Deficiency of the paternally inherited gene <i>Magel2</i> alters the development of separation‐induced vocalization and maternal behavior in mice

Ortiz, Gabriela M Bosque; Santana, Gustavo M.; Dietrich, Marcelo O

doi:10.1111/gbb.12776

Cited by 14 publications

(23 citation statements)

References 46 publications

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“…We have demonstrated the existence of a substantial proportion of unretrieved Magel2 +/−p pups by their WT dams as well as a delayed latency to retrieve the rest of them under cool exposure. Deficit in maternal care of Magel2 +/−p has been reported recently to occur specifically at P8 but not P6 [ 57 ]. Whilst they used a different Magel2 mutant mouse model (Magel2 tm1Stw ) and a distinct experimental approach, the difference in age is also an important factor.…”

Section: Discussionmentioning

confidence: 99%

Early life oxytocin treatment improves thermo-sensory reactivity and maternal behavior in neonates lacking the autism-associated gene Magel2

Prato

Zayan

Abdallah

et al. 2022

Neuropsychopharmacol.

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Atypical responses to sensory stimuli are considered as a core aspect and early life marker of autism spectrum disorders (ASD). Although recent findings performed in mouse ASD genetic models report sensory deficits, these were explored exclusively during juvenile or adult period. Whether sensory dysfunctions might be present at the early life stage and rescued by therapeutic strategy are fairly uninvestigated. Here we found that under cool environment neonatal mice lacking the autism-associated gene Magel2 present pup calls hypo-reactivity and are retrieved with delay by their wild-type dam. This neonatal atypical sensory reactivity to cool stimuli was not associated with autonomic thermoregulatory alteration but with a deficit of the oxytocinergic system. Indeed, we show in control neonates that pharmacogenetic inactivation of hypothalamic oxytocin neurons mimicked atypical thermosensory reactivity found in Magel2 mutants. Furthermore, pharmacological intranasal administration of oxytocin to Magel2 neonates was able to rescue both the atypical thermosensory response and the maternal pup retrieval. This preclinical study establishes for the first-time early life impairments in thermosensory integration and suggest a therapeutic potential benefit of intranasal oxytocin treatment on neonatal atypical sensory reactivity for autism.

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Section: Discussionmentioning

confidence: 99%

Early life oxytocin treatment improves thermo-sensory reactivity and maternal behavior in neonates lacking the autism-associated gene Magel2

Prato

Zayan

Abdallah

et al. 2022

Neuropsychopharmacol.

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“…An analogous affect on attention-getting is also seen in a mouse model for AS that have increased ultrasonic vocalisations (USVs), which are used to signal to their mothers and elicit care-giving [ 109 ]. Fascinatingly, a recent study of mice lacking the PWS gene Magel2 demonstrated the opposite phenotype; decreased USVs that led to reduced caregiving from the dam [ 110 ].…”

Section: Why Should Imprinted Genes Be Involved In Brain Function At ...mentioning

confidence: 99%

The contribution of imprinted genes to neurodevelopmental and neuropsychiatric disorders

Isles

2022

Transl Psychiatry

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Imprinted genes are a subset of mammalian genes that are subject to germline parent-specific epigenetic modifications leading monoallelic expression. Imprinted gene expression is particularly prevalent in the brain and it is unsurprising that mutations affecting their expression can lead to neurodevelopmental and/or neuropsychiatric disorders in humans. Here I review the evidence for this, detailing key neurodevelopmental disorders linked to imprinted gene clusters on human chromosomes 15q11-q13 and 14q32, highlighting genes and possible regulatory links between these different syndromes. Similarly, rare copy number variant mutations at imprinted clusters also provide strong links between abnormal imprinted gene expression and the predisposition to severe psychiatric illness. In addition to direct links between brain-expressed imprinted genes and neurodevelopmental and/or neuropsychiatric disorders, I outline how imprinted genes that are expressed in another tissue hotspot, the placenta, contribute indirectly to abnormal brain and behaviour. Specifically, altered nutrient provisioning or endocrine signalling by the placenta caused by abnormal expression of imprinted genes may lead to increased prevalence of neurodevelopmental and/or neuropsychiatric problems in both the offspring and the mother.

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“…In particular, neonate Magel2 -KO mice show feeding defects due to an altered onset of suckling activity, leading to neonatal growth retardation and a high mortality rate (approx. 50%) ( Schaller et al, 2010 ); feeding defects are accompanied by low rates of separation-induced vocalizations and altered spectral features ( Bosque Ortiz et al, 2022 ). The surviving adult Magel2 -KO mice have been extensively investigated for alterations in sensory-motor, cognitive and social abilities.…”

Section: Introductionmentioning

confidence: 99%

Oxytocin receptors in the Magel2 mouse model of autism: Specific region, age, sex and oxytocin treatment effects

et al. 2023

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The neurohormone oxytocin (OXT) has been implicated in the regulation of social behavior and is intensively investigated as a potential therapeutic treatment in neurodevelopmental disorders characterized by social deficits. In the Magel2-knockout (KO) mouse, a model of Schaaf-Yang Syndrome, an early postnatal administration of OXT rescued autistic-like behavior and cognition at adulthood, making this model relevant for understanding the actions of OXT in (re)programming postnatal brain development. The oxytocin receptor (OXTR), the main brain target of OXT, was dysregulated in the hippocampus of Magel2-KO adult males, and normalized upon OXT treatment at birth. Here we have analyzed male and female Magel2-KO brains at postnatal day 8 (P8) and at postnatal day 90 (P90), investigating age, genotype and OXT treatment effects on OXTR levels in several regions of the brain. We found that, at P8, male and female Magel2-KOs displayed a widespread, substantial, down-regulation of OXTR levels compared to wild type (WT) animals. Most intriguingly, the postnatal OXT treatment did not affect Magel2-KO OXTR levels at P8 and, consistently, did not rescue the ultrasonic vocalization deficits observed at this age. On the contrary, the postnatal OXT treatment reduced OXTR levels at P90 in male Magel2-KO in a region-specific way, restoring normal OXTR levels in regions where the Magel2-KO OXTR was upregulated (central amygdala, hippocampus and piriform cortex). Interestingly, Magel2-KO females, previously shown to lack the social deficits observed in Magel2-KO males, were characterized by a different trend in receptor expression compared to males; as a result, the dimorphic expression of OXTR observed in WT animals, with higher OXTR expression observed in females, was abolished in Magel2-KO mice. In conclusion, our data indicate that in Magel2-KO mice, OXTRs undergo region-specific modifications related to age, sex and postnatal OXT treatment. These results are instrumental to design precisely-timed OXT-based therapeutic strategies that, by acting at specific brain regions, could modify the outcome of social deficits in Schaaf-Yang Syndrome patients.

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Deficiency of the paternally inherited gene Magel2 alters the development of separation‐induced vocalization and maternal behavior in mice

Cited by 14 publications

References 46 publications

Early life oxytocin treatment improves thermo-sensory reactivity and maternal behavior in neonates lacking the autism-associated gene Magel2

Early life oxytocin treatment improves thermo-sensory reactivity and maternal behavior in neonates lacking the autism-associated gene Magel2

The contribution of imprinted genes to neurodevelopmental and neuropsychiatric disorders

Oxytocin receptors in the Magel2 mouse model of autism: Specific region, age, sex and oxytocin treatment effects

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