Never too early. Alterations in social interactions are a hallmark of austism spectrum disorders and research has pointed for probable cause the defects in neuronal circuits made by oxytocin neurons. The authors had previously shown that daily administration of oxytocin (OT) in neonates improved the social life of the Prader-Willi Syndrome mouse, a model of autism, well into adulthood. Here, they investigate the mechanisms and find that the treatment normalizes the development of the somatostatin-inhibitory circuit, a target of OT-neurons, and it normalizes a key actor in the maturation of GABAergic synaptic transmission, the chloride transporter KCC2. Their results call for testing OT-treatments in infancy to improve the life of persons with autism.  (I. Bureau)

Authors: Bertoni, Schaller, Tyzio, Gaillard, Santini, Xolin, Diabira, Vaidyanathan, Matarazzo, Medina, Hammock, Zhang, Chini, Gaiarsa and Muscatelli

Scientific abstract: Oxytocin is an important regulator of the social brain. In some animal models of autism, notably in Magel2tm1.1Mus-deficient mice, peripheral administration of oxytocin in infancy improves social behaviors until adulthood. However, neither the mechanisms responsible for social deficits nor the mechanisms by which such oxytocin administration has long-term effects are known. Here, we aimed to clarify these oxytocin-dependent mechanisms, focusing on social memory performance. Using in situ hybridization (RNAscope), we have established that Magel2 and oxytocin receptor are co-expressed in the dentate gyrus and CA2/CA3 hippocampal regions involved in the circuitry underlying social memory. Then, we have shown that Magel2tm1.1Mus-deficient mice, evaluated in a three- chamber test, present a deficit in social memory. Next, in hippocampus, we conducted neuroanatomical and functional studies using immunostaining, oxytocin-binding experiments, ex vivo electrophysiological recordings, calcium imaging and biochemical studies. We demonstrated: an increase of the GABAergic activity of CA3-pyramidal cells associated with an increase in the quantity of oxytocin receptors and of somatostatin interneurons in both DG and CA2/CA3 regions. We also revealed a delay in the GABAergic development sequence in Magel2tm1.1Mus-deficient pups, linked to phosphorylation modifications of KCC2. Above all, we demonstrated the positive effects of subcutaneous administration of oxytocin in the mutant neonates, restoring hippocampal alterations and social memory at adulthood. Although clinical trials are debated, this study highlights the mechanisms by which peripheral oxytocin administration in neonates impacts the brain and demonstrates the therapeutic value of oxytocin to treat infants with autism spectrum disorders.

Published in Molecular Psychatry, 2021