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.
Highlights
The nonapeptide oxytocin (OT) and its signaling pathway, the OTsystem, are important regulators in the development of the social brain, suggesting that OT plays a role in both childhood and adult neuropsychiatric disorders characterized by social cognition impairment [1]
Taking into account the developmental and dynamic expression of oxytocin receptor (Oxtr) [31, 32], we looked at the expression of Magel2 and Oxtr transcripts in the anterior hippocampus at P7 and P28, using RNAscope technique
At P7, we detected Oxtr and Magel2 mRNAs in the aCA2/CA3d region with Magel2 more expressed in the deep layer of the stratum pyramidale (Fig. 1A)
Summary
The nonapeptide oxytocin (OT) and its signaling pathway, the OTsystem, are important regulators in the development of the social brain, suggesting that OT plays a role in both childhood and adult neuropsychiatric disorders characterized by social cognition impairment [1]. MAGEL2 is a gene that is involved in Prader–Willi (PWS) [11] and Schaaf-Yang (SYS) syndromes [12] and is classified as one of the highest relevant gene to ASD risk (SFARI gene scoring), 75–80% of SYS patients meet the formal clinical diagnostic criteria of ASD [13, 14]. Both of these genetic neurodevelopmental disorders have in common autistic features with alterations in social behavior and deficits in cognition that persist over the lifespan [15]. The mechanisms by which OTtreatment in infancy exerts its long-lasting beneficial effects, remain mysterious
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