Distinct promoter regions of the oxytocin receptor gene are hypomethylated in Prader-Willi syndrome and in Prader-Willi syndrome associated psychosis

Heseding, Hannah M.; Jahn, Kirsten; Eberlein, Christian; Maier, Henk; Proskynitopoulos, Phileas Johannes; Glahn, Alexander; Bleich, Stefan; Frieling, Helge; Deest, Maximilian

doi:10.1038/s41398-022-02014-9

Cited by 5 publications

(7 citation statements)

References 64 publications

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“…However, given that OXT receptors in Magel2 KO mice are downregulated (24), it is likely that the increased activity results from homeostatic compensation. A similar compensation is seen in PWS patients – while on one hand they report reduced methylation of OXT-receptor (25) and increased plasma OXT (26), treatment with OXT-receptor agonist improves symptoms of PWS in some clinical studies (27–29) (but not others (30)). Furthermore, spike broadening of OXT neurons as seen here is observed during lactation (31,32), suggesting that reduction of Ca 2+ spike duration observed in Magel2 KO mice reflects a physiologically relevant deficit.…”

Section: Discussionmentioning

confidence: 70%

Acquiring social safety engages oxytocin neurons in the supraoptic nucleus – role of Magel2 deficiency

Chakraborty,

Lamat,

André

et al. 2024

Preprint

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Introduction: Exposure to social trauma may alter engagement with both fear-related and unrelated social stimuli long after. Intriguingly, how simultaneous discrimination of social fear and safety is affected in neurodevelopmental conditions like autism remains underexplored. The role of the neuropeptide oxytocin is established in social behaviors, and yet unexplored during such a challenge post-social trauma. Methods: Using Magel2-knockout mice, an animal model of Prader Willi Syndrome (PWS) and autism spectrum disorders, we tested memory of social fear and safety after a modified social fear conditioning task. Additionally, we tracked the activity of oxytocin neurons in the supraoptic (SON) and paraventricular (PVN) nuclei of the hypothalamus by fibre photometry, as animals were simultaneously presented with a choice between a fear and safe social cue during recall. Results: Male Magel2 KO mice trained to fear females with electrical footshocks avoided both unfamiliar females and males during recalls, lasting even a week post-conditioning. On the contrary, trained Magel2 WT avoided only females during recalls, lasting days rather than a week postconditioning. Inability to overcome social fear and avoidance of social safety in Magel2 KO mice were associated with reduced engagement of oxytocin neurons in the SON, but not the PVN. Conclusion: In a preclinical model of PWS, we demonstrated region-specific deficit in oxytocin activity associated with behavioral generalization of social fear to social safety. Insights from this study add to our understanding of oxytocin action in the brain at the intersection of social trauma, PWS and related autism spectrum disorders.

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Section: Discussionmentioning

confidence: 70%

Acquiring social safety engages oxytocin neurons in the supraoptic nucleus – role of Magel2 deficiency

Chakraborty,

Lamat,

André

et al. 2024

Preprint

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“…A recent study reported lower methylation of the OXTR exon region 1 in males with PWS with psychosis compared to those without psychosis ( 28 ). We found no difference in OT or AVP levels between people with PWS with and without psychosis, however, only five individuals with PWS in our cohort had psychosis.…”

Section: Discussionmentioning

confidence: 97%

“…A recent study reported lower methylation in the intron 1 region of the OT receptor gene in DNA blood samples of individuals with PWS compared to age-, sex-and body mass index (BMI) matched controls. The authors further found males with PWS and psychosis showed significantly lower methylation of the OXTR exon region 1 than those without psychosis, suggesting that an OT deficiency in PWS might be associated with the higher rate of psychosis found in PWS (28). Regarding brain function, PWS has long been considered a disorder of the hypothalamus.…”

Section: Introductionmentioning

confidence: 99%

“…AVP has been shown to play a role in aggressive behaviours ( 44 ) and the regulation of emotion and autonomic systems ( 45 ). Since people with PWS have reduced OT-producing neurons ( 17 ) and their OT receptor gene may be methylated ( 28 ) it is possible that they also have a deficit in OT receptors ( 42 ). However, even if the OT receptor is not available, exogenous OT might potentially stimulate the AVP receptors, assuming these are still functional in PWS.…”

Section: Introductionmentioning

confidence: 99%

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The relationship between endogenous oxytocin and vasopressin levels and the Prader-Willi syndrome behaviour phenotype

Rice,

Agu,

Carter

et al. 2023

Front. Endocrinol.

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BackgroundOxytocin and vasopressin systems are altered in Prader Willi syndrome (PWS). However, investigations into endogenous oxytocin and vasopressin levels as well as clinical trials evaluating the effect of exogenous oxytocin on PWS symptoms have had mixed results. It is also unknown whether endogenous oxytocin and vasopressin levels are associated with certain PWS behaviours.MethodWe compared plasma oxytocin and vasopressin and saliva oxytocin levels in 30 adolescents and adults with PWS to 30 typically developing age-matched controls. We also compared neuropeptide levels between gender and genetic subtypes within the PWS cohort and examined the relationship between neuropeptide levels and PWS behaviours.ResultsWhile we did not measure a group difference in plasma or saliva oxytocin levels, plasma vasopressin was significantly lower in individuals with PWS compared to controls. Within the PWS cohort, saliva oxytocin levels were higher in females compared to males and individuals with the mUPD compared to the deletion genetic subtype. We also found the neuropeptides correlated with different PWS behaviours for males and females and for genetic subtypes. For the deletion group, higher plasma and saliva oxytocin levels were related to fewer behaviour problems. For the mUPD group, higher plasma vasopressin levels were related to more behaviour problems.ConclusionThese findings support existing evidence of a vasopressin system defect in PWS and for the first time identify potential differences in the oxytocin and vasopressin systems across PWS genetic subtypes.

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“…Prader–Willi Syndrome (PWS) is a rare neurodevelopmental disorder caused by a loss of paternally expressed genes on chromosome 15q11-q13 [ 1 ]. PWS newborn individuals are characterized by hypotonia that can lead to difficulties in sucking and require assisted feeding.…”

Section: Introductionmentioning

confidence: 99%

Oxytocin’s Regulation of Thermogenesis May Be the Link to Prader–Willi Syndrome

Camerino

2023

CIMB

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Prader–Willi Syndrome (PWS) is a genetic neurodevelopmental disorder that is caused by either the deletion of the paternal allele of 15q11-q13, maternal uniparental disomy of chromosome 15 or defects in the chromosome 15 imprinting centre and is characterized by cognitive impairment, hyperphagia and low metabolic rate with significant risk of obesity, as well as a variety of other maladaptive behaviours and autistic spectrum disorder (ASD). Many of the features seen in PWS are thought to be due to hypothalamic dysfunction resulting in hormonal abnormalities and impaired social functioning. The preponderance of evidence indicates that the Oxytocin system is dysregulated in PWS individuals and that this neuropeptide pathways may provide promising targets for therapeutic intervention although the process by which this dysregulation occurs in PWS awaits mechanistic investigation. PWS individuals present abnormalities in thermoregulation an impaired detection for temperature change and altered perception of pain indicating an altered autonomic nervous system. Recent studies indicate that Oxytocin is involved in thermoregulation and pain perception. This review will describe the update on PWS and the recent discoveries on Oxytocin regulation of thermogenesis together with the potential link between Oxytocin regulation of thermogenesis and PWS to create a new groundwork for the treatment of this condition.

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Distinct promoter regions of the oxytocin receptor gene are hypomethylated in Prader-Willi syndrome and in Prader-Willi syndrome associated psychosis

Cited by 5 publications

References 64 publications

Acquiring social safety engages oxytocin neurons in the supraoptic nucleus – role of Magel2 deficiency

Acquiring social safety engages oxytocin neurons in the supraoptic nucleus – role of Magel2 deficiency

The relationship between endogenous oxytocin and vasopressin levels and the Prader-Willi syndrome behaviour phenotype

Oxytocin’s Regulation of Thermogenesis May Be the Link to Prader–Willi Syndrome

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