The MAGEL2 gene appears as one of the main genes involved in feeding and behavioral (autistic like behavior) alterations observed in Prader-Willi Syndrome. We showed that, in mouse, the deficiency of Magel2 results in a phenotype similar to the clinical description of patients with mutations in MAGEL2. Indeed, we showed that Magel2-deficient mice display a deficiency of oxytocin at birth and are a pertinent model for Prader-Willi Syndrome, mimicking a disturbance in early feeding, with poor sucking activity, and later on in adulthood showing alterations in social behavior and learning abilities. Importantly, an administration of oxytocin in Magel2-deficient pups at birth restores a normal sucking activity and normalizes the social behavior and learning abilities in adulthood.
Our results suggest that, in Magel2 deficient mice, an administration of oxytocin in a critical period of post-natal development allows altered behavior to be corrected, even though a transient and partial rescue can follow an acute administration at any developmental stage. This concept opens the door to a powerful pharmacological therapy for the PWS and might be considered for other pathologies such as autism spectrum disorders. However, the relationship between the inactivation of Magel2 and the alteration of the oxytocin system is not yet elucidated and needs further investigation. Furthermore we do not know how an administration of exogenous oxytocin acts during brain development to allow a long term effect in Magel2-KO mice. A better knowledge of these two last points is required to establish adapted therapeutic protocols. With this in mind, this project will reveal the consequences of Magel2 inactivation in oxytocin neurons only.
Research Outcomes: Project Summary
We have, in our laboratory, new Magel2 mouse models that are relevant to study the Schaaf-Yang Syndrome. As observed in rodent models presenting ASD-like symptoms, the excitation/inhibition (E/I) balance is altered in hippocampal pyramidal neurons of Magel2-KO mice, as shown in acute brain slices and in mass cultures of hippocampus: the increase of GABAergic activity has a presynaptic origin while the reduction of glutamatergic activity has a postsynaptic cause. Both pre-and post-synaptic components suggest that the lack of Magel2 causes the E/I imbalance by two different mechanisms. Hippocampal cultures from Magel2-/- mice show also an E/I imbalance with a decrease of the densities of inhibitory synapses which is reverted following a treatment with TGOT (an oxytocin-receptor agonist). Preliminary data suggest that one cause of the E/I imbalance might be the delay of the developmental "GABA-shift" as it has been reported in other ASD-like rodent models and in oxytocin-receptor KO mice. We are now investigating more animals to confirm or not these results. The lack of Magel2 causes an alteration in the expression of genes involved in the regulation of the "OT-system" and an oxytocin treatment changes in a lasting way the level of expression of those genes. Oxytocin treatment might have a therapeutical effect via an action on gene expression.
Research Outcomes: Publications
Wired for eating: how is an active feeding circuitry established in the postnatal brain? Muscatelli F, Bouret SGC. Current Opinion in Neurobiology. Volume 52: 165-171, 2018.
Francoise Muscatelli, Ph.D.
$75,000; Funded in collaboration with Prader-Willi France
Mediterranean Institute of Neurobiology, INMED, France