P3.30. RELAXIN-3 AND OXYTOCIN SIGNALING IN THE VENTRAL DENTATE GYRUS: DIVERGENT NEUROMODULATORY ROLES IN STRESS- AND ANXIETY-RELATED CIRCUITS
Aleksandra Trenk1, Kinga Przybylska1,2, Anna Gugula1, Gabriela Stopka1,2, Aleksandra Nogaj1,2, Filip Danielkis1, Camila de Ávila3, Mohammed Akhter Hossain4, Anthony J. Intorcia5, Geidy E. Serrano5, Thomas G. Beach5, Diego F. Mastroeni3, Andrew L. Gundlach4, Anna Blasiak5
1 Department of Neurophysiology and Chronobiology, Institute of Zoology and Biomedical Research, Faculty of Biology, Jagiellonian University, Krakow, Poland
2 Doctoral School of Exact and Natural Sciences, Jagiellonian University, Kraków, Poland
3 ASU-Banner Neurodegenerative Disease Research Center, Biodesign Institute, and School of Life Sciences, Tempe, Arizona, USA
4 The Florey Institute of Neuroscience and Mental Health, and Florey Department of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, Australia
5 Neuropathology Laboratory, Banner Sun Health Research Institute, Sun City, Arizona, USA
INTRODUCTION: Oxytocin (OXT) and relaxin-3 (RLN3) are neuropeptides that exert largely opposing effects on neuronal circuits controlling social, stress, and anxiety-related behaviors. OXT enhances social bonding and attenuates stress, whereas RLN3 promotes anxiety and social avoidance. However, how these signaling systems interact, particularly within the ventral dentate gyrus (vDG) of the hippocampus, an area highly involved in the control of social memory and interactions, remains poorly understood.
AIM(S): We aimed to elucidate the functional interaction between OXT and RLN3 and their receptors (OXTR and RXFP3, respectively) systems.
METHOD(S): We combined anatomical, molecular, and electrophysiological approaches in rats, alongside complementary anatomical studies in the human hippocampus.
RESULTS: Multiplex in situ hybridization in both rat and human DG revealed moderate co-expression of OXTR and RXFP3 mRNAs within vGAT1-positive neurons. Interestingly, immunohistochemistry staining results showed dense RLN3-containing fibers, but a lack of OXT-expressing fibers innervating rat vDG. Multielectrode array recordings showed that OXT caused an increase in neuronal firing, whereas RLN3 suppressed it; when applied together, each peptide’s effect was significantly attenuated. Pharmacological experiments using selective OXT and RLN3 receptors agonists (TGOT for OXTR, A2 for RXFP3) demonstrated that blockade of KCNQ channels with XE991 reduced both OXTR- and RXFP3-mediated responses. Consistent with this, HiPlex in situ hybridization confirmed co-expression of RXFP3, OXTR, and KCNQ2 mRNAs in individual rat vDG neurons.
CONCLUSIONS: Together, these results identify the vDG as a critical hub where OXT and RLN3 exert antagonistic effects via KCNQ channels to shape neuronal excitability and, ultimately, stress, anxiety, and social behaviors. The conservation of OXTR and RXFP3 co-expression patterns in human DG underscores the translational relevance of these findings.
FINANCIAL SUPPORT: National Science Centre Poland: UMO-2023/49/B/NZ4/01885; MiniGrant 2023 ID.UJ; Bright Focus Foundation – A2021006; Alzheimer’s Association – AARFD-22-972099