Oxytocin (OXT) signaling through the OXT receptor plays a significant role in a variety of physiological processes throughout the lifespan. OXT's effects depend on the tissue distribution of the receptor. This tissue specificity is dynamic and changes across development, and also varies with sex, experience, and species. The purpose of this review is to highlight these themes with examples from several life stages and several species. Important knowledge gaps will also be emphasized. Understanding the effective sites of action for OXT via its receptor will help refine hypotheses about the roles of this important neuropeptide in the experience-dependent development and expression of species-typical social behavior. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 77: 143-157, 2017.
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.
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.
Huntington's disease (HD), an autosomal dominant neurodegenerative syndrome, has a world-wide distribution. An estimated 2.5-10/100,000 people of European ancestry are affected with HD, while the Asian populations have lower prevalence (0.6-3.8/100,000). The epidemiology of HD is not well described in India, and the distribution of the pathogenic CAG expansion, and the associated haplotype, in this population needs to be better understood. This study demonstrates a distribution of CAG repeats, at the HTT locus, comparable to the European population in both normal and HD affected chromosomes. Further, we provide an evidence for similarity of the HD halpotype in Indian sample to the European HD haplogroup. Funding StatementThis study is supported by Indian Council of Medical Research (ICMR/002/208/2012/00126). The sponsor of this study had no role in study design, data collection, analysis, interpretation, or writing of the report. No private corporations or other agency paid to write this article. All the authors had full access to all the data in the study. All authors have seen and given their approval for submission of the manuscript. All the authors declare no conflict of interest in study undertaken. IntroductionThe diagnosis of Huntington's disease (HD) is based on estimation of the CAG repeat length at the HTT locus 1 . The normal HTT gene contains less than 27 CAG repeats 2 , 3 , and a few normal individuals have intermediate CAG (27)(28)(29)(30)(31)(32)(33)(34)(35) repeat expansion 2 and display no symptoms suggestive of HD. Subjects with borderline CAG (36)(37)(38)(39) repeats may or may not develop symptoms. Individuals affected with HD typically have at least one HTT allele containing CAG repeat size of 40 or greater 2 , 4 .The age at onset (AAO) is inversely correlated with length of the pathogenic CAG stretch in the HTT gene 5 . Almost 50-70% of the variation observed is determined by the CAG repeat length, the remaining maybe explained by the additional influence of other cis and trans elements, as well as environmental factors 5 . Highly expanded CAG sequences cause disease onset at a younger age 6 . The fundamental mechanisms of CAG repeat instability are poorly understood.The prevalence of HD varies among different populations, with prevalence rates of 2.5 -10 per 100,000 in people of European ancestry, while the Japanese (0.11-0.45 per 100,000), Chinese ( 0.5-1 per 100,000) and African populations (<0.01 per 100, 000) show significantly lower prevalence 7 . Indian and other South Asian populations are expected to have intermediate prevalence of HD. Prevalence studies of Indian immigrants in UK, predominantly from the northern regions of the Indian subcontinent 8 suggest that HD occurs in 1.75 per 100,000 individuals. It is generally accepted from clinical experience, and family studies of different geographical regions, that HD is distributed widely in India 9 , 10 , 11 , 12 . The origin of the pathogenic CAG expansion in India is not well understood. Multiple founder effects, and admix...
Parental care and sensory stimulation are critical environmental factors that influence oxytocin (OXT) and its receptor (OXTR). Because developmental Oxt mRNA expression is enhanced by sensory‐rich early life experience and reduced by sensory deprivation, we predicted that compared to wild‐type (WT) littermates, mice with congenital loss of OXTR (OXTR KO), as a genetically induced deprivation, would show impaired Oxt mRNA expression in the offspring hypothalamus during development. Oxt mRNA levels of male and female OXTR KO mice were not different from WT littermates from postnatal day (P)0 to P6, although, by P8, OXTR KO showed significantly decreased Oxt mRNA expression in the hypothalamus compared to WT littermates. At P14, male and female OXTR KO mice had significantly decreased Oxt mRNA expression specifically in the paraventricular nucleus (PVN), but not the supraoptic nucleus (SON), compared to WT littermates. We investigated whether this effect persisted in adulthood (P90) and found a significant genotype by sex interaction where male OXTR KO mice displayed a reduction in Oxt expression specific to the PVN compared to male WT littermates. By contrast, male and female OXTR KO adults had increased Oxt mRNA levels in the SON. These findings suggest that OXTR plays a role in developmental Oxt mRNA expression with sex by genotype interactions apparent at adulthood. We then measured OXT and neural activation in the PVN and SON at P14. We observed more OXT‐immunoreactive cells in the PVN of OXTR KO mice but significantly fewer c‐Fos immunoreactive cells. There were no genotype differences in immunoreactivity for OXT and no c‐Fos activity in the SON at P14. Combined, these data suggest that OXTR WT P14 mice have more PVN activity and are more likely to release OXT than OXTR KO mice. Future experiments are warranted to understand which OXTR‐expressing neural circuits modulate the development of the PVN oxytocin system.
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