Complement receptor C3ar1 deficiency does not alter brain structure or functional connectivity across early life...

Area of Science:

• Neuroscience
• Immunology
• Genetics

Background:

• The complement C3a anaphylatoxin chemotactic receptor (C3ar1) is crucial for innate immunity.
• Previous studies suggest C3ar1 deletion induces anxiety and hyperactivity, hinting at a neurodevelopmental role.
• The precise timing and location of C3ar1's function in the brain remain unclear, complicated by its microglial expression.

Purpose of the Study:

• To conduct a brain-wide assessment of developmental C3ar1 activity using longitudinal MRI in mice.
• To investigate potential neurodevelopmental roles of C3ar1 and its implications for therapeutic targeting in disorders like schizophrenia.

Main Methods:

• Longitudinal MRI (including tensor-based morphometry, diffusion-weighted imaging, and fMRI) was used in C3ar1-deficient and wild-type mice.
• Behavioral assessments were conducted in adulthood.
• Structural MRI was repeated ex vivo for higher resolution and in a second cohort in vivo to confirm findings.

Main Results:

• The study successfully detected established effects like sexually dimorphic regional brain volume and developmental increases in fractional anisotropy.
• Despite the sensitivity of the methods, no robust C3ar1-dependent phenotype was observed in brain structure, function, or behavior.
• This is the first study to use littermate controls in behavioral assessments of C3ar1-deficient mice.

Conclusions:

• The data do not support a neurodevelopmental role for C3ar1.
• These findings are encouraging for therapeutic strategies targeting C3ar1, as interventions are unlikely to negatively impact brain development.
• C3ar1's role as a potential therapeutic target for complement-related disorders like schizophrenia remains viable without developmental concerns.