The role of oxytocin receptor-expressing astrocytes in Schaaf-Yang syndrome and Prader-Willi syndrome

Funding Summary

Prader-Willi (PWS) and Schaaf-Yang syndromes (SYS) are disorders that are both caused by alterations of the MAGEL2 gene, which is either completely missing (PWS) or non-functional (SYS). Working with PWS and SYS mouse models, Dr. Schaaf will investigate the function of a brain ‘support cell’ (astrocytes), which have recently been found to be activated by oxytocin. They will analyze the 3D structure and function of these astrocytes and will investigate how they modulate neuronal activity in different brain regions, in the typical situation and when MAGEL2 is deficient. This approach could yield important information about how changes in astrocyte function in PWS and SYS may lead to cognitive and/or social manifestations in both disorders.

Dr. Theresa Strong, Director of Research Programs, shares details on this project in this short video clip.

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Lay Abstract

Prader-Willi (PWS) and Schaaf-Yang syndromes (SYS) are diseases that are both caused by alterations affecting the gene MAGEL2, which is either completely missing or non-functional. Individuals suffering from PWS or SYS display unique behavioral traits, including learning disabilities and altered social behavior.

To be able to better study these two diseases, genetically modified mouse models have been created that manifest behavioral patterns replicating the social deficits of PWS and SYS. Working with these mouse models, researchers found that the lack or dysfunction of the Magel2 gene results in changes to neurons producing the oxytocin hormone. Intriguingly, oxytocin administration appears to ameliorate several of the symptoms associated with PWS and SYS. This proposal aims to investigate the effect of oxytocin on star-shaped cells within the brain called astrocytes, which have recently been found to be activated by oxytocin.

We will analyze the three-dimensional structure and function of these astrocytes to better understand their role in PWS and SYS and will investigate how these astrocytes modulate neuronal activity in different brain regions. This approach is entirely novel and could yield important information about how a previously ignored cell type in the brain plays a critical role in brain dysfunction, leading to cognitive and/or social manifestations in these two diseases.

Research Outcomes: Public Summary

Prader-Willi syndrome (PWS) is a complex genetic disorder that affects individuals from birth and impacts various aspects of their lives. Researchers have been diligently investigating the underlying mechanisms of PWS to shed light on potential therapeutic strategies. In this study, we focused on the neuropeptide oxytocin that plays a crucial role in social behavior, bonding, and reproductive processes. We aimed to understand the involvement of oxytocin signaling in a specific type of brain cells, called astrocytes, in PWS using a mouse model. To achieve this, we focused on a particular protein receptor expressed by astrocytes, known as the oxytocin receptor. By employing a technique called RNAScope in situ hybridization, which allows visualization of mRNA within cells, we compared healthy mice with a specific genetic mutation called Magel2 KO mice, which exhibit characteristics similar to PWS. Excitingly, the study revealed significant differences between the magel2 KO mice and their healthy counterparts in various brain regions associated with social behavior. This suggests that the absence of the Magel2 protein affects the functioning of astrocytes and, consequently, social behaviors in individuals with PWS. Moreover, we also observed sex-specific differences, implying that oxytocin signaling in astrocytes may play a vital role during lactation or childbirth in female mice. These findings provide valuable insights into the intricate interactions between astrocytes, oxytocin, and the underlying mechanisms of PWS. By unraveling the role of astrocytes and oxytocin in PWS, this study brings us closer to understanding the complexities of this syndrome. These findings not only enhance our knowledge of PWS but also open up new avenues for potential therapeutic interventions. Studying oxytocin signaling in astrocytes is an entirely new research avenue in PWS research and with continued research in this direction, scientists may uncover novel strategies to improve the lives of individuals living with PWS and their families, offering hope for a brighter future.

Research Outcomes: Publications

Analysis of the hypothalamic oxytocin system and oxytocin receptor-expressing astrocytes in a mouse model of Prader–Willi syndrome. Althammer F, Wimmer MC, Krabichler Q, Küppers S, Schimmer J, Fröhlich H, Dötsch L, Gruber T, Wunsch S, Schubert T, Kirchner MK, Stern JE, Charlet A, Grinevich V, Schaaf CP. Journal of Neuroendocrinology (2022): https://doi.org/10.1111/jne.13217.