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

Gigliucci, Valentina; Busnelli, Marta; Santini, Francesca; Paolini, Camilla; Bertoni, Alessandra; Schaller, Fabienne; Muscatelli, Françoise; Chini, Bice

doi:10.3389/fnins.2023.1026939

Cited by 11 publications

(2 citation statements)

References 72 publications

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“…Magel2 was expressed in arcuate nucleus of hypothalamus, overlapping with vasopressin positive neurons 44 . The abnormality of Magel2 has been confirmed to be involved in neurological disease development 45 . Cybb is mainly expressed in granulocyte, and mouse brain microglia 46 .…”

Section: Discussionmentioning

confidence: 92%

Transplantation of gut microbiota derived from patients with schizophrenia induces schizophrenia-like behaviors and dysregulated brain transcript response in mice

Wei,

Ju,

et al. 2024

Schizophr

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Schizophrenia (SCZ), as a neurodevelopmental disorder and devastating disease, affects approximately 1% of the world population. Although numerous studies have attempted to elucidate the causes of SCZ occurrence, it is not clearly understood. Recently, the emerging roles of the gut microbiota in a range of brain disorders, including SCZ, have attracted much attention. While the molecular mechanism of gut microbiota in regulating the pathogenesis of SCZ is still lacking. Here, we first confirmed the difference of gut microbiome between SCZ patients and healthy controls, and then, we performed fecal microbiota transplantation (FMT) to clarify the roles of SCZ patients-derived microbiota in a specific pathogen free (SPF) mice model. 16 S rDNA sequencing confirmed that a significant difference of gut microbiome was present between two groups of FMT mice, which has a similar trend with the above human gut microbiome. Furthermore, we found that transplantation of fecal microbiota from SCZ patients into SPF mice was sufficient to induce schizophrenia-like (SCZ-like) symptoms, such as deficits in sociability and hyperactivity. Furthermore, the brains of mice colonized with SCZ microbiota displayed dysregulated transcript response and alternative splicing of SCZ-relevant genes. Moreover, 10 key genes were identified to be correlated with SCZ by an integrative transcriptome data analysis. Finally, 4 key genes were identified to be correlated with the 12 differential genera between two groups of FMT mice. Our results thus demonstrated that the gut microbiome might modify the transcriptomic profile in the brain, thereby modulating social behavior, and our present study can help better understand the link between gut microbiota and SCZ pathogenesis through the gut-brain axis.

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Section: Discussionmentioning

confidence: 92%

Transplantation of gut microbiota derived from patients with schizophrenia induces schizophrenia-like behaviors and dysregulated brain transcript response in mice

Wei,

Ju,

et al. 2024

Schizophr

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“…This is in apparent contrast to previous reports suggesting reduced OXT signaling contributes to heightened social fear (11,22,23). 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)).…”

Section: Discussionmentioning

confidence: 99%

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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Spatiotemporal Mapping of the Oxytocin Receptor at Single-Cell Resolution in the Postnatally Developing Mouse Brain

Li,

Wang

et al. 2024

Neurosci. Bull.

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The oxytocin receptor (OXTR) has garnered increasing attention for its role in regulating both mature behaviors and brain development. It has been established that OXTR mediates a range of effects that are region-specific or period-specific. However, the current studies of OXTR expression patterns in mice only provide limited help due to limitations in resolution. Therefore, our objective was to generate a comprehensive, high-resolution spatiotemporal expression map of Oxtr mRNA across the entire developing mouse brain. We applied RNAscope in situ hybridization to investigate the spatiotemporal expression pattern of Oxtr in the brains of male mice at six distinct postnatal developmental stages (P7, P14, P21, P28, P42, P56). We provide detailed descriptions of Oxtr expression patterns in key brain regions, including the cortex, basal forebrain, hippocampus, and amygdaloid complex, with a focus on the precise localization of Oxtr+ cells and the variance of expression between different neurons. Furthermore, we identified some neuronal populations with high Oxtr expression levels that have been little studied, including glutamatergic neurons in the ventral dentate gyrus, Vgat+Oxtr+ cells in the basal forebrain, and GABAergic neurons in layers 4/5 of the cortex. Our study provides a novel perspective for understanding the distribution of Oxtr and encourages further investigations into its functions.

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

Cited by 11 publications

References 72 publications

Transplantation of gut microbiota derived from patients with schizophrenia induces schizophrenia-like behaviors and dysregulated brain transcript response in mice

Transplantation of gut microbiota derived from patients with schizophrenia induces schizophrenia-like behaviors and dysregulated brain transcript response in mice

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

Spatiotemporal Mapping of the Oxytocin Receptor at Single-Cell Resolution in the Postnatally Developing Mouse Brain

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