Oxytocin Effects in Neurodevelopment in an Experimental Model

Abstract

Oxytocin, a known neuropeptide produced in the hypothalamus, has been extensively studied for its neuromodulatory effects in the brain. However, its impact on brain development remains poorly understood. Oxytocin contributes to the regulation of social behavior and social interactions, which are significantly influenced by the structure and activity of dopaminergic brain regions [1], which are involved in numerous physiological processes such as reward, cognition, etc. Hence, changes in the development of dopaminergic brain areas can be associated with social deficits and etiology of neurodevelopmental disorders, such as those seen in the autistic phenotype. Research suggests that one of the factors contributing to the development of Autistic Spectrum Disorder (ASD) is the involvement of various genetic variations. Many have effect on genes encoding synaptic proteins critical for brain circuit development and function, such as SHANK proteins. These are one of the factors influencing molecular neuronal composition due to their scaffolding (“linking”) properties which involve regulation of cytoskeletal organization, the growth of neurites, and dendritic spines. As it is currently unknown whether oxytocin can affect the morphology of dopaminergic neurons and neuritogenesis in cells with downregulated SHANK3 protein, studying properties of neurons in these cells could provide new insights into cytoskeleton's role in neurodevelopmental disorders, including autism. Consequently, evidence suggests that synaptic dysfunction could serve as a shared underlying mechanism for a specific subset of ASDs [3].

Therefore, the aim of this work is to examine the effect of oxytocin on the outcomes of transient silencing of the SHANK3 gene in primary dopaminergic neuronal cell cultures. Cells were harvested from neonatal rats on the day of birth. Specifically, the study focuses on 1) neurite arborization and length, and 2) the intensity of fluorescence signals of selected synaptic parameters. This will be achieved by analyzing images of neurons obtained from histological samples using fluorescence microscopy. The main hypothesis is that oxytocin would elongate neurites, increase their number, and simultaneously enhance the intensity of the observed signals, thereby compensating for the deficits caused by SHANK3 downregulation.

Structural changes observed in vitro may be significant for brain tissue remodeling in vivo and for alterations in social behavior. Particularly during specific postnatal developmental stages of the brain, variations in oxytocin levels and their interaction with genetic deficits could be crucial for either the development or prevention of autism.

References

[1] Bakos, J., Srancikova, A., Havranek, T., & Bacova, Z. (2018). Molecular Mechanisms of Oxytocin Signaling at the Synaptic Connection. Neural plasticity, 2018, 4864107. https://doi.org/10.1155/2018/4864107

[2] Havranek, T., Bacova, Z., & Bakos, J. (2024). Oxytocin, GABA, and dopamine interplay in autism. Endocrine Regulations, 58(1), 105–114. https://doi.org/10.2478/enr-2024-0012

[3] Mihalj, D., Borbelyova, V., Pirnik, Z., Bacova, Z., Ostatnikova, D., & Bakos, J. (2024). Shank3 Deficiency Results in a Reduction in GABAergic Postsynaptic Puncta in the Olfactory Brain Areas. Neurochemical research, 49(4), 1008–1016. https://doi.org/10.1007/s11064-023-04097-2