title: Relaxin-3 receptor (Rxfp3) gene knockout mice display reduced running wheel activity: implications for role of relaxin-3/RXFP3 signalling in sustained arousal.
abstract: Anatomical and pharmacological evidence suggests the neuropeptide, relaxin-3, is the preferred endogenous ligand for the relaxin family peptide-3 receptor (RXFP3) and suggests a number of putative stress- and arousal-related roles for RXFP3 signalling. However, in vitro and in vivo evidence demonstrates exogenous relaxin-3 can activate other relaxin peptide family receptors, and the role of relaxin-3/RXFP3 signalling in specific brain circuits and associated behaviours in mice is not well described. In this study, we characterised the behaviour of cohorts of male and female Rxfp3 gene knockout (KO) mice (C57/B6J(RXFP3TM1/DGen)), relative to wild-type (WT) littermates to determine if this receptor KO strain has a similar phenotype to its ligand KO equivalent. Rxfp3 KO mice displayed similar performance to WT littermates in several acute behavioural paradigms designed to gauge motor coordination (rotarod test), spatial memory (Y-maze), depressive-like behaviour (repeat forced-swim test) and sensorimotor gating (prepulse inhibition of acoustic startle). Notably however, male and female Rxfp3 KO mice displayed robust and consistent (dark phase) hypoactivity on voluntary home-cage running wheels (∼20-60% less activity/h), and a small but significant decrease in anxiety-like behavioural traits in the elevated plus maze and light/dark box paradigms. Importantly, this phenotype is near identical to that observed in two independent lines of relaxin-3 KO mice, suggesting these phenotypes are due to the elimination of ligand or receptor and RXFP3-linked signalling. Furthermore, this behavioural characterisation of Rxfp3 KO mice identifies them as a useful experimental model for studying RXFP3-linked signalling and assessing the selectivity and/or potential off-target actions of RXFP3 agonists and antagonists, which could lead to an improved understanding of dysfunctional arousal in mental health disorders, including depression, anxiety, insomnia and neurodegenerative diseases.
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Victoria, Australia; Florey Department of Neuroscience and Mental Health, The University of Melbourne, Victoria, Australia.
authors.forename: Ihaia T
authors.initials: IT
authors.lastname: Hosken
authors.affiliation: Neuroscience Drug Discovery, Janssen Pharmaceutical Companies of Johnson & Johnson, San Diego, CA, USA.
authors.forename: Steven W
authors.initials: SW
authors.lastname: Sutton
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Victoria, Australia; Florey Department of Neuroscience and Mental Health, The University of Melbourne, Victoria, Australia.
authors.forename: Craig M
authors.initials: CM
authors.lastname: Smith
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Victoria, Australia; Florey Department of Neuroscience and Mental Health, The University of Melbourne, Victoria, Australia; Department of Anatomy and Neuroscience, The University of Melbourne, Victoria, Australia. Electronic address: andrew.gundlach@florey.edu.au.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Gundlach
mesh_terms: D000221:Adaptation, Ocular / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D001143:Arousal / Q000235:genetics*; D005106:Exploratory Behavior / Q000502:physiology; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000235:genetics*; D065808:Prepulse Inhibition / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000172:deficiency* / Q000235:genetics; D021641:Recognition, Psychology; D013216:Reflex, Startle / Q000235:genetics; D012065:Relaxin / Q000378:metabolism*; D045442:Rotarod Performance Test; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D043562:Receptors, G-Protein-Coupled; C505050:SALPR protein, mouse; C512898:relaxin-3 protein, mouse; D012065:Relaxin
keywords: Arousal; Neuropeptide receptor; RXFP3; Relaxin-3; Running wheel activity