Evidence for the involvement of genetic variation in the <i>oxytocin receptor</i> gene (<i>OXTR</i>) in the etiology of autistic disorders on high‐functioning level

Human social behavior develops under the influence of genetic, environmental, and cultural factors. Social cognition comprises our ability to understand and respond appropriately to other people's social approaches or responses. The concept embraces self-knowledge and theory of mind, or the ability to think about emotions and behavior from the perspective of another person. The neuropeptides oxytocin (OT) and vasopressin (AVP) are now known to play an important role, affecting individual differences in parenting behavior, social recognition, and affiliative behaviors. The processes of social cognition are also supported by reward circuitry, underpinned by the dopaminergic neurotransmitter system. Reward processes build social relationships, in parenting and pair-bonding, and influence social interactions that require trust, or display altruism. The impact of emotional regulation upon social behavior, including mood and anxiety, is also mediated through the serotonergic system. Variation in activity of serotonergic networks in the brain influences emotional responsivity, including subjective feelings, physiological responses, emotional expressions, and the tendency to become engaged in action as a consequence of a feeling state. Genetic variation in the receptors associated with OT, AVP, dopamine, and serotonin has been intensively studied in humans and animal models. Recent findings are building an increasingly coherent picture of regulatory mechanisms. (Pediatr Res 69: 85R-91R, 2011) W e, as humans, usually possess the ability to rapidly process social information about the thoughts and actions of other people and to interact in complex ways with them. Social cognition comprises a set of skills that enable us to understand thoughts and intentions that may differ from our own experiences or predispositions. As we develop through early childhood, we are increasingly capable of taking another person's perspective, and we develop self-knowledge. We can accurately predict how another person might behave in the future, from our social perceptions and experiences. We become capable of learning what motivates other people in their social interactions, even if these do not directly involve us. All these skills map onto schemas that are encoded in an associative network in memory and is orchestrated to ensure normal, skilled social adaptation (1).The process by which we acquire social cognitive competence evolves with development and is modified in response to the environment. To begin with, infants cannot easily differentiate between themselves and other people, but they rapidly become aware that their actions have an impact on the physical and social world around them. In due course, they develop social understanding, language, and imitation. Eventually, most of us acquire the ability to "read the mind" of others. By this, we mean that it becomes possible for us to understand why other people behave the way they do and to respond appropriately to them in social situations. If we have not acquired this ability...

show abstract

“…Although the association that Wu et al (38) reported was replicated (39), no such association with this allele has been found by others (40,41).…”

Section: Ot and Genetic Influences On Regulationmentioning

confidence: 82%

Genetic Influences on Social Cognition

Skuse

Gallagher

2011

Pediatric Research

View full text Add to dashboard Cite

show abstract

“…Firstly, significant association between OXTR SNPs [21][22][23][24][25][26] and risk for autism has been provisionally shown (but also see [27,28]) and, notably, was mediated by socialization skills in our study [23]. Additionally, SNPs associated with ASD are also associated with amygdala volume [29], depression/anxiety [29], negative emotionality [30], attention deficit [31], adult attachment styles [32,33] (but see [34]), affectivity, emotional loneliness and IQ [35], empathy and stress reactivity [36], observed parenting [37], with sexual phenotypes [38] and in our own studies with prosocial behavior [39].…”

Section: Oxytocin and Autism Spectrum Disorders (Asd)mentioning

confidence: 99%

Are retinoids potential therapeutic agents in disorders of social cognition including autism?

et al. 2011

View full text Add to dashboard Cite

Edited by Sergio Papa, Gianfranco Gilardi and Wilhelm JustKeywords: Autism spectrum disorder (ASD) All-trans retinoic acid (ATRA) CD38 Oxytocin Polymorphism a b s t r a c t Increasing evidence suggests that the nonapeptide, oxytocin (OT), helps shape social and affiliative behaviors not only in lower mammals but also in humans. Recently, an essential mediator of brain OT release has been discovered, ADP-ribosyl cyclase and/or CD38. We have subsequently shown that polymorphisms across the CD38 gene are associated with autism spectrum disorders (ASD). Notably, CD38 expression in lymphoblastoid cells (LBC) is reduced in cell lines derived from ASD subjects compared to parental cell lines. Intriguingly, a correlation was observed between CD38 expression and measures of social function in ASD. Finally, we have shown that all-trans retinoic acid (ATRA), a known inducer of CD38 transcription, can rescue low CD38 expressing LBC lines derived from ASD subjects and restore normal levels of transcription of this ectoenzyme providing 'proof of principle' in a peripheral model that retinoids are potential therapeutic agents in ASD. Ó 2011 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. OxytocinClassically, the nonapeptide oxytocin (OT) has been viewed as a hypothalamic neuropeptide that is released into the general circulation from the neural lobe of the pituitary, inducing uterine contractions during parturition and milk ejection during lactation. OT is derived from a pre-prohormone precursor that is synthesized in the hypothalamus and stored in vesicles at the posterior pituitary for storage and subsequent release into the bloodstream (see [1] for comprehensive review of the oxytocin receptor system). OT and social behaviorBeyond the long-known peripheral effects of OT, a wealth of animal studies have elaborated the role of OT, or their analogues such as isotocin and vasotocin [2], in molding social behavior from fish to mammals [3]. In the past few years the role of OT has also been examined in our own species, and similar to what has been learned from animal studies, it appears that this nonapeptides also influence social behaviors in humans [4,5]. Indeed, OT has been suggested as the 'great facilitator of life' in a recent review [6].In humans, intranasal administration of OT has been shown to increase trust [7], facilitate mind-reading [8], enhance human memory for social identity [9], increase positive communication between couples [10], increase gaze to the eye region [11] and increase generosity [12]. Intriguingly, OT plasma levels have been linked to individual patterns of maternal-fetal attachment [13] and salivary OT levels were associated with bonding to own parents and inversely related to psychological distress, particularly depressive symptoms [14]. Social anxiety symptom severity, adjusted for age and gender in a healthy group of subjects, was associated with higher plasma oxytocin levels [15]. Imaging studies reinforce the role of OT in influencing human social ...

show abstract

“…As regards this latter pathway, decreased circulating oxytocin levels in individuals with ASD has been observed (Modahl et al, 1998), and administration of oxytocin to individuals with ASD has been reported to reduce repetitive behaviors (Hollander et al, 2003), enhance retention of social cognition (Hollander et al, 2007) and improve emotional recognition (Guastella et al, 2010). Furthermore, OXTR, which is located at chromosome 3p25 and encodes a G-protein coupled receptor, has been associated with ASD in numerous studies (Wu et al, 2005;Ylisaukko-oja et al, 2006;Jacob et al, 2007;Lerer et al, 2008;Yrigollen et al, 2008;Gregory et al, 2009;Liu et al, 2010;Wermter et al, 2010).…”

Section: The Oxytocin System In Asd and Its Interactions With Other Pmentioning

confidence: 99%

A Candidate Circuit Approach to Investigating Autism

Page

2011

The Anatomical Record

View full text Add to dashboard Cite

A major problem in understanding mechanisms of pathogenesis in autism spectrum disorder (ASD) is deciphering how risk factors act via the brain to influence the behavioral symptoms of this disorder. We may start to bridge this gap in our understanding by systematically examining the structure and function of cell types that make up circuits underlying behavioral endophenotypes in animal models for ASD. A confluence of advances in basic behavioral neurobiology, in ASD mechanisms and animal models, and in genetic tools for imaging and manipulating brain circuits will make this possible. Through a process of elimination of candidates and comparison across models, we may hope to understand how ASD risk factors influence the development and function of neural circuitry at the level of genetically defined cell types. As an example of how this candidate circuit approach may be applied to investigating ASD, here I focus on social behavior as an endophenotype, and I discuss recent findings regarding the development and function of the oxytocin system, which is implicated in both normal social behavior and ASD pathogenesis. I stress the importance of a collaborative, multidisciplinary approach to probing candidate cell types and circuits across mouse models of ASD.

show abstract

Evidence for the involvement of genetic variation in the oxytocin receptor gene (OXTR) in the etiology of autistic disorders on high‐functioning level

Cited by 152 publications

References 41 publications

Genetic Influences on Social Cognition

Genetic Influences on Social Cognition

Are retinoids potential therapeutic agents in disorders of social cognition including autism?

A Candidate Circuit Approach to Investigating Autism

Contact Info

Product

Resources

About