Oxytocin and vasopressin systems in genetic syndromes and neurodevelopmental disorders

doi:10.1016/j.brainres.2014.01.021

Brain Research

Volume 1580, 11 September 2014, Pages 199-218

https://doi.org/10.1016/j.brainres.2014.01.021 Get rights and content

Abstract

Oxytocin (OT) and arginine vasopressin (AVP) are two small, related neuropeptide hormones found in many mammalian species, including humans. Dysregulation of these neuropeptides have been associated with changes in behavior, especially social interactions. We review how the OT and AVP systems have been investigated in Autism Spectrum Disorder (ASD), Prader–Willi Syndrome (PWS), Williams Syndrome (WS) and Fragile X syndrome (FXS). All of these neurodevelopmental disorders (NDD) are marked by social deficits. While PWS, WS and FXS have identified genetic mutations, ASD stems from multiple genes with complex interactions. Animal models of NDD are invaluable for studying the role and relatedness of OT and AVP in the developing brain. We present data from a FXS mouse model affecting the fragile X mental retardation 1 (Fmr1) gene, resulting in decreased OT and AVP staining cells in some brain regions. Reviewing the research about OT and AVP in these NDD suggests that altered OT pathways may be downstream from different etiological factors and perturbations in development. This has implications for ongoing studies of the therapeutic application of OT in NDD.

This article is part of a Special Issue entitled Oxytocin and Social Behav.

Section snippets

Introduction to OT and AVP neuropeptide hormones

Oxytocin (OT) and arginine vasopressin (AVP) are small mammalian neuropeptides nine amino acids in length, which differ by only two amino acids. OT is produced primarily in hypothalamic nuclei, including the supraoptic (SON) and paraventricular nuclei (PVN). AVP is also synthesized in the PVN and SON. In males, additional brain regions including the amygdala and the bed nucleus of the stria terminalis (BNST) also produce AVP. OT and AVP of hypothalamic origins are transported from the SON and

Autism spectrum disorders

In 1943, Leo Kanner described a male patient with repetitive behaviors—“stereotyped movements [and]…repetitions carried out in exactly the same way in which they had been performed originally” and difficulties with social communication—“he always seemed to be parroting what he had heard said to him at one time or another…Words to him had a specifically literal, inflexible meaning. He seemed unable to generalize, to transfer an expression to another similar object or situation” (Kanner, 1943).

Prader–Willi syndrome and OT

Prader–Willi syndrome (PWS) is a complex disorder with multisystem effects and a distinct behavioral phenotype. It occurs in approximately 1/10,000–1/30,000 births, and is initially characterized by severe infantile hypotonia and difficulty feeding, although later in infancy and into adolescence individuals with PWS often eat excessively and develop morbid obesity. Other characteristics of PWS include hypogonadism, short stature, small hands and feet and strabismus. The cognitive phenotype is

Williams syndrome and OT

Williams syndrome (WS) was first described over 50 years ago (Williams et al., 1961). The first reported cases were focused on infants with hypercalcemia, developmental delays, cardiac malformations and dysmorphic facial features (Morris, 1993). However, better characterization of this syndrome has elucidated a distinct behavioral phenotype marked by an increased social drive paired with social fearlessness, poor judgment, difficulty forming peer relationships and high anxiety levels (Jarvinen

Fragile X syndrome

Named for the fragile site observed at Xq27.3, Fragile X Syndrome (FXS) is the most common inherited form of intellectual disability and the most common known single gene mutation associated with ASD (O׳Donnell and Warren, 2002). Prevalence estimates range from ~1 case in 1000 to 1 case in 4000 males and has settled at 1 case in 6000 world-wide for females (Brown, 1990, Morton et al., 1997, Turner et al., 1996, Webb, 2010). This rare genetic disorder is characterized by specific physical

Conclusion and next steps

Each of the disorders described here (ASD, PWS, WS and FXS) is unique and each condition is characterized by atypical social behaviors, often with a tendency toward high levels of anxiety. Given the importance of OT and AVP to mammalian social behaviors and anxiety, the neuropeptides׳ investigative value in these syndromes is not unexpected. This review summarized the possible role of OT in these NDD (Table 4) through experiments conducted by others and ourselves.

Each of these early

Acknowledgments

This work was supported in part by NIH K23MH082121 (SJ). The authors would like to acknowledge Dr. John Larson for his contribution of the Fmr1 KO mice. We would also like to thank Jeanine Leary and Jennifer Speak for their assistance in manuscript formatting and preparation.

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Research ReportOxytocin and vasopressin systems in genetic syndromes and neurodevelopmental disorders

Abstract

Section snippets

Introduction to OT and AVP neuropeptide hormones

Autism spectrum disorders

Prader–Willi syndrome and OT

Williams syndrome and OT

Fragile X syndrome

Conclusion and next steps

Acknowledgments

Elevated blood serotonin in autistic probands and their first-degree relatives

J. Autism Dev. Disord.

Diagnostic and Statistical Manual of Mental Disorders

Intranasal oxytocin versus placebo in the treatment of adults with autism spectrum disorders: a randomized controlled trial

Mol. Autism

Promoting social behavior with oxytocin in high-functioning autism spectrum disorders

Proc. Natl. Acad. Sci. USA

Vasopressin administration modulates anxiety-related behavior in rats

Physiol. Behav.

Stimulation of 5-HT1A and 5-HT2/5-HT1C receptors induce oxytocin release in the male rat

Brain Res.

Autism as a strongly genetic disorder: evidence from a British twin study

Psychol. Med.

Fmr1 knockout mice—a model to study fragile-X mental-retardation

Cell

The neuroscience of affiliation: forging links between basic and clinical research on neuropeptides and social behavior

Horm. Behav.

Oxytocin shapes the neural circuitry of trust and trust adaptation in humans

Neuron

Fmr1 KO mice as a possible model of autistic features

Sci. World J.

Understanding fragile X syndrome

Curr. Paediatr.

Targeted treatments for fragile X syndrome

J. Neurodev. Disord.

Etiological heterogeneity in autism spectrum disorders: more than 100 genetic and genomic disorders and still counting

Brain Res.

Whole genome microarray analysis of gene expression in an imprinting center deletion mouse model of Prader–Willi syndrome

Am. J. Med. Genet. A

Whole genome microarray analysis of gene expression in Prader–Willi syndrome

Am. J. Med. Genet. A

The human MAGEL2 gene and its mouse homologue are paternally expressed and mapped to the Prader–Willi region

Hum. Mol. Genet.

The phenotypic manifestations of interstitial duplications of proximal 15q with special reference to the autistic spectrum disorders

Am. J. Med. Genet.

Psychological profile and behavioural characteristics in 12 patients with Prader–Willi syndrome

Genet. Couns.

Sniffing neuropeptides: a transnasal approach to the human brain

Nat. Neurosci.

BALB/c mice: low sociability and other phenotypes that may be relevant to autism

Behav. Brain Res.

The fragile X: progress toward solving the puzzle

Am. J. Hum. Genet.

Association of oxytocin receptor (OXTR) gene variants with multiple phenotype domains of autism spectrum disorder

J. Neurodev. Disord.

Neuroendocrine perspectives on social attachment and love

Psychoneuroendocrinology

Sex differences in oxytocin and vasopressin: implications for autism spectrum disorders?

Behav. Brain Res.

Response of neural reward regions to food cues in autism spectrum disorders

J. Neurodev. Disord.

Prader–Willi syndrome

Genet. Med.

Prader–Willi syndrome

Genet. Med.

Autism risk factors: genes, environment, and gene-environment interactions

Dialogues Clin. Neurosci.

Fragile X mice develop sensory hyperreactivity to auditory stimuli

Neuroscience

Two aromatic residues regulate the response of the human oxytocin receptor to the partial agonist arginine vasopressin

FEBS Lett.

The effects of oxytocin and vasopressin on partner preferences in male and female prairie voles (Microtus ochrogaster)

Behav. Neurosci.

Developmental changes in brain serotonin synthesis capacity in autistic and nonautistic children

Ann. Neurol.

Abnormal dendritic spines in fragile X knockout mice: maturation and pruning deficits

Proc. Natl. Acad. Sci. USA

Autism or atypical autism in maternally but not paternally derived proximal 15q duplication

Am. J. Hum. Genet.

Spatial cognition in males with Fragile-X syndrome: evidence for a neuropsychological phenotype

Research Report
Oxytocin and vasopressin systems in genetic syndromes and neurodevelopmental disorders