Oxytocin-based therapies for treatment of Prader-Willi and Schaaf-Yang syndromes: evidence, disappointments, and future research strategies

Abstract

The prosocial neuropeptide oxytocin is being developed as a potential treatment for various neuropsychiatric disorders including autism spectrum disorder (ASD). Early studies using intranasal oxytocin in patients with ASD yielded encouraging results and for some time, scientists and affected families placed high hopes on the use of intranasal oxytocin for behavioral therapy in ASD. However, a recent Phase III trial obtained negative results using intranasal oxytocin for the treatment of behavioral symptoms in children with ASD. Given the frequently observed autism-like behavioral phenotypes in Prader-Willi and Schaaf-Yang syndromes, it is unclear whether oxytocin treatment represents a viable option to treat behavioral symptoms in these diseases. Here we review the latest findings on intranasal OT treatment, Prader-Willi and Schaaf-Yang syndromes, and propose novel research strategies for tailored oxytocin-based therapies for affected individuals. Finally, we propose the critical period theory, which could explain why oxytocin-based treatment seems to be most efficient in infants, but not adolescents.

Analysis of the hypothalamic oxytocin system and oxytocin receptor-expressing astrocytes in a mouse model of Prader-Willi syndrome

“…While the cause for the reduction in OT cells in the caudal part of the PVN remains unclear, it seems possible that Magel2 tm1.Stw mice send fewer axons to hindbrain areas such as the dorsal vagal complex or nucleus tractus solitarii, in which OT plays an important role in mediating the satiety effect (11). It is important to note however that while the vast majority of PWS patients develops hyperphagia and obesity, deletion of Magel2 in Magel2 tm1.Stw mice does not reliably cause morbid obesity (8,9), potentially indicating a contribution of other genes within the PWS locus such as SNORD116 (2). Future studies are clearly needed to investigate the consequence of reduction of OT neurons in the caudal PVN and whether other cell types such as preautonomic vasopressin neurons (58) or corticotropin-releasing hormone neurons (59) are also affected.…”

“…It is important to note however that while the vast majority of PWS patients develops hyperphagia and obesity, deletion of Magel2 in Magel2 tm1 . Stw mice does not reliably cause morbid obesity (8, 9), potentially indicating a contribution of other genes within the PWS locus such as SNORD116 (2). Future studies are clearly needed to investigate the consequence of reduction of OT neurons in the caudal PVN and whether other cell types such as preautonomic vasopressin neurons (58) or corticotropin-releasing hormone neurons (59) are also affected.…”

“…Magel2 KO mice display unique behavioral patterns, including reduced levels of anxiety, lack of social discrimination (Magel2 tm1Stw mouse) (5), as well as altered exploration behavior and social interaction (Magel2 tm1.1Mus mouse) (6,7), while hyperphagia seems to be less common (8,9). The main difference between these two genetically engineered mice lines lies in the alteration of the Magel2 gene sequence (2). In the Magel2 tm1.1Mus mouse, no transcript is produced due to deletion of the gene by homologous recombination.…”

“…Prader-Willi syndrome (PWS) is characterized by infantile hypotonia, weight gain and overeating during childhood, as well as developmental delay and intellectual disability (1). Individuals with PWS lack the paternal copy of the protein-coding gene MAGEL2 , albeit other relevant genes in the PWS gene locus such as SNORD116 or NECDIN are typically also affected in PWS (2). Truncating point mutations of paternal MAGEL2 cause a neurodevelopmental disorder that is molecularly and clinically related to PWS, i.e.…”

“…1Mus mouse) (6, 7), while hyperphagia seems to be less common (8, 9). The main difference between these two genetically engineered mice lines lies in the alteration of the Magel2 gene sequence (2). In the Magel2 tm1 .…”