Complement receptor <i>C3ar1</i> deficiency does not alter brain structure or functional connectivity across early life development
Bibliographic record
Abstract
Abstract Genetic deletion of the complement C3a anaphylatoxin chemotactic receptor (C3ar1), a key component of the innate immune response, is reported to induce behavioural phenotypes resembling anxiety and hyperactivity in mice, suggesting a neurodevelopmental role for this gene in health. However, it is not currently clear when and where C3ar1 is needed in the brain, which is further complicated by the fact that C3ar1 is expressed predominantly by microglia and therefore does not localize to specific brain regions, warranting exploratory and brain-wide assessment through neuroimaging. Resolving when and where C3ar1 is needed are questions of significant translational importance because, as a G-protein-coupled receptor, human C3AR1 serves as a potential therapeutic target for disorders associated with complement upregulation, such as schizophrenia. To provide a brain-wide assessment of developmental C3ar1 activity, we used longitudinal MRI in male and female adolescent and adult mice (N = 34 C3ar1tm1Cge/tm1Cge and N = 35 C3ar1+/+) to estimate regional brain volume using tensor based morphometry, white matter microstructure using fractional anisotropy from diffusion-weighted MRI, and functional connectivity from blood oxygen-level dependent MRI, with behavioural assessment in adulthood. We repeated structural MRI measures in this cohort ex vivo to achieve higher resolution. We further repeated in vivo structural assessment preceded by behavioural testing in adulthood in a second cohort of mice (N = 20 C3ar1tm1Cge/tm1Cge and N = 19 C3ar1+/+) to improve confidence in our findings. We achieved low regional brain volume variability, allowing us to resolve previously reported sexually dimorphic effects. We were further able to confirm a well-known developmental increase in fractional anisotropy. Despite being able to detect these established effects, we did not find a robust C3ar1-dependent phenotype in any of the measures we tested, including behaviour, which may be attributed to our study being the first behavioural study in C3ar1-deficient mice to include littermate controls. Therefore, our data do not support neurodevelopmental hypotheses for C3ar1, which is encouraging for therapeutic strategies targeting this receptor since interventions are unlikely to disrupt brain development.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.005 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".