Translational investigation of oxytocinergic signaling in Prader-Willi and Schaaf-Yang syndromes

• Applicant: Ferdinand Althammer, Ph.D.
• Subject Area: Human Genetics
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 519115453

The progress of research on rare diseases such as Prader-Willi syndrome (PWS, OMIM #176270) or Schaaf-Yang syndrome (SYS, OMIM #615547) has remarkably increased our understanding of the genetic causes, etiology and pathophysiology of disease. Its impact goes well beyond the affected individuals and their families, because the respective scientific discoveries reveal underlying mechanisms that are often highly relevant to a more general understanding of biology, pathophysiology, and the entire scientific community. PWS is characterized by infantile hypotonia, weight gain and overeating during childhood, as well as developmental delay and intellectual disability, while SYS has several overlapping features with PWS and was thus initially considered to be a PWS-like syndrome. To study gene-related behavioral deficits, different transgenic Magel2 knockout (KO) mouse lines have been generated. Magel2ko mice display unique behavioral patterns, including reduced levels of anxiety, lack of social discrimination (lacZ knock-in model, Magel2tm1.Stw mouse), as well as altered exploration behavior and social interaction (LoxP-hygro-LoxP model, Magel2tm1.1Mus mouse). Intriguingly, some of the deficits in social recognition and learning abilities in Magel2ko mice could be rescued by daily administration of the neuropeptide oxytocin (OT). Many of the observed behavioral abnormalities in Magel2ko mice are very similar to those described in oxytocin receptor-deficient (OTR-KO) mice. One study investigated the effect of intranasal OT administration in infants with PWS and reported normalization of suckling in 88% of infants, which provides crucial evidence that a dysfunctional OT system underlies many of the observed symptoms in children with PWS. However, to this date, no detailed study investigating the physiological, molecular or morphological changes in OT neurons in PWS/SYS has been conducted. Thus, understanding the precise underlying mechanisms of dysregulated OT signaling in PWS/SYS is pivotal for the development of novel therapeutic strategies. The overarching goal of this proposal is to identify the genetic, molecular and physiological alterations in the oxytocin system in Prader-Willi and Schaaf-Yang syndromes using cell culture and rodent models of Prader-Willi and Schaaf-Yang syndromes, as well as post-mortem patient brain samples.

• DFG Programme: Independent Junior Research Groups