Central relaxin-3 receptor (RXFP3) activation reduces elevated, but not basal, anxiety-like behaviour in C57BL/6J mice

Zhang, Cary; Chua, Berenice E.; Yang, Annie; Shabanpoor, Fazel; Hossain, Mohammed Akhter; Wade, John D.; Rosengren, K. Johan; Smith, Craig; Gundlach, Andrew L.

doi:10.1016/j.bbr.2015.06.010

Cited by 45 publications

(34 citation statements)

References 72 publications

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“…This, in turn, could produce impaired learning and memory, via effects within the directly targeted hippocampus and via remote, relayed effects in the MS/DB. Further studies are required to explore this hypothesis, including an examination of the effect of RXFP3 activation by validated RXFP3‐specific agonist peptides (Liu et al, ; Shabanpoor et al, ; Zhang et al, ) on DG hilus SST neuron activity, perhaps in a strain of SST reporter mice (Ma et al, ; Peng et al, ).…”

Section: Discussionmentioning

confidence: 99%

“…However, the viral injections in the present study did not cover the entire dorsoventral extent of the DG hilus in ventral hippocampus, reducing the likelihood of observing an effect on anxiety‐like behavior. The RLN3/RXFP3 system in mice and rats has been shown to be involved in stress responses (Tanaka et al, ; Banerjee et al, ) and modulation of anxiety‐like behavior (Ryan et al, ; Zhang et al, ), with pronounced changes in RLN3 mRNA expression and RLN3‐IR levels in response to stressors (Tanaka et al, ; Lenglos et al, ; Ma et al, ; Walker et al, ; Calvez et al, ). Therefore, further studies with more extensive and/or focused depletion of RXFP3 in ventral hippocampus are warranted.…”

Section: Discussionmentioning

confidence: 99%

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Relaxin‐3 inputs target hippocampal interneurons and deletion of hilar relaxin‐3 receptors in “floxed‐RXFP3” mice impairs spatial memory

et al. 2017

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Hippocampus is innervated by γ-aminobutyric acid (GABA) "projection" neurons of the nucleus incertus (NI), including a population expressing the neuropeptide, relaxin-3 (RLN3). In studies aimed at gaining an understanding of the role of RLN3 signaling in hippocampus via its G -protein-coupled receptor, RXFP3, we examined the distribution of RLN3-immunoreactive nerve fibres and RXFP3 mRNA-positive neurons in relation to hippocampal GABA neuron populations. RLN3-positive elements were detected in close-apposition with a substantial population of somatostatin (SST)- and GABA-immunoreactive neurons, and a smaller population of parvalbumin- and calretinin-immunoreactive neurons in different hippocampal areas, consistent with the relative distribution patterns of RXFP3 mRNA and these marker transcripts. In light of the functional importance of the dentate gyrus (DG) hilus in learning and memory, and our anatomical data, we examined the possible influence of RLN3/RXFP3 signaling in this region on spatial memory. Using viral-based Cre/LoxP recombination methods and adult mice with a floxed Rxfp3 gene, we deleted Rxfp3 from DG hilar neurons and assessed spatial memory performance and affective behaviors. Following infusions of an AAV -Cre-IRES-eGFP vector, Cre expression was observed in DG hilar neurons, including SST-positive cells, and in situ hybridization histochemistry for RXFP3 mRNA confirmed receptor depletion relative to levels in floxed-RXFP3 mice infused with an AAV -eGFP (control) vector. RXFP3 depletion within the DG hilus impaired spatial reference memory in an appetitive T-maze task reflected by a reduced percentage of correct choices and increased time to meet criteria, relative to control. In a continuous spontaneous alternation Y-maze task, RXFP3-depleted mice made fewer alternations in the first minute, suggesting impairment of spatial working memory. However, RXFP3-depleted and control mice displayed similar locomotor activity, anxiety-like behavior in light/dark box and elevated-plus maze tests, and learning and long-term memory retention in the Morris water maze. These data indicate endogenous RLN3/RXFP3 signaling can modulate hippocampal-dependent spatial reference and working memory via effects on SST interneurons, and further our knowledge of hippocampal cognitive processing. © 2017 Wiley Periodicals, Inc.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Relaxin‐3 inputs target hippocampal interneurons and deletion of hilar relaxin‐3 receptors in “floxed‐RXFP3” mice impairs spatial memory

et al. 2017

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“…Our future goals are to identify the source of these glutamatergic inputs and to determine if pharmacological RXFP3 activation can attenuate HPA axis activity via these inputs in vivo. Additionally, recent studies indicate that it would be of interest to determine whether RXFP3 modulation is able to influence the HPA axis via direct or indirect mechanisms under different in vivo conditions, such as after a chronic stress protocol (Walker et al 2015;Zhang et al 2015), to further explore the plasticity and capability of RXFP3 signalling beyond basal conditions. Psychopharmacology…”

Section: Discussionmentioning

confidence: 99%

“…Injections (1 μL) were made via an injector protruding beyond the guide cannulae into the target area as described above. Doses and timing of experiments were based on studies using the same peptide in rats and mice (Ryan et al 2013a;Smith et al 2014a;Zhang et al 2015).…”

Section: Peptide Injectionsmentioning

confidence: 99%

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

et al. 2017

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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/6J) 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.

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“…NI neurons expressing relaxin-3 are highly responsive to stress signals (Tanaka et al, 2005), whereas relaxin-3 projections into the septohippocampal system/pathway modulates memory (Ma et al, 2009). Stimulating the relaxin-3 signaling system is beneficial for reducing anxiety-like behavior (Zhang et al, 2015a). RXFP3 is expressed in neurons in the paraventricular region of the hypothalamus (Liu et al, 2003;Ma et al, 2007;Smith et al, 2010), and stimulation of these neurons with relaxin-3 agonists or antagonists regulates appetite in rodent models.…”

Section: Introductionmentioning

confidence: 99%

Development of Relaxin-3 Agonists and Antagonists Based on Grafted Disulfide-Stabilized Scaffolds

et al. 2020

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Relaxin-3 is a neuropeptide with important roles in metabolism, arousal, learning and memory. Its cognate receptor is the relaxin family peptide-3 (RXFP3) receptor. Relaxin-3 agonist and antagonist analogs have been shown to be able to modulate food intake in rodent models. The relaxin-3 B-chain is sufficient for receptor interactions, however, in the absence of a structural support, linear relaxin-3 B-chain analogs are rapidly degraded and thus unsuitable as drug leads. In this study, two different disulfide-stabilized scaffolds were used for grafting of important relaxin-3 B-chain residues to improve structure and stability. The use of both Veronica hederifolia Trypsin inhibitor (VhTI) and apamin grafting resulted in agonist and antagonist analogs with improved helicity. VhTI grafted peptides showed poor binding and low potency at RXFP3, on the other hand, apamin variants retained significant activity. These variants also showed improved half-life in serum from ∼5 min to >6 h, and thus are promising RXFP3 specific pharmacological tools and drug leads for neuropharmacological diseases.

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Central relaxin-3 receptor (RXFP3) activation reduces elevated, but not basal, anxiety-like behaviour in C57BL/6J mice

Abstract: Overall, these data suggest exogenous RXFP3 agonists can reduce elevated (FG-7142-induced) levels of anxiety in mice; data important for gauging how conserved such effects are, with a view to modelling human pathophysiology and the likely therapeutic potential of RXFP3-targeted drugs.

Cited by 45 publications

References 72 publications

Relaxin‐3 inputs target hippocampal interneurons and deletion of hilar relaxin‐3 receptors in “floxed‐RXFP3” mice impairs spatial memory

Relaxin‐3 inputs target hippocampal interneurons and deletion of hilar relaxin‐3 receptors in “floxed‐RXFP3” mice impairs spatial memory

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

Development of Relaxin-3 Agonists and Antagonists Based on Grafted Disulfide-Stabilized Scaffolds

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