Oxytocin Variants Induce Cellular Signaling and Neurite Outgrowth in Human-Derived Neuron-like SH-SY5Y Cell Line

In the central nervous system, the neuropeptide oxytocin stimulates neural networks that regulate social behaviors, including social attachment, aggression, and complex social cognition. Perturbations in oxytocin and/or oxytocin receptor expression results in social behavioral deficits and are associated with a number of psychopathologies including autism spectrum disorder, schizophrenia, anxiety, and depression. In rodent models of autism spectrum disorder, oxytocin is effective at improving social behavior. However, limited translatability between animal models and human physiology has hindered successful translation of these findings into human therapeutics. Oxytocin variant-induced cellular signaling pathways and G-protein coupling have largely been investigated in HEK and CHO heterologous expression systems; however, cellular context is crucial, and these profiles likely differ from intact neurons. This project assessed oxytocin variants in in vitro human-derived neuron-like SH-SY5Y cells that endogenously express the oxytocin receptor. Results demonstrated that the naturally occurring oxytocin variants Leu⁸-OT, Pro⁸-OT and Val³-Pro⁸-OT activated intracellular signaling pathways and promoted neuronal differentiation-associated responses, including calcium mobilization, membrane hyperpolarization, and neurite outgrowth in a concentration-dependent manner. Knowledge of how oxytocin variants alter cellular structure and function has the potential to both identify mechanisms that produce social dysfunction and to inform the development of therapeutic agents.