Relaxin-3/RXFP3 signalling in mouse hypothalamus: no effect of RXFP3 activation on corticosterone, despite reduced presynaptic excitatory input onto paraventricular CRH neurons in vitro.
Relaxin-3/RXFP3 signalling is proposed to be involved in the neuromodulatory control of arousal- and stress-related neural circuits. Furthermore, previous studies in rats have led to the proposal that relaxin-3/RXFP3 signalling is associated with activation of the hypothalamic-pituitary-adrenal axis, but direct evidence for RXFP3-related actions on the activity of hypothalamic corticotropin-releasing hormone (CRH) neurons is lacking. In this study, we investigated characteristics of the relaxin-3/RXFP3 system in mouse hypothalamus. Administration of an RXFP3 agonist (RXFP3-A2) intra-cerebroventricularly or directly into the paraventricular nucleus of hypothalamus (PVN) of C57BL/6J mice did not alter corticosterone levels. Similarly, there were no differences between serum corticosterone levels in Rxfp3 knockout (C57BL/6JRXFP3TM1) and wild-type mice at baseline and after stress, despite detection of the predicted stress-induced increases in serum corticosterone. We examined the nature of the relaxin-3 innervation of PVN in wild-type mice and in Crh-IRES-Cre;Ai14 mice that co-express the tdTomato fluorophore in CRH neurons, identifying abundant relaxin-3 fibres in the peri-PVN region, but only sparse fibres associated with densely packed CRH neurons. In whole-cell voltage-clamp recordings of tdTomato-positive CRH neurons in these mice, we observed a reduction in sEPSC frequency following local application of RXFP3-A2, consistent with an activation of RXFP3 on presynaptic glutamatergic afferents in the PVN region. These studies clarify the relationship between relaxin-3/RXFP3 inputs and CRH neurons in mouse PVN, with implications for the interpretation of current and previous in vivo studies and future investigations of this stress-related signalling network in normal and transgenic mice, under normal and pathological conditions.
The Florey Institute of Neuroscience and Mental Health, 30 Royal Parade, Parkville, VIC, 3052, Australia.|Florey Department of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, 3010, Australia.
C
C
Zhang
Department of Physiology and Pharmacology, Hotchkiss Brain Institute, University of Calgary, Calgary, AB, T2N 4N1, Canada.
D V
DV
Baimoukhametova
The Florey Institute of Neuroscience and Mental Health, 30 Royal Parade, Parkville, VIC, 3052, Australia.|Florey Department of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, 3010, Australia.
C M
CM
Smith
Department of Physiology and Pharmacology, Hotchkiss Brain Institute, University of Calgary, Calgary, AB, T2N 4N1, Canada.
J S
JS
Bains
The Florey Institute of Neuroscience and Mental Health, 30 Royal Parade, Parkville, VIC, 3052, Australia. andrew.gundlach@florey.edu.au.|Florey Department of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, 3010, Australia. andrew.gundlach@florey.edu.au.
Andrew L
AL
Gundlach
D000818:Animals; D003345:Corticosterone / Q000097:blood*; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism*; D005260:Female; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism; D007031:Hypothalamus / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism; D010286:Paraventricular Hypothalamic Nucleus / Q000378:metabolism*; D010913:Pituitary-Adrenal System / Q000378:metabolism; D017729:Presynaptic Terminals / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000172:deficiency*; D015398:Signal Transduction / Q000502:physiology
D043562:Receptors, G-Protein-Coupled; C505050:SALPR protein, mouse; D003346:Corticotropin-Releasing Hormone; D003345:Corticosterone
Corticotropin-releasing hormone (factor); Glutamatergic afferents; HPA axis; Relaxin-3; Stress; Transgenic mice