oxytocin and Intellectual-Disability

The prosocial neuropeptide oxytocin is being developed as a potential treatment for various neuropsychiatric disorders including autism spectrum disorder (ASD). Early studies using intranasal oxytocin in patients with ASD yielded encouraging results and for some time, scientists and affected families placed high hopes on the use of intranasal oxytocin for behavioral therapy in ASD. However, a recent Phase III trial obtained negative results using intranasal oxytocin for the treatment of behavioral symptoms in children with ASD. Given the frequently observed autism-like behavioral phenotypes in Prader-Willi and Schaaf-Yang syndromes, it is unclear whether oxytocin treatment represents a viable option to treat behavioral symptoms in these diseases. Here we review the latest findings on intranasal OT treatment, Prader-Willi and Schaaf-Yang syndromes, and propose novel research strategies for tailored oxytocin-based therapies for affected individuals. Finally, we propose the critical period theory, which could explain why oxytocin-based treatment seems to be most efficient in infants, but not adolescents.

Topics: Administration, Intranasal; Arthrogryposis; Autism Spectrum Disorder; Craniofacial Abnormalities; Humans; Hypopituitarism; Intellectual Disability; Oxytocin; Prader-Willi Syndrome; Research Design

In mentally retarded (MR) prepubertal children, investigated both before and after six months of treatment, synthetic arginine vasotocin (AVT) (10(-6) mg/day/0.1 ml, intranasally), but not oxytocin or saline alone, significantly increased the intelligence quotient (IQ) and improved the attention parameters without affecting the short-term memory. Taking into account both the psychometric results and the clinical observations, the effects of AVT could be mainly explained by assuming the improvement of attention. Since there was a significant inverse correlation between the pretreatment levels of the IQ and attention scores and their increase after AVT, and since the AVT effects tend to be more intense in autistic children, we hypothesize that the more affected the attention mechanisms, the more they are sensitive to AVT. The present results are tentatively explained by the paradoxical sleep-enhancing properties of AVT, mechanisms by which AVT could improve the brain plasticity in MR subjects and by this, the attention performance.

Topics: Attention; Child; Double-Blind Method; Female; Follow-Up Studies; Humans; Intellectual Disability; Intelligence; Male; Memory, Short-Term; Oxytocin; Vasotocin

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by specific social symptoms, restricted interests, stereotyped repetitive behaviors, and delayed language development. The 3q29 microdeletion (3q29del), a recurrent copy number variant, confers a high risk for ASD and schizophrenia, and serves as an important pathological model for investigating the molecular pathogenesis of a large number of neurodevelopmental and psychiatric conditions. Recently, mouse models carrying a deletion of the chromosomal region corresponding to the human 3q29 region (Df/+ mice) were generated and demonstrated neurodevelopmental and psychiatric conditions associated behavioral abnormalities, pointing to the relevance of Df/+ mice as a model for these conditions with high construct and face validity. Currently, the molecular pathogenesis of these behavioral phenotypes in Df/+ mice remains unclear. The oxytocin (OXT) system plays a central role in social behavior across species and has a potential role in ASD. In this study, to elucidate the molecular mechanisms behind impaired social behavior in Df/+ mice, we investigated the possible involvement of OXT signaling in impaired social behavior in Df/+ mice. We demonstrated that OXT administration restored the impaired social behavior in Df/+ mice. We also demonstrated that the number of OXT-positive cells in the paraventricular nucleus (PVN) was significantly lower in Df/+ mice than in wild-type (WT) littermates. Consistent with this, the level of OXT peptide in the cerebral cortex of Df/+ mice was lower than in WT littermates. Our study may provide important insights into the molecular pathophysiological basis of neurodevelopmental and psychiatric conditions, including ASD.

Topics: Animals; Autism Spectrum Disorder; Brain; Chromosome Deletion; Chromosomes, Human, Pair 3; Developmental Disabilities; Disease Models, Animal; Intellectual Disability; Mice; Oxytocin; Social Behavior

There were few reports of oxytocin (OXT) concentrations of autism spectrum disorder (ASD) patients with severe intellectual disabilities. We measured serum OXT concentrations in 79 hospitalized patients with severe intellectual disabilities (16-60 years old, 50 males and 29 females, 54 ASD patients) and investigated the associations between serum OXT concentration, symptom scores, sex differences, and autism spectrum disorder. There were no significant effects of diagnosis, severity of intellectual disabilities, and total score of the Japanese version of the Aberrant Behavior Checklist (ABC-J), the Childhood Autism Rating Scale-Tokyo Version (CARS-TV), and the Japanese version of the Repetitive Behavior Scale-Revised (RBS-R). However, there were sex differences in the correlations between OXT concentrations and subscale scores in the ASD group. The male ASD group (n = 39) showed negative correlations between RBS-R Self-injurious and Sameness subscale scores and serum OXT concentrations. In the female ASD group(n = 15), CARS-TV Nonverbal communication subscale scores and RBS-R Compulsive subscale scores were seen to positively correlate with serum OXT concentrations. These findings suggest that OXT functions differ in males and females with severe intellectual disabilities and that OXT partly affects autism and related to some of the repetitive behaviors and nonverbal communication, in ASD patients with severe intellectual disabilities.

Topics: Adolescent; Adult; Autism Spectrum Disorder; Biomarkers; Female; Humans; Intellectual Disability; Male; Middle Aged; Oxytocin; Severity of Illness Index; Sex Characteristics; Young Adult

Genetic studies of intellectual disability and identification of monogenic causes of obesity in humans have made immense contribution toward the understanding of the brain and control of body mass. The leptin > melanocortin > SIM1 pathway is dysregulated in multiple monogenic human obesity syndromes but its downstream targets are still unknown. In ten individuals from six families, with overlapping 6q16.1 deletions, we describe a disorder of variable developmental delay, intellectual disability, and susceptibility to obesity and hyperphagia. The 6q16.1 deletions segregated with the phenotype in multiplex families and were shown to be de novo in four families, and there was dramatic phenotypic overlap among affected individuals who were independently ascertained without bias from clinical features. Analysis of the deletions revealed a ∼350 kb critical region on chromosome 6q16.1 that encompasses a gene for proneuronal transcription factor POU3F2, which is important for hypothalamic development and function. Using morpholino and mutant zebrafish models, we show that POU3F2 lies downstream of SIM1 and controls oxytocin expression in the hypothalamic neuroendocrine preoptic area. We show that this finding is consistent with the expression patterns of POU3F2 and related genes in the human brain. Our work helps to further delineate the neuro-endocrine control of energy balance/body mass and demonstrates that this molecular pathway is conserved across multiple species.

Topics: Adolescent; Adult; Animals; Basic Helix-Loop-Helix Transcription Factors; Body Mass Index; Cell Line; Child; Child, Preschool; Chromosomes, Human, Pair 6; Disease Models, Animal; Energy Metabolism; Female; Homeodomain Proteins; Humans; Hypothalamus; Intellectual Disability; Male; Middle Aged; Obesity; Oxytocin; Pedigree; Phenotype; POU Domain Factors; Repressor Proteins; Sequence Deletion; Young Adult; Zebrafish

To determine the incidence of moderate to severe neonatal encephalopathy (NE) and neonatal seizures without encephalopathy, and the association with metabolic acidemia. Secondly, to investigate the occurrence of suboptimal intrapartum care and its impact on neonatal outcome.. Clinical audit.. Two university hospitals in Sweden.. Neonates ≥34 weeks with moderate or severe NE and neonatal seizures alone, i.e. without encephalopathy, from a population of 71 189 births, where umbilical blood gases were routinely analyzed.. Neonates were categorized depending on the presence of metabolic acidemia at birth by umbilical artery pH < 7.00, base deficit ≥12 mmol/L. Records were audited for suboptimal care and a decision was made on whether management was assessed to have impacted neonatal outcome.. Encephalopathy and seizures alone.. We identified 80 neonates with NE and 30 with seizures alone, of which 48 (60%) and none, respectively, had metabolic acidemia. Suboptimal care could be assessed in 77 and occurred in 28 (36%) NE cases and in one neonate with seizures alone (p < 0.001). In 47 NE cases with metabolic acidemia, suboptimal care occurred in 22 (47%) vs. 6/30 (20%) without metabolic acidemia (p = 0.02). Suboptimal care had an impact on outcome in 18/77 (23%) NE cases but in no cases with seizures alone.. Suboptimal care was commonly seen with NE, particularly in neonates with metabolic acidemia, and also affected neonatal outcome. No such associations were found in neonates with seizures alone.

Topics: Acidosis; Blood Gas Analysis; Cardiotocography; Cerebral Palsy; Child Behavior Disorders; Child, Preschool; Clinical Audit; Cognition Disorders; Fetal Blood; Humans; Incidence; Infant, Newborn; Intellectual Disability; Mental Disorders; Oxytocics; Oxytocin; Perinatal Care; Quality of Health Care; Retrospective Studies; Seizures; Speech Disorders; Sweden; Vacuum Extraction, Obstetrical

Oxytocin plays an important role in social-affiliative behaviors. It has been proposed that exposure to high levels of exogenous oxytocin at birth, via pitocin induction of delivery, might increase susceptibility to autism by causing a downregulation of oxytocin receptors in the developing brain. This study examined the rates of labor induction using pitocin in children with autism and matched controls with either typical development or mental retardation. Birth histories of 41 boys meeting the criteria for autistic disorder were compared to 25 age- and IQ-matched boys without autism (15 typically developing and 10 with mental retardation). There were no differences in pitocin induction rates as a function of either diagnostic group (autism vs. control) or IQ level (average vs. subaverage range), failing to support an association between exogenous exposure to oxytocin and neurodevelopmental abnormalities.

Topics: Adolescent; Autistic Disorder; Causality; Child; Child, Preschool; Female; Follow-Up Studies; Humans; Infant; Infant, Newborn; Intellectual Disability; Intelligence; Labor, Induced; Male; Oxytocin; Pregnancy; Reference Values; Risk Factors

Topics: Autistic Disorder; Child, Preschool; Female; Humans; Intellectual Disability; Labor, Induced; Language Disorders; Oxytocin; Pregnancy; Prevalence

Topics: Acidosis, Respiratory; Apgar Score; Female; Half-Life; Humans; Indocyanine Green; Infant, Newborn; Intellectual Disability; Jaundice, Neonatal; Labor, Induced; Male; Oxytocin

Topics: Female; Fetal Diseases; Hematoma, Epidural, Cranial; Hemorrhage; Humans; Infant Mortality; Infant, Newborn; Infant, Newborn, Diseases; Intellectual Disability; Labor, Induced; Muscles; Obstetric Labor Complications; Oxytocin; Perfusion; Pregnancy; Statistics as Topic