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Manipulating immune pathways differentially impact emotionality: dissociable effects of complement C3 and C3aR on learned fear and innate anxiety

By Laura J. Westacott, Trevor Humby, Niels Haan, Sophie A. Brain, Emma-Louise Bush, Margarita Toneva, Anna L. Moon, Jack Reddaway, Michael J. Owen, Jeremy Hall, Timothy R. Hughes, B. Paul Morgan, William P. Gray, Lawrence S Wilkinson

Posted 27 Jun 2019
bioRxiv DOI: 10.1101/685537

Background Recent findings implicate complement, a key component of the immune system, in healthy brain functioning and risk for psychiatric disorders. Altered emotional function, in particular maladaptive fear and anxiety, is a pervasive and clinically important symptom across several neuropsychiatric disorders. In this work we examined the extent to which different complement pathways impact on dissociable components of anxiety and learned fear. Methods C3 -/- and C3aR -/- mice were assessed in a battery of tests assaying innate anxiety and learned fear. The effects of systemic diazepam (2mg/kg) and the C3aR antagonist SB290157 (10mg/kg) on behaviour was assessed. Expression of genes linked to anxiety, stress responses and risk for psychiatric disorder were assessed in brain regions implicated in fear and anxiety. Results The data indicated a robust and highly reproducible double-dissociation of C3 and C3aR on learned fear and innate anxiety, respectively. We probed downstream complement pathways responsible for the C3-specific effects on learned fear and excluded contributions from the terminal pathway, C6 to C9. The selective anxiety phenotype in C3aR -/- mice was resistant to the anxiolytic properties of diazepam and acute SB290157 administration in wildtypes did not phenocopy constitutive C3aR knockout, suggesting C3aR -/- anxiety phenotypes resulted from long-term C3aR deficiency. Expression of the calcium voltage-gated channel subunit Alpha1c ( Cacna1c ) mRNA, an established psychiatric risk gene, was selectively increased in C3aR -/- mice. Conclusions These findings reveal novel functions and unexpected dissociations between the C3 and C3aR pathways impacting on specific emotional behaviours relevant to psychiatric disorder.

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