at clinical high risk for psychosis.

Main Methods:

  • Positron emission tomography (TSPO [18F]FEPPA) and magnetic resonance imaging were used in 111 participants (psychosis patients, high-risk individuals, healthy controls).
  • Brain C4A expression was genetically predicted based on structural gene elements.
  • Microglial marker (TSPO) and brain morphology were assessed.

Main Results:

  • Higher genetically predicted C4A expression correlated with increased brain TSPO (microglial marker) and altered hippocampal morphology (reduced CA1 surface area).
  • Individuals at clinical high risk for psychosis showed significantly lower genetically predicted C4A compared to healthy controls.
  • Sex significantly influenced genetically predicted C4A expression, and both sex and cannabis use affected brain TSPO levels.

Conclusions:

  • This study provides the first evidence of complement C4A coupling with microglial markers and hippocampal morphology in the living human brain.
  • Findings suggest a potential link between C4A, glial function, and the pathophysiology of psychosis and schizophrenia.
  • Further research into C4A and glial cell interactions may offer insights into schizophrenia mechanisms.