Postnatal development of the brain oxytocin system and Prader-Willi syndrome. – PRADOX

Oxytocin (OT) is widely accepted as a prosocial neuropeptide essential to maternal bonding and later on in social interactions. Prader-Willi Syndrome (PWS) is a neurodevelopmental genetic disease and the MAGEL2 gene is the main gene involved in the early feeding behavioral deficit and autistic like symptoms described in PWS. Studying this rare disease opens new research avenues to study the physiopathology of feeding and social behavioral disorders that are observed in many pathologies. Indeed, we created a mouse model deficient for Magel2 and demonstrated that it is a pertinent model for PWS, showing a phenotype similar to the patients with MAGEL2 mutations. We revealed an alteration of central oxytocin* (OT) and demonstrated that an acute injection of OT in these mice just after birth restores a normal suckling activity and prevents the deficits of social behavior and learning abilities in adulthood. However, the mechanisms by which an early developmental alteration of the OT system** leads to early feeding and social impairments are not yet elucidated. Furthermore we do not know how an injection of exogenous OT in early infancy acts during brain development to allow a long term therapeutical effect in the mutant adult mice. This mouse model (Magel2-KO) is particularly well adapted for understanding the alterations of the OT system and for designing therapeutic strategies. Therefore, the aim of this proposal is to elucidate the role of OT and its receptor in the pathogenesis of PWS and to develop appropriate approaches for treating this disease in human infants. To study the pathophysiological role of OT in postnatal ontogenesis we will study Magel2-deficient mice to identify alterations in structural connections of OT system, OT neuron properties and in the quantity and distribution of mature OT and OT receptors into the brain. For translational aspects we will use different timing and ways of OT administration to monitor strength and duration of OT effects on the restoration of suckling in newborns and social interactions and cognition in adults.
PRADOX will be achieved using newly created and available genetically engineered mice combined with new methodological approaches. The project will unite three teams with complementary experience: F. Muscatelli’s team is an international expert of mouse models for PWS; M. Desarmenien’s team has a strong background in the oxytocin/vasopressin pharmacology and in the development of OT neurons and D. Lafitte’s team has developed biophysical peptide dosage technology, in particular on brain slices.
Recently, the organization of the central OT-network of adult mice has been partly described, however maturation of this central OT system throughout post-natal development has been poorly investigated and is a prerequisite for this project and for any project aiming to understand the role of OT in neuropathology. It is expected that understanding the mechanisms underlying the action of OT, from birth until adulthood, will allow the role of ot in establishing early feeding behavior and social interactions to be pin pointed. It is also essential to know how and when the central OT system dysfunctions in the Magel2-KO mouse model in order to provide the data for designing and evaluating the most adapted therapeutical protocols in babies with PWS. PRADOX aims to demonstrate that OT plays a crucial role in setting feeding and social behaviors during a critical period just after birth. We also propose that a deficit in feeding behavior in early postnatal development might be considered as an early indicator of autistic-like symptoms. This concept opens the door to a powerful pharmacological therapy in early infancy for the treatment of PWS and might be considered for other pathologies such as autism spectrum disorders.

*Central oxytocin: referred to OT produced and released into the brain. **Oxytocin system: is defined here as the OT-neurons, their targeted neurons and the OT receptors.