FXR1 regulation of parvalbumin interneurons in the prefrontal cortex is critical for schizophrenia-like behaviors

Guo, Yu; Dong, Qiaoxiang; Gao, Yu; Stockton, Michael E.; Li, Meng; Kannan, Sudharsan; Korabelnikov, Tomer; Schoeller, Keegan A.; Sirois, Carissa L.; Zhou, Chen; Le, Jonathan; Wang, Daifeng; Chang, Qiang; Sun, Qian‐Quan; Zhao, Xinyu

doi:10.1038/s41380-021-01096-z

Cited by 27 publications

(20 citation statements)

References 92 publications

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“…Variants in FXR1 have been associated with several neuropsychiatric diseases, notably insomnia, bipolar disorder and schizophrenia 11 12. In addition, differential expression of FXR1 was reported in patients with schizophrenia 13. All three patients from family D had significant psychiatric manifestations (depression, bipolar disorder, social anxiety disorder, generalised anxiety disorder, attention deficit disorder, bulimia); however, the association of psychiatric manifestations with FXR1 pathogenic variants requires further study.…”

Section: Discussionmentioning

confidence: 98%

FXR1-related congenital myopathy: expansion of the clinical and genetic spectrum

et al. 2022

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BackgroundBiallelic pathogenic variants in FXR1 have recently been associated with two congenital myopathy phenotypes: a severe form associated with hypotonia, long bone fractures, respiratory insufficiency and infantile death, and a milder form characterised by proximal muscle weakness with survival into adulthood.ObjectiveWe report eight patients from four unrelated families with biallelic pathogenic variants in exon 15 of FXR1.MethodsWhole exome sequencing was used to detect variants in FXR1.ResultsCommon clinical features were noted for all patients, which included proximal myopathy, normal serum creatine kinase levels and diffuse muscle atrophy with relative preservation of the quadriceps femoris muscle on muscle imaging. Additionally, some patients with FXR1-related myopathy had respiratory involvement and required bilevel positive airway pressure support. Muscle biopsy showed multi-minicores and type I fibre predominance with internalised nuclei.ConclusionFXR1-related congenital myopathy is an emerging entity that is clinically recognisable. Phenotypic variability associated with variants in FXR1 can result from differences in variant location and type and is also observed between patients homozygous for the same variant, rendering specific genotype–phenotype correlations difficult. Our work broadens the phenotypic spectrum of FXR1-related congenital myopathy.

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Section: Discussionmentioning

confidence: 98%

FXR1-related congenital myopathy: expansion of the clinical and genetic spectrum

et al. 2022

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“…Besides neuroimaging studies, genetic studies have indicated mPFC as a potential key region in the pathophysiological mechanisms behind insomnia problems in SCZ. Shen et al found that deleting FXR1 gene, of which the variants are linked to shorter sleep duration 68 , from parvalbumin interneurons of mPFC leads to impaired mPFC gamma oscillation and SCZ-like behaviors 69 . The large GWAS study in 1,331,010 individuals also showed insomnia-related gene set enrichments in frontal cortex, which have correlations with psychiatric traits 70 .…”

Section: Discussionmentioning

confidence: 99%

Comparisons of resting-state brain activity between insomnia and schizophrenia: a coordinate-based meta-analysis

et al. 2022

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Growing evidence shows that insomnia is closely associated with schizophrenia (SCZ), but the neural mechanism under the association remains unclear. A direct comparison of the patterns of resting-state brain activities would help understand the above question. Using meta-analytic approach, 11 studies of insomnia vs. healthy controls (HC) and 39 studies of SCZ vs. HC were included to illuminate the common and distinct patterns between insomnia and SCZ. Results showed that SCZ and insomnia shared increased resting-state brain activities in frontolimbic structures including the right medial prefrontal gyrus (mPFC) and left parahippocampal gyrus. SCZ additionally revealed greater increased activities in subcortical areas including bilateral putamen, caudate and right insula and greater decreased activities in precentral gyrus and orbitofrontal gyrus. Our study reveals both shared and distinct activation patterns in SCZ and insomnia, which may provide novel insights for understanding the neural basis of the two disorders and enlighten the possibility of the development of treatment strategies for insomnia in SCZ in the future.

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“…A number of studies have implicated inhibitory neurons in NDDs [ 2 , 3 , 17 , 18 ]. Telencephalic inhibitory neurons are born in the transitory ganglionic eminences (GEs), which are subdivided into three regions—the medial, caudal, and lateral eminences (MGE, CGE, and LGE, respectively) (Fig.…”

Section: The Developing Human Brain In High Resolutionmentioning

confidence: 99%

Neurodevelopmental disorders—high-resolution rethinking of disease modeling

Khodosevich

Sellgren

2022

Mol Psychiatry

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Neurodevelopmental disorders arise due to various risk factors that can perturb different stages of brain development, and a combinatorial impact of these risk factors programs the phenotype in adulthood. While modeling the complete phenotype of a neurodevelopmental disorder is challenging, individual developmental perturbations can be successfully modeled in vivo in animals and in vitro in human cellular models. Nevertheless, our limited knowledge of human brain development restricts modeling strategies and has raised questions of how well a model corresponds to human in vivo brain development. Recent progress in high-resolution analysis of human tissue with single-cell and spatial omics techniques has enhanced our understanding of the complex events that govern the development of the human brain in health and disease. This new knowledge can be utilized to improve modeling of neurodevelopmental disorders and pave the way to more accurately portraying the relevant developmental perturbations in disease models.

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FXR1 regulation of parvalbumin interneurons in the prefrontal cortex is critical for schizophrenia-like behaviors

Cited by 27 publications

References 92 publications

FXR1-related congenital myopathy: expansion of the clinical and genetic spectrum

FXR1-related congenital myopathy: expansion of the clinical and genetic spectrum

Comparisons of resting-state brain activity between insomnia and schizophrenia: a coordinate-based meta-analysis

Neurodevelopmental disorders—high-resolution rethinking of disease modeling

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