Oxytocin administration in neonates shapes the hippocampal circuitry and restores social behavior in a mouse model of autism

Abstract

Several studies on rodent models with an Autism Spectrum Disorders-like (ASD) phenotype, notably Magel2-deficient mice, have shown a rescue of deficits in adult social behavior after neonatal administration of oxytocin. However, the neurobiological alterations responsible for the social deficits and the mechanism by which oxytocin-administration in infancy has a rescue effect in adulthood remain unclear.Here we show that Magel2-deficient adult mice exhibit a deficit in social memory that is corrected by neonatal oxytocin administration. We studied hippocampal regions known to be associated with social memory engrams involving the OT-system. At critical stages of development, we characterized cellular, physiological and biochemical alterations of these hippocampal regions in Magel2-deficient mice, alterations present in several ASD models. Overall we demonstrate a strong impact of oxytocin-administration at key stages of postnatal hippocampal neurodevelopment, shedding light on the role for oxytocin in treating neurodevelopmental disorders characterized by deficits in social memory.

The impact of oxytocin on neurite outgrowth and synaptic proteins in Magel2‐deficient mice

“…In line with that, we previously observed an increase of GABAergic activity in Magel2-deficient hippocampal neurons (Bertoni et al, 2020). Indeed, it appears that Magel2 deficiency is associated with GABAergic and glutamatergic alterations.…”

“…Although in this study, we did not stain OXTRs in primary cultures of hippocampal neurons, it appears that, in vivo, during development OXTRs are expressed in pyramidal neurons and notably in inhibitory interneurons in hippocampal regions. Using RNAscope technology, we detected that Oxtr transcripts were more concentrated in the CA2 region (Bertoni et al, 2020). Moreover, the public Allen brain RNAseq data from mouse cortex and hippocampal samples (http://cellt ypes.brain -map.org/rnase q/mouse/ corte x-and-hippo campus) define the GABAergic interneuron types expressing Magel2 and Oxtr.…”

“…A second limitation is that we cannot directly associate the action of oxytocin in immature hippocampal neurons with the presence of OXTRs, as far we have not stained them. We rely on the fact that OXTRs are expressed in the hippocampal excitatory pyramidal neurons and inhibitory interneurons as proved by our own (Bertoni et al, 2020) and other studies (Raam et al, 2017;Lin et al, 2018;Meira et al, 2018;Young & Song, 2020). A third limitation is the extent of the transport of oxytocin across the blood − brain barrier.…”

“…More specifically, in Magel2-deficient mice, we revealed cellular, physiological and biochemical alterations of hippocampal regions, which are known to be associated with social memory engrams involving the OT-system; those alterations are corrected following the perinatal administration of OT (Bertoni et al, 2020).…”

“…To date, two mouse models deficient for Magel2 have been established (Kozlov et al, 2007;Schaller et al, 2010) and show an impairment of social behavior and cognition at adulthood (Fountain et al, 2017;Meziane et al, 2015). In one of these models, the neonatal treatment of Magel2 tm1.1Mus mice with OT has been sufficient for the prevention of social and learning deficits in adulthood, in particular social memory (Bertoni et al, 2020;Meziane et al, 2015;Schaller et al, 2010).…”