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Complement C3 and C3aR mediate different aspects of emotional behaviours; relevance to risk for psychiatric disorder

Westacott, Laura J., Humby, Trevor, Haan, Niels, Brain, Sophie A., Bush, Emma-Louise, Toneva, Margarita, Baloc, Andreea-Ingrid, Moon, Anna L., Reddaway, Jack, Owen, Michael J., Hall, Jeremy, Hughes, Timothy R., Morgan, B. Paul, Gray, William P. and Wilkinson, Lawrence S. 2022. Complement C3 and C3aR mediate different aspects of emotional behaviours; relevance to risk for psychiatric disorder. Brain, Behavior, and Immunity 99 , pp. 70-82. 10.1016/j.bbi.2021.09.005

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Abstract

Complement is a key component of the immune system with roles in inflammation and host-defence. Here we reveal novel functions of complement pathways impacting on emotional reactivity of potential relevance to the emerging links between complement and risk for psychiatric disorder. We used mouse models to assess the effects of manipulating components of the complement system on emotionality. Mice lacking the complement C3a Receptor (C3aR−/−) demonstrated a selective increase in unconditioned (innate) anxiety whilst mice deficient in the central complement component C3 (C3−/−) showed a selective increase in conditioned (learned) fear. The dissociable behavioural phenotypes were linked to different signalling mechanisms. Effects on innate anxiety were independent of C3a, the canonical ligand for C3aR, consistent with the existence of an alternative ligand mediating innate anxiety, whereas effects on learned fear were due to loss of iC3b/CR3 signalling. Our findings show that specific elements of the complement system and associated signalling pathways contribute differentially to heightened states of anxiety and fear commonly seen in psychopathology.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Psychology
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Publisher: Elsevier
ISSN: 0889-1591
Funders: Wellcome Trust
Date of First Compliant Deposit: 8 October 2021
Date of Acceptance: 13 September 2021
Last Modified: 31 May 2022 11:10
URI: https://orca.cardiff.ac.uk/id/eprint/144754

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