Structural and Lipidomic Alterations of Striatal Myelin in 16p11.2 Deletion Mouse Model of Autism Spectrum Disorder

Ju, Jun; Yang, Xiuyan; Jiang, Jian; Wang, Dilong; Zhang, Yumeng; Zhao, Xiaofeng; Fang, Xiaoyi; Liao, Huanquan; Zheng, Lei; Li, Shupeng; Hou, Sheng T.; Liang, Liyang; Pan, Yihang; Li, Hui‐Liang; Li, Ningning

doi:10.3389/fncel.2021.718720

Cited by 9 publications

(11 citation statements)

References 31 publications

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“…In spinal cord, the thickness of the myelin sheath was decreased on an ultrastructural level accordingly, while in corpus callosum such alterations were not visible. Alterations of MBP expression usually are reported to be accompanied by changes in myelin thickness and g-ratio, respectively [ 65 , 66 ]. MBP is an essential structural protein of the myelin sheath ensuring the compaction of the myelin membranes [ 67 ].…”

Section: Discussionmentioning

confidence: 99%

SHANK3 deficiency leads to myelin defects in the central and peripheral nervous system

Malara

Lutz

Incearap

et al. 2022

Cell. Mol. Life Sci.

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Mutations or deletions of the SHANK3 gene are causative for Phelan–McDermid syndrome (PMDS), a syndromic form of autism spectrum disorders (ASDs). We analyzed Shank3Δ11(−/−) mice and organoids from PMDS individuals to study effects on myelin. SHANK3 was found to be expressed in oligodendrocytes and Schwann cells, and MRI analysis of Shank3Δ11(−/−) mice revealed a reduced volume of the corpus callosum as seen in PMDS patients. Myelin proteins including myelin basic protein showed significant temporal and regional differences with lower levels in the CNS but increased amounts in the PNS of Shank3Δ11(−/−) animals. Node, as well as paranode, lengths were increased and ultrastructural analysis revealed region-specific alterations of the myelin sheaths. In PMDS hiPSC-derived cerebral organoids we observed an altered number and delayed maturation of myelinating cells. These findings provide evidence that, in addition to a synaptic deregulation, impairment of myelin might profoundly contribute to the clinical manifestation of SHANK3 deficiency.

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Section: Discussionmentioning

confidence: 99%

SHANK3 deficiency leads to myelin defects in the central and peripheral nervous system

Malara

Lutz

Incearap

et al. 2022

Cell. Mol. Life Sci.

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“…Three-chamber test Social preference and social recognition of mice were assessed in a three-chamber apparatus (60 x 40 x 20 cm, L x W x H) as previously described [34,35]. Brie y, the apparatus was divided into three interconnected chambers with the left and right chambers contained one small cage each, while the middle chamber was empty.…”

Section: Behavioral Tests On Micementioning

confidence: 99%

“…Open eld test Grooming, voluntary movement and anxiety behavior of mice were assessed in an open box (40 x 40 x 40 cm, L x W x H) as previously described [35,37]. Brie y, the open box was divided equally into 16 smaller grids and the central 4 grids were set as the central area (20 x 20 cm).…”

Section: Behavioral Tests On Micementioning

confidence: 99%

“…Novel object recognition Recognition memoryof mice was assessed in a box (40 x 40 x 40 cm, L x W x H) as previously described [35,38]. After 10-min habituation in the box, the test mouse was exposed to two identical objects for another 10 min.…”

Section: Behavioral Tests On Micementioning

confidence: 99%

“…Elevated plus maze The anxiety behavior of mice was assessed in a 1 m height platform consisting of 4 arms (two open arms and two closed arms crossed together) as previously described [35]. The test mouse was initially placed in the central area and their trails were recorded for 5 min.…”

Section: Behavioral Tests On Micementioning

confidence: 99%

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Excess Escherichia elicits mild autism spectrum disorder in young subjects via disturbing the balance of gut microbial GABA metabolism

Wang¹,

Wang²,

Pan³

et al. 2022

Preprint

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Background: Accumulating clinical evidence demonstrated that gut microbiota (GM) transfer substantially ameliorated autistic symptoms, implying a role of GM in autism spectrum disorder (ASD). Continuous investigation reported GM alteration in ASD individuals, while inconsistency also persists in the abundance of bacterial taxon, as well as their metabolites. Due to deficiencies of stringent study designs, multi-omics assessment, and even animal tests, such data heterogeneity is yet to be addressed, which impedes establishing a causal effect of a specific microbiome-metabolome axis on pathogenesis of ASD.Results: We developed a participant recruitment and sampling procedure that fully considered possible intergroup and intragroup confounders, including age, diet, severity of ASD, and stool consistency. To tease out biological features of ASD from an overarching investigation on metabolome, composition and function of GM, we compared faecal samples collected from 123 children with either mild ASD (n=56) or typical development (TD) (n=67). Metabolite profiling of targeted metabolomics screened and validated a significantly higher ratio of gamma-aminobutyric acid (GABA) to glutamate (Glu) as a metabolic signature of ASD. Linked to autistic symptomatology, the microbial GABA/Glu ratio independently distinguished ASD from TD subjects, particularly at 3-5 years. The 16S rRNA gene sequencing displayed substantially declined GM richness but over-presented genus Escherichia in ASD, which was profoundly associated with the increased GABA/Glu ratio. Metagenomics confirmed both structural and metabolic dysbiosis of GM via revealing consistent changes in microbial components and Escherichia abundance, and highlighting overall hypofunction of the GM and imbalanced GABA/Glu synthesis in ASD. We further identified a series of E. coli-specific adhesins that linked Escherichia colonization with GABA production. Quantitative PCR validation supported increment of Escherichia-specific glutamate decarboxylase, promoting GABA synthesis. Further, challenge of healthy weaning mice with gut commensal E. coli induced significant social deficiency, but not abnormalities in repetitive, locomotor, recognition memory- and anxiety-related behaviors. Conclusions: Our multi-omics study elucidated a microbe-metabolite axis out of GM dysbiosis in mild ASD, characterized by over-presented Escherichia and concomitant GABA/Glu imbalance, which were well-marked features of ASD-linked GM at an early age, and potential causal factors of autistic symptomology. Our study provided insight into importance of microbial excitatory/inhibitory neurotransmitters imbalance in diagnosis and therapeutic treatment of ASD.

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Microduplication of 16p11.2 locus Potentiates Hypertrophic Obesity in Association with Imbalanced Triglyceride Metabolism in White Adipose Tissue

Wang

Mai

Yang

et al. 2022

Molecular Nutrition Food Res

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Scope: Copy number variation (CNV) of 16p11.2 is a common genetic factor contributing to the etiology of abnormal weight status, while the underlying mechanism is not fully elucidated yet. Methods and Results: The 16p11.2 CNV mouse model with microduplication of the 7Slx1b-Sept1 region (dp/+) is evaluated under normal chow conditions. Compared to the wild type littermates (WT), the dp/+ mice exhibit obvious obese phenotype characterized by significant increase in body mass index, fat pad mass, and fat ratio, with visceral-dominant fat deposits at 12-week age. White adipose tissue (WAT), liver tissue, and plasma are sampled to assess the comorbid metabolic syndrome. In dp/+ mice, histopathologic analyses reveal hypertrophic adipocytes and hepatic steatosis; serological examinations show hyperlipemia and hyperinsulinemia. Further, by comparing lipidomic and transcriptomic profiling of epididymal WAT between dp/+ and WT mice, the study finds the triglyceride (TG) accumulation in dp/+ mice in association with the dysfunction of lipid droplets. Validation of TG-metabolism-associated genes in WAT and in primary cultured adipocytes show enhanced TG synthesis and declined TG hydrolysis in the dp/+ model. Conclusion: This study elucidates that the imbalanced TG synthesis/hydrolysis in adipocytic lipid droplets may contribute to the hypertrophic obesity and metabolic disorders in mice with 16p11.2 microduplication.

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Structural and Lipidomic Alterations of Striatal Myelin in 16p11.2 Deletion Mouse Model of Autism Spectrum Disorder

Cited by 9 publications

References 31 publications

SHANK3 deficiency leads to myelin defects in the central and peripheral nervous system

SHANK3 deficiency leads to myelin defects in the central and peripheral nervous system

Excess Escherichia elicits mild autism spectrum disorder in young subjects via disturbing the balance of gut microbial GABA metabolism

Microduplication of 16p11.2 locus Potentiates Hypertrophic Obesity in Association with Imbalanced Triglyceride Metabolism in White Adipose Tissue

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