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Cited by 101Neuroendocrine regulation and behaviorGenetics and Neurodevelopmental DisordersAutism Spectrum Disorder Research

Oxytocin and vasopressin systems in genetic syndromes and neurodevelopmental disorders

Open access
Francis, S.M., Sagar, A., Levin-Decanini, T., Liu, W., Carter, C.S., Jacob, S.·2014·Brain Research
DOI 10.1016/j.brainres.2014.01.021PMC PMC4305432
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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.

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Written from the paper’s full text.

TL;DR

This review synthesizes evidence that oxytocin (OT) and vasopressin (AVP) systems are altered in autism spectrum disorder (ASD), Prader–Willi syndrome (PWS), Williams syndrome (WS), and fragile X syndrome (FXS), with OT/AVP dysregulation linked to social deficits and anxiety. It also presents preliminary Fmr1 knockout mouse data showing reduced OT- and AVP-positive cells in the paraventricular nucleus (PVN), suggesting OT pathways may be downstream of diverse etiologies.

Key findings

  • In ASD, single-dose intravenous OT reduced repetitive behaviors: after 4 hours, 13 patients (86.7%) versus 6 controls (40%) had decreases in restricted/repetitive behaviors (RRB; Hollander et al., 2003). Single-dose intranasal OT improved emotion recognition in 16 males with ASD ages 12–19 (Guastella et al., 2010), and a six-week daily intranasal OT trial reported improvements in social cognition, quality of life, RRB, and some measures of emotional well-being (Anagnostou et al., 2012).
  • Peripheral OT/AVP findings: Modahl et al. (1998) reported low plasma OT in 29 ASD versus 30 age-matched control children; Miller et al. (2013) measured OT/AVP in 75 children/adolescents (40 high-functioning ASD, 35 typically developing) aged 8–18 and found higher OT in all girls and higher AVP in all boys, with AVP positively associated with RRB in ASD girls.
  • In PWS, there is a deficit of OT-producing neurons in the PVN and lower cerebrospinal fluid OT; intranasal OT increased trust and decreased disruptive behavior in a randomized placebo-controlled trial in 24 patients (Tauber et al., 2011). In WS, baseline OT levels were increased and correlated positively with increased approach to strangers and decreased adaptive social behavior (Dai et al., 2012).
  • In FXS, a randomized double-blind placebo-controlled single-dose intranasal OT trial in 8 low-functioning males aged 13–28 found 24 IU OT significantly increased eye gaze frequency and 48 IU OT significantly decreased salivary cortisol versus placebo, with no effects on heart rate, heart rate variability, or respiratory sinus arrhythmia. Preliminary Fmr1 knockout mouse data showed reduced OT-positive and AVP-positive cells in the PVN versus wild type, a nonsignificant trend for lower OT-positive cells in the supraoptic nucleus, and no significant OXTR-immunoreactive cell density differences in hippocampus, retrosplenial granular, or piriform cortices (p>0.05).

Methods

  • Narrative review of human and animal studies on OT and AVP in ASD, PWS, WS, and FXS, including genetic, plasma/CSF, intranasal/intravenous OT, and mouse model studies.
  • The paper also presents preliminary original data from an FXS mouse model (Fmr1 KO) using counts of OT- and AVP-immunoreactive cells in brain regions (PVN, supraoptic nucleus) and OXTR-immunoreactive cell density in hippocampus, retrosplenial granular, and piriform cortices compared with wild type.
  • Main analysis is qualitative synthesis; no meta-analysis or pooled effect estimates are reported.

Limitations

  • The paper states that many experiments have small sample sizes due to rarity of the disorders and complex animal models; the preliminary Fmr1 KO data need replication in a larger sample and in other animal models.
  • It notes a lack of human data on pathophysiology and pharmacological interventions for FXS, WS, and PWS, and that OT assay methodologies vary widely and can yield different results.
  • Evident from the text: this is a narrative review without systematic search or meta-analysis, and many included studies differ in dosing, duration, outcome measures, and sample characteristics, limiting comparability.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.brainres.2014.01.021

Cites

208 of 208 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 111 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    In a fragile X syndrome mouse model affecting the Fmr1 gene, there were decreased OT and AVP staining cells in some brain regions.

    “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.”
    Quote in the paperSubstantial claim
  • Findingown data

    A trend, although not significant, towards lower OT-positive cells was noted in the SON of Fmr1 KO mice.

    “A trend, although not significant, towards lower OT-positive cells was also noted in the SON (Table 3).”
    Quote in the paperNot a substantial claim
  • Findingown data

    Preliminary results based upon counts of immune-reactive cells suggest a reduction in both OT-positive and AVP-positive cells in the PVN of Fmr1 KO as compared to WT.

    “These preliminary results, based upon counts of immune-reactive cells, suggest a reduction in both OT-positive (Fig. 1) and AVP-positive (Fig. 2) cells in the PVN of Fmr1 KO as compared to WT (Table 2).”
    Quote in the paperSubstantial claim
  • Findingown data

    None of the areas hippocampus, retrosplenial granular and piriform cortices showed a significant difference in OXTR-immunoreactive cell density as compared to WT mice.

    “None of these areas showed a significant difference in OXTR-immunoreactive cell density as compared to WT mice (p>0.05).”
    Quote in the paperNot a substantial claim
  • Interpretationreasoning

    Reviewing research about OT and AVP in ASD, PWS, WS and FXS suggests that altered OT pathways may be downstream from different etiological factors and perturbations in development.

    “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.”
    Quote in the paperSubstantial claim
  • May combine two claims. 57
  • Classified as probably not a substantial claim. 24
  • The quote only partly states this claim. 1

  • May combine two claims.

    Interpretationreasoning

    All three mouse models of ASD have alterations in the OT system or respond to OT administration, suggesting that OT may be affected downstream in strains of mice that have different etiological factors influencing social and repetitive behaviors.

    “It is striking that all three mouse models of ASD have alterations in the OT system or respond to OT administration. This suggests that OT may be affected downstream in strains of mice that have different etiological factors influencing social and repetitive behaviors.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    A failure to completely process the prohormone OT-X might lead to a deficiency in OT, thus exacerbating some symptoms of ASD such as features of social deficits.

    “Consequently, changes in OT processing, specifically a failure to completely process the prohormone OT-X, might lead to a deficiency in OT, thus exacerbating some of the symptoms of ASD, such as features of social deficits.”
    Quote in the paperSubstantial claim

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    Premisecitation

    A six-week daily IN-OT trial in adults with ASD suggested therapeutic potential, with improvements in social cognition, quality of life, RRB, and some measures of emotional well-being.

    “This pilot study suggested therapeutic potential with daily administration of IN-OT in this population of adults with ASD. This six-week study noted improvements in social cognition, quality of life, RRB, and some measures of emotional well-being with IN-OT, in essence, improvement in the core domains of ASD.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Anagnostou et al., 2012 source

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    Premisenone given

    There is some evidence in animal and human studies that OT improves the core symptoms of ASD.

    “There is some evidence in animal and human studies that OT improves the core symptoms of ASD.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: There are currently no approved medications to treat the social deficits or restricted, repetitive behaviors that are core symptoms of ASD.

  • May combine two claims.

    Interpretationreasoning

    There appears to be disruption of the OT system in individuals with PWS, which is recapitulated in different animal models.

    “Consequently, there appears to be disruption of the OT system in individuals with PWS, which is recapitulated in different animal models.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. The quote only partly states this claim.

    Interpretationreasoning

    The suggestion that altered OT pathways may be downstream from different etiological factors has implications for ongoing studies of the therapeutic application of OT in neurodevelopmental disorders.

    “This has implications for ongoing studies of the therapeutic application of OT in NDD.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    IN-OT administration increases trust in others and decreases disruptive behavior in individuals with PWS.

    “IN-OT administration increases trust in others and decreases disruptive behavior in individuals with PWS (Tauber et al., 2011).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Tauber et al., 2011 source

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    Premisecitation

    Williams syndrome has a distinct behavioral phenotype marked by increased social drive, social fearlessness, poor judgment, difficulty forming peer relationships, and high anxiety levels.

    “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 et al., 2013).”
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    Premisecitation

    ELN disruption affects connective tissue, particularly of the aorta.

    “While ELN disruption affects connective tissue, particularly of the aorta (Lowery et al., 1995)”
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    Premisecitation

    Individuals with Williams syndrome show deficits in social understanding, as evidenced by difficulty identifying affect or other's mental states.

    “In addition, affected individuals show deficits in social understanding, as evidenced by difficulty identifying affect (Gagliardi et al., 2003; Plesa-Skwerer et al., 2006) or other’s mental states (Jarvinen-Pasley et al., 2008).”
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    Premisecitation

    Individuals with Williams syndrome show difficulty with social adjustment and social judgment.

    “However, this does not translate into the development of social relationships as individuals show difficulty with social adjustment (Gosch and Pankau, 1994, 1997) and social judgment (Einfeld et al., 1997; Gosch and Pankau, 1997).”
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    Premisecitation

    The social phenotype of Williams syndrome includes hypersociability, preference for novel social over non-social stimuli, and increased eye contact.

    “The social phenotype associated with WS is striking due to the hypersociability of the affected individuals, as well as the preference for novel social over non-social stimuli (Jarvinen-Pasley et al., 2008; Jarvinen-Pasley et al., 2010) and increased eye contact (Mervis et al., 2003).”
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    • cites Jarvinen-Pasley et al., 2008 source

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    • cites Mervis et al., 2003 source

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    Premisecitation

    Individuals with Williams syndrome show prolonged face gaze, whereas those with ASD display reduced face gaze.

    “Whereas individuals with WS show prolonged face gaze, those with ASD display reduced face gaze (Riby and Hancock, 2009).”
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    Premisecitation

    Fragile X syndrome is the most common inherited form of intellectual disability and the most common known single gene mutation associated with ASD.

    “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).”
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    Premisecitation

    Children with Williams syndrome and ASD display high levels of anxiety; individuals with ASD have higher levels of RRB as well as greater rates of social phobia and separation anxiety.

    “In addition, although children with WS and ASD display high levels of anxiety, individuals with ASD have higher levels of RRB as well as greater rates of social phobia and separation anxiety (Cascio et al., 2012).”
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    Premisecitation

    GTF2I deficient mice display increased social interaction with novel mice and diminished social habituation.

    “Mouse models of WS include GTF2I deficient mice which display increased social interaction with novel mice and diminished social habituation (Sakurai et al., 2011)”
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    Premisecitation

    De novo duplications of regions of 7q11.23 are associated with ASD, whereas deletions of the same region lead to Williams syndrome.

    “Recently, de novo duplications of regions of 7q11.23 have been shown to be associated with ASD, whereas deletions of the same region lead to WS (Sanders et al., 2011).”
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    • cites Sanders et al., 2011 source

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    Interpretationreasoning

    Both ASD and Williams syndrome phenotypes include abnormal social relationships, although through different mechanisms.

    “but it should be noted that both ASD and WS phenotypes include abnormal social relationships, although through different mechanisms.”
    Quote in the paperNot a substantial claim

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    Interpretationreasoning

    There may be a dose-dependent effect of OT, as high levels may impair adaptive social behavior and may partly underlie the maladaptive social phenotype of Williams syndrome.

    “These results suggest that there may be a dose dependent effect of OT, as high levels may impair adaptive social behavior and may partly underlie the maladaptive social phenotype of WS.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In individuals with Williams syndrome, OT levels correlate positively with increased approach to strangers and decreased adaptive social behaviors.

    “Additionally, OT levels correlated positively with increased approach to strangers as well as decreased adaptive social behaviors.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Dai et al., 2012 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Fragile X syndrome is characterized by specific physical features, as well as cognitive and behavioral phenotypes.

    “This rare genetic disorder is characterized by specific physical features, as well as cognitive and behavioral phenotypes (Berry-Kravis et al., 2002, 2011; McLennan et al., 2011).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Berry-Kravis et al., 2002, 2011

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    • cites McLennan et al., 2011 source

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    Premisecitation

    Physical features of Fragile X syndrome can include a long narrow face with large protruding ears, connective tissue abnormalities, macroorchidism, macrocephaly, obesity, loose skin over the hands, a high arched palate, a vertical plantar crease and flat feet.

    “The physical features can include: a long narrow face with large protruding ears, connective tissue abnormalities (i.e. hyperextensive joints), macroorchidism, macrocephaly, obesity (especially in young males), loose skin over the hands, a high arched palate, a vertical plantar crease and flat feet (Moy et al., 2009; Schapiro et al., 1995).”
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    Premisecitation

    The Fragile X syndrome population has susceptibility to ASD, ADHD, anxiety disorders, and neurological disorders such as epilepsy.

    “This population also has susceptibility to certain other neuropsychiatric disabilities including ASD, ADHD, anxiety disorders, and neurological disorders such as epilepsy (Hessl et al., 2001; Pretorius et al., 1998).”
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    Premisecitation

    Published studies report the prevalence rate of Fragile X syndrome and autistic behaviors/ASD diagnosis to range from 25-47%, but sample sizes are often small.

    “Published studies have reported the prevalence rate of FXS and autistic behaviors/ASD diagnosis to range from 25–47%, however sample sizes are often small (Hatton et al., 2006; Morton et al., 1997).”
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    • cites Hatton et al., 2006 source

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    • cites Morton et al., 1997 source

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    Premisecitation

    Individuals with Fragile X syndrome exhibit deficits in visuospatial tasks, quantitative skills, short-term and working memory, expressive language skills, sequential processing and executive function.

    “FXS individuals exhibit deficits in visuospatial tasks, quantitative skills, short-term and working memory, expressive language skills, sequential processing and executive function (Berry-Kravis et al., 2002; Cornish et al., 1999; Freund and Reiss, 1991; Hall et al., 2012; Kwon et al., 2001; Maes et al., 1994).”
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    • cites Cornish et al., 1999 source

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    • cites Freund and Reiss, 1991

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    Premisecitation

    Relative strengths in Fragile X syndrome include receptive language skills, visual memory, acquisition of factual information, imitation skills and gestalt processing.

    “Relative strengths include receptive language skills, visual memory, acquisition of factual information, imitation skills and gestalt processing (Berry-Kravis et al., 2002).”
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    Premisecitation

    The majority of Fragile X syndrome patients have social anxiety and almost a third have symptoms that overlap with ASD.

    “The majority of FXS patients have social anxiety and almost a third have symptoms that overlap with ASD (Hagerman et al., 2010).”
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    • cites Hagerman et al., 2010 source

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    Premisecitation

    Many behaviors in Fragile X syndrome are linked to anxiety level, and physiological studies have noted increased sympathetic and decreased parasympathetic activity and poor coordination between the systems in children and adolescents with FXS.

    “Many of these behaviors are linked to the anxiety level of the individual, a meaningful link because physiological studies have noted increased sympathetic and decreased parasympathetic activity and poor coordination between the systems in children and adolescents with FXS (Hall et al., 2009).”
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    Premisecitation

    MRI studies have found that individuals with Fragile X syndrome have enlarged lateral ventricles and increased caudate nucleus volumes relative to control subjects.

    “MRI studies have found that individuals with FXS have enlarged lateral ventricles and increased caudate nucleus volumes relative to control subjects (Reiss et al., 1995).”
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    Premisecitation

    Dendritic spines of neocortical pyramidal neurons of Fragile X syndrome subjects are longer and thinner than those of matched controls, indicating perhaps the spines fail to mature normally in FXS patients.

    “Anatomical studies of post-mortem brains have revealed that dendritic spines of neocortical pyramidal neurons of FXS subjects are longer and thinner than those of matched controls, indicating perhaps the spines fail to mature normally in FXS patients (Hinton et al., 1991; Irwin et al., 2001; Rudelli et al., 1985; Wisniewski et al., 1991).”
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    Premisecitation

    Mice lacking FMRP have impaired long-term potentiation in somatosensory cortex, visual cortex, olfactory cortex, cingulate cortex, and amygdala and enhanced long-term depression in hippocampus.

    “Mice lacking FMRP have impaired long-term potentiations in somatosen-sory cortex (Li et al., 2002), visual cortex (Wilson and Cox, 2007), olfactory cortex (Larson et al., 2005), cingulate cortex, and amygdala (Zhao et al., 2005) and enhanced long-term depression in hippocampus (Huber et al., 2002).”
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    Premisecitation

    Premutation in FMR1 is associated with Fragile X-associated tremor/ataxia syndrome, has a repeat length of 50-200, and does not usually cause mental deficits, but shyness, anxiety, and premature ovarian failure have been known to occur.

    “Premutation, associated with Fragile X-associated tremor/ataxia syndrome (FXTAS; Wang et al., 2010), has a repeat length of 50–200 and does not usually cause mental deficits, but shyness, anxiety, and premature ovarian failure have been known to occur.”
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    Premisecitation

    Diagnosis of Fragile X syndrome is based on DNA analysis that identifies the number of CGG repeats in the FMR1 gene at the Xq27.3 site.

    “Diagnosis is based on DNA analysis that identifies the number of CGG repeats in the fragile X mental retardation 1 (FMR1) gene at the Xq27.3 site (Turner et al., 1996).”
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    Premisecitation

    Expression of FMRP in the brain seems to be experience dependent and is produced in the soma and near the synapse.

    “The expression of FMRP in the brain seems to be experience dependent and is produced in the soma and near the synapse (Berry-Kravis et al., 2002, 2011).”
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    • cites Berry-Kravis et al., 2002, 2011

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    Premisecitation

    FMR1 encodes FMRP, a 69kDa protein found in most adult and fetal tissues, with high concentrations in the brain and testes.

    “FMR1 encodes the fragile X mental retardation protein (FMRP); a 69kDa protein found in most adult and fetal tissues, high concentrations are noted in the brain and testes.”
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    Premisenone given

    In most affected individuals, Fragile X syndrome is caused by a trinucleotide (CGG) repeat expansion in the 5' untranslated promoter region of the FMR1 gene.

    “In most affected individuals, this genetic disorder is caused by a trinucleotide (CGG) repeat expansion in the 5’ untranslated (promoter) region of the FMR1 gene.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    This creates an FMRP deficiency in the brain, which leads to Fragile X syndrome presentation.

    “This creates an FMRP deficiency in the brain, which leads to FXS presentation (McLennan et al., 2011; Tassone et al., 2000a).”
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    Premisecitation

    In many individuals with premutations, excess FMR1 mRNA is produced, yet below normal FMRP is synthesized, and this may contribute to approximately 10% of male and 2-3% of female ASD cases.

    “In many individuals with premutations, excess FMR1 mRNA is produced, yet below normal FMRP is synthesized (Tassone et al., 2000a, 2000b) and may contribute to approximately 10% of male and 2–3% of female ASD cases (Wang et al., 2010).”
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    Premisecitation

    OT, released endogenously or given exogenously, has been associated with positive social behaviors, reductions in anxiety, obsessiveness and stress reactivity, the central release of AVP and other peptides such as corticotropin-releasing factor, and may serve to counter the defensive behavioral strategies associated with stressful experiences.

    “As described earlier OT, released endogenously or given exogenously, has been associated with positive social behaviors, reductions in anxiety, obses-siveness and stress reactivity, the central release of AVP and other peptides such as corticotropin-releasing factor, and may serve to counter the defensive behavioral strategies associated with stressful experiences (Carter, 2007).”
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    Premisecitation

    Available treatments for Fragile X syndrome focus on managing symptoms: stimulants for attention deficit and hyperactivity; SSRI and antipsychotics for aggression associated with anxiety; and carbamazepine for seizures.

    “However, similar to ASD, available treatments for FXS focus on managing symptoms: stimulants are prescribed for attention deficit and hyperactivity; SSRI and antipsychotics treat aggression associated with anxiety; and carbamazepine are used for treatment of seizures (Hampson et al., 2011).”
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    Fragile X syndrome is caused by full mutation which is 4200 trinucleotide repeats, and results in hypermethylation of the gene and transcriptional silencing.

    “FXS is caused by full mutation which is 4200 trinucleotide repeats, and results in hypermethylation of the gene and transcriptional silencing (Tassone et al., 2000a).”
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    • cites Tassone et al., 2000a

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    Premisereasoning

    The Fmr1 KO mouse model developed by the Dutch-Belgian Fragile X Consortium lacks FMRP throughout its lifespan and corresponds to the molecular endpoint of the human disease.

    “This mouse model, which lacks FMRP throughout its lifespan, corresponds to the molecular endpoint of the human disease.”
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    Premisecitation

    Among behavioral phenotypes displayed in Fmr1 KO are deficits in object recognition memory (including a failure to habituate to objects), and impairment of spatial memory.

    “Among the behavioral phenotypes displayed in Fmr1 KO are deficits in object recognition memory (including a failure to habituate to objects), and impairment of spatial memory (Mineur et al., 2002).”
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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    The Fmr1 KO mouse was created by inserting a neomycin cassette into exon 5 of the murine Fmr1 gene, disrupting transcription of Fmr1 mRNA and causing absence of FMRP.

    “This mouse was created by inserting a neomycin cassette into exon 5 of the murine Fmr1 gene. The insert disrupts the transcription of Fmr1 mRNA causing an absence of FMRP.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The behavioral and cognitive deficits of Fmr1 KO mice are actually quite subtle and parallel Fragile X syndrome patients.

    “By most accounts Fmr1 KO mice appear to have relatively normal behavior, but research has shown that the behavioral and cognitive deficits of the KO are actually quite subtle and parallel FXS patients (Berry-Kravis et al., 2002; D’Hooge et al., 1997; Paradee et al., 1999; Peier et al., 2000).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Berry-Kravis et al., 2002 source

      Not checked in the free run.

    • cites D’Hooge et al., 1997 source

      Not checked in the free run.

    • cites Paradee et al., 1999 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Macroorchidism is observed in Fmr1 KO animals as well as in Fragile X syndrome patients.

    “While macroorchidism is observed in the Fmr1 KO animals (Bakker et al., 1994) as well as in FXS patients, the behavioral patterns differ between the patients and the KO.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Bakker et al., 1994

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    There are several Fragile X syndrome animal models, three in mice and a drosophila model, that meet multiple criteria.

    “There are several FXS animal models, three in mice and a drosophila model that meet multiple criteria.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Fmr1 KO mice are hyperactive and show indications of increased anxiety and sensory hyperresponsiveness, especially to auditory stimuli.

    “Several studies indicate that Fmr1 KO mice are hyperactive and show indications of increased anxiety (Bakker et al., 1994; Mineur et al., 2002; Spencer et al., 2005) and sensory hyperre-sponsiveness, especially to auditory stimuli (Chen and Toth, 2001; Frankland et al., 2004; Nielsen et al., 2002).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Bakker et al., 1994

      Not checked in the free run.

    • cites Mineur et al., 2002 source

      Not checked in the free run.

    • cites Spencer et al., 2005 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The quality of an animal model is ascertained based on how well it can meet criteria of validity: construct, face and predictive validity.

    “The quality of an animal model is ascertained based on how well it can meet certain criteria of validity. Three of these criteria are construct, face and predictive validity (Bernardet and Crusio, 2006).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Bernardet and Crusio, 2006

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Fmr1 KO mice, compared to wild-type, have lower than normal levels of initial social interactions, fail to show a preference for social novelty, and display inappropriate social responses.

    “Fmr1 KO, in comparison to the wild-type (WT) strain, are described as having lower than normal levels of initial social interactions (Mineur et al., 2006), fail to show a preference for social novelty, and display inappropriate social responses (Pietropaolo et al., 2011).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Mineur et al., 2006 source

      Not checked in the free run.

    • cites Pietropaolo et al., 2011 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    OT and AVP knockout mice display high levels of social contact that does not diminish over time, but also fail to show indication of familiarity.

    “In contrast, the OT and AVP knockout (OTKO or AVPKO) mice display high levels of social contact that does not diminish over time, but also fail to show indication of familiarity (Crawley et al., 2007).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Crawley et al., 2007 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In research by Pietropaolo et al. (2011), the Fmr1 KO on the B6 background was found to be a good model for Fragile X syndrome and a suitable model for ASD.

    “They found the Fmr1 KO on the B6 background to be a good model for FXS and a suitable model for ASD (Pietropaolo et al., 2011; Yan et al., 2004).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Pietropaolo et al., 2011 source

      Not checked in the free run.

    • cites Yan et al., 2004 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationnone given

    Symptom variability among mouse models for Fragile X syndrome may be due to differences in genetic backgrounds.

    “The symptom variability among mouse models for FXS may be due to differences in genetic backgrounds.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Fmr1 KO mice have neuropathologic phenotypes similar to Fragile X syndrome patients including density of dendritic spines of pyramidal neurons in the visual and somatosensory cortices that are greater in adult Fmr1 KO than WT.

    “These mice also have neuropathologic phenotypes that are similar to FXS patients including density of dendritic spines of pyramidal neurons in the visual and somatosensory cortices that are greater in adult Fmr1 KO than WT.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    The preliminary data shown here for Fmr1 KO mice need to be replicated in a larger sample and in other animal models.

    “Although the preliminary data shown here for Fmr1 KO mice need to be replicated in a larger sample and in other animal models, we include these findings as an example of possible approaches to examining the role of peptides including, OT and AVP, in molecularly characterized genetic syndromes.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    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.

    “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.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Earlier work in voles has suggested that either OT or AVP may support a general tendency toward social contact.

    “Earlier work in voles has suggested that either OT or AVP may support a general tendency toward social contact (Cho et al., 1999).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Cho et al., 1999 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    These changes may impact behavior and emotional regulation through a variety of molecular and neuroendocrine pathways.

    “These changes may impact behavior and emotional regulation through a variety of molecular and neuroendocrine pathways.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Fmr1 KO mice exhibit abnormal social interactions, including a general reduction in social contact and a failure to show social recognition.

    “Fmr1 KO also exhibit abnormal social interactions, including a general reduction in social contact and a failure to show social recognition (Bernardet and Crusio, 2006; Mineur et al., 2006; Spencer et al., 2005; Yan et al., 2004).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Bernardet and Crusio, 2006

      Not checked in the free run.

    • cites Mineur et al., 2006 source

      Not checked in the free run.

    • cites Spencer et al., 2005 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A subset of the genetic region associated with Prader-Willi syndrome is also associated with an increased risk for ASD, as maternally inherited duplications of the 15q11-13 region are associated with 1-3% of ASD cases.

    “A subset of the genetic region associated with PWS is also associated with an increased risk for ASD, as maternally inherited duplications of the 15q11–13 region are associated with 1–3% of ASD cases (Bolton et al., 2001; Cook et al., 1997; Vorstman et al., 2006).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Bolton et al., 2001 source

      Not checked in the free run.

    • cites Cook et al., 1997

      Not checked in the free run.

    • cites Vorstman et al., 2006 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    As summarized in this review, the dysregulation of the OT system in animals and humans is associated with marked deficits in social behavior as well as anxiety.

    “As summarized in this review, the dysregulation of the OT system in animals and humans is associated with marked deficits in social behavior as well as anxiety.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: OT and AVP are important to mammalian social behaviors and anxiety.

  • May combine two claims.

    Premisecitation

    Mutations in mGluR5 can contribute to the diagnosis of Fragile X syndrome or ASD, and mGluR5 antagonists have shown promise in alleviating ASD symptoms in mouse models as well as Fragile X syndrome pathology.

    “Studies of FXS and ASD mechanisms may also inform each other, as mutations in mGluR5 can contribute to the diagnosis of FXS or ASD, and mGluR5 antagonists have shown promise in alleviating ASD symptoms in mouse models (Silverman et al., 2012) as well as FXS pathology.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Silverman et al., 2012 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    As in ASD, individuals with Prader-Willi syndrome have difficulty with social competence, are aloof and avoid eye contact.

    “For example, as in ASD, individuals with PWS have difficulty with social competence (Dimitropoulos et al., 2013), are aloof and avoid eye contact (Dimitropoulos et al., 2009).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Dimitropoulos et al., 2013 source

      Not checked in the free run.

    • cites Dimitropoulos et al., 2009 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Individuals with Prader-Willi syndrome have shown lower levels of OT in CSF and fewer OT producing cells in the PVN.

    “Individuals with PWS have shown lower levels of OT in CSF (Martin et al., 1998) and fewer OT producing cells in the PVN (Swaab et al., 1995).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Martin et al., 1998 source

      Not checked in the free run.

    • cites Swaab et al., 1995

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    There are over 103 disease genes and 44 genomic loci reported to be involved in ASD.

    “In contrast, there are over a 103 disease genes and 44 genomic loci reported to be involved in ASD (Betancur, 2011).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Betancur, 2011 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisereasoning

    Due to the rarity of these disorders and the complex animal models needed to study them, many of these experiments have small sample sizes.

    “Due to the rarity of these disorders and the complex animal models needed to study them, many of these experiments have small sample sizes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Williams syndrome is characterized by an increase in OT levels, as well as a deletion of the 7q11.23 region, as opposed to a de novo duplication which leads to ASD.

    “WS is characterized by an increase in OT levels (Dai et al., 2012), as well as a deletion of the 7q11.23 region, as opposed to a de novo duplication which leads to ASD (Sanders et al., 2011).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Dai et al., 2012 source

      Not checked in the free run.

    • cites Sanders et al., 2011 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Individuals with ASD show higher levels of social phobia and separation anxiety, as well as higher rates of RRB, while individuals with Williams syndrome have higher scores on measures of generalized anxiety.

    “Although both groups are at risk for anxiety, individuals with ASD show higher levels of social phobia and separation anxiety, as well as higher rates of RRB. However, individuals with WS have higher scores on measures of generalized anxiety (Rodgers et al., 2012).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Rodgers et al., 2012 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Williams syndrome and ASD share commonalities as both are marked by abnormal social phenotypes and anxiety.

    “WS and ASD also share commonalities as both are marked by abnormal social phenotypes and anxiety.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Unlike ASD research, there is a lack of human data on the pathophysiology of Fragile X syndrome, Williams syndrome and Prader-Willi syndrome, and pharmacological interventions.

    “However, unlike ASD research, there is a lack of human data on the pathophysiology of FXS, WS and PWS, and pharmacological interventions.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Many effective medical treatments, such as drugs for hypertension, modulate common neurochemical or hormone pathways that are downstream from etiologically contributing factors.

    “However, many effective medical treatments, such as drugs for hypertension, modulate common neurochemical or hormone pathways that are downstream from etiologically contributing factors.”
    Quote in the paperNot a substantial claim
71 of 71

  • The paper relies on this without support.

    There are currently no approved medications to treat the social deficits or restricted, repetitive behaviors that are core symptoms of ASD.

    “Unfortunately there are currently no approved medications to treat the social deficits or restricted, repetitive behaviors (RRB) that are the core symptoms of ASD.”

  • The paper relies on this without support.

    Peripheral OT levels can serve as proxies for OT levels in the brain.

    “The inability to directly access the brain’s oxytocinergic pathways has constrained human research. Therefore, peripheral OT levels have been used as proxies for OT levels in the brain.”

  • The paper relies on this without support.

    OT and AVP are important to mammalian social behaviors and anxiety.

    “Given the importance of OT and AVP to mammalian social behaviors and anxiety, the neuropeptides’ investigative value in these syndromes is not unexpected.”

  • The paper relies on this without support.

    The neurological basis of Fragile X syndrome symptoms is unknown.

    “While the genetic cause of FXS has been found, the neurological basis of FXS symptoms continues to be unknown.”

  • The paper relies on this without support.

    Very few studies had been performed to research the effect of intranasal oxytocin on Fragile X syndrome, especially in humans.

    “As of the time of publication, very few studies had been performed to research the effect of IN-OT on FXS, especially in humans.”

  • The paper relies on this without support.

    There is a lack of human data on the pathophysiology of Fragile X syndrome, Williams syndrome and Prader-Willi syndrome, and pharmacological interventions.

    “However, unlike ASD research, there is a lack of human data on the pathophysiology of FXS, WS and PWS, and pharmacological interventions.”
6 of 6

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Altered levels of OXT and OXTR in specific brain regions have been reported in animal models of psychiatric and neurodevelopmental disorders.

    “Altered levels of OXT and OXTR in specific regions of the brain have been reported in a number of animal models of psychiatric and neurodevelopmental disorders [116-119].”

    From Oxytocin Signaling in the Central Amygdala Modulates Emotion Discrimination in Mice (2019) · cites this paper as [119]

  • Hypothalamic disruptions of OT neurons have been reported in human patients with ASD related disorders and in knockout mice for ASD risk genes including Fmr1, Cntnap2, and Pten.

    “hypothalamic disruptions of OT neurons have been reported in human patients with ASD related disorders such as Prader Willi syndrome (Swaab et al., 1995), as well as in knockout mice for ASD risk genes including Fmr1 (Francis et al., 2014), Cntnap2 (Peñagarikano et al., 2015), and Pten (Page et al., 2009)”

    From Parallel social information processing circuits are differentially impacted in autism (2020) · cites this paper as Francis et al., 2014

Cites

Flagged first, then by citations

6 of the 214 references couldn’t be matched to a known paper.

Research works printed but not linked: 1

  1. Kirsch, 2005, Oxytocin modulates neural circuitry for social cognition and fear in humans, J. Neurosci., 25, 11489, 10.1523/jneurosci.3984-05.2005 · DOI · Paper page

Cited by

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Related

Authors
Francis, S. M., Sagar, A., Levin-Decanini, T., Liu, W., Carter, C. S., & Jacob, S.
Affiliations
  • University of Minnesota (US)
  • University of California, Irvine (US)
  • Northwestern University (US)
  • University of North Carolina at Chapel Hill (US)
Corresponding author
Jacob, S.
ORCID
Venue
Brain Research
Publisher
Elsevier BV
Published
2014-09
Volume
1580
Pages
199-218
ISSN
0006-8993 (ISSN-L)
DOI
10.1016/j.brainres.2014.01.021
PMC
PMC4305432
OpenAlex
W1975206718
Semantic Scholar
ab37baa7ebd0517780b105dfcd434982cfb73662
Cited by
101
References
214
Citations by year
2026: 1 · 2025: 6 · 2024: 5 · 2023: 6 · 2022: 10 · 2021: 12 · 2020: 9 · 2019: 7 · 2018: 6 · 2017: 7 · 2016: 14 · 2015: 11 · 2014: 6
FWCI
1.81
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Brain Research (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
  • UNC Libraries
Funders
  • National Institutes of Health
  • National Institute of Mental Health (L40 MH072451, K23MH082121)
Topics
  • Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
Keywords
oxytocin, vasopressin, neurodevelopmental disorders, autism spectrum disorder, Prader-Willi syndrome, Williams syndrome, fragile X syndrome, FMR1 gene, social behavior deficits, oxytocin therapy
MeSH terms
Animals, Brain, Child Development Disorders, Pervasive, Fragile X Syndrome, Humans, Oxytocin, Prader-Willi Syndrome, Psychotropic Drugs, Vasopressins, Williams Syndrome

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

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