Vascular contributions to 16p11.2 deletion autism syndrome modeled in mice

Ouellette, Julie; Toussay, Xavier; Comin, César H.; Costa, Luciano da Fontoura; Ho, M.; Lacalle‐Aurioles, María; Freitas-Andrade, Moises; Liu, Qing Yan; Leclerc, Sonia; Pan, Youlian; Liu, Ziying; Thibodeau, Jean-François; Yin, Melissa; Carrier, Micaël; Morse, Cameron J; Dyken, Peter Van; Bergin, Christopher J.; Baillet, Sylvain; Kennedy, C. R.; Tremblay, Marie‐Ève; Benoit, Yannick D.; Stanford, William L.; Burger, Dylan; Stewart, Duncan J.; Lacoste, Baptiste

doi:10.1038/s41593-020-0663-1

Cited by 90 publications

(122 citation statements)

References 71 publications

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“…Indeed, the CLAMS consists of relatively small individual cages, limiting animal mobility. For instance, in a normal home cage environment, male and female 16p11.2 df/+ mice are hyperactive ( Horev et al, 2011 ; Ouellette et al, 2020 ), and the majority of 16p11.2 deletion human carriers display hyperactivity ( Miller et al, 2009 ). However, the limited space offered by CLAMS cages serves to control for metabolic measures, enabling accurate assessment of basal metabolism independent of activity.…”

Section: Discussionmentioning

confidence: 99%

“…Compared with their wild-type (WT) littermates, 16p11.2 df/+ mice display alterations including social interactions deficits and hyperactivity. These mice also display lower birthweight and decreased adiposity in adults, improved glucose tolerance, decreased leptin and free fatty acid levels, as well as cerebrovascular deficits ( Horev et al, 2011 ; Portmann et al, 2014 ; Arbogast et al, 2016 ; Ouellette et al, 2020 ). Finally, Fmr1 −/− knock-out (KO) mice are commonly used to model human FXS.…”

Section: Introductionmentioning

confidence: 99%

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Distinct Basal Metabolism in Three Mouse Models of Neurodevelopmental Disorders

Menzies

Naz

Patten

et al. 2021

eNeuro

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C.M. performed all in vivo experiments involving CLAMS and EchoMRI with data analysis, extracted metabolites from blood samples, and prepared the manuscript draft. S.N. and D.P. performed all in vitro metabolomic measurements of plasma metabolites and associated data analysis, as well as assisted with writing. T.A. supplied expertise in metabolic phenotyping and assisted with data interpretation and writing. B.M.B. supplied Down syndrome mice, expertise in metabolism and Down syndrome, and assisted with writing. B.L. conceived and led the project, performed and supervised data analysis, and finalized the manuscript. Distinct basal metabolism in three mouse models of neurodevelopmental disorders

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Distinct Basal Metabolism in Three Mouse Models of Neurodevelopmental Disorders

Menzies

Naz

Patten

et al. 2021

eNeuro

Self Cite

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“…For example, Gfap-mediated deletion of Cerebral cavernous malformation 3 (Ccm3) in mice demonstrate cell non-autonomous effects on vascular development similar to Cerebral cavernous malformation disease in humans (Louvi et al, 2011). Additionally, a recent study with a 16p11.2 deletion autism syndrome mouse model displays cerebral angiogenesis impairments that lead to future neurovascular detriments (Ouellette et al, 2020). While Ouellette and colleagues did not see any changes in astrocytes surrounding postnatal and adult blood vessels, it would be interesting to look at embryonic stages and assess the radial glial that may stabilize the nascent This is a provisional file, not the final typeset article vessels that develop abnormally.…”

Section: Future Directionsmentioning

confidence: 99%

Using zebrafish to elucidate glial-vascular interactions during CNS development

Umans

Pollock

Mills

et al. 2021

Preprint

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An emerging area of interest in Neuroscience is the cellular relationship between glia and blood vessels, as many of the presumptive support roles of glia require an association with the vasculature. These interactions are best studied in vivo and great strides have been made using mice to longitudinally image glial-vascular interactions. However, these methods are cumbersome for developmental studies, which could benefit from a more accessible system. Zebrafish (Danio rerio) are genetically tractable vertebrates, and given their translucency, are readily amenable for daily live imaging studies. We set out to examine whether zebrafish glia have conserved traits with mammalian glia regarding their ability to interact with and maintain the developing brain vasculature. We utilized transgenic zebrafish strains in which oligodendrocyte transcription factor 2 (olig2) and glial fibrillary acidic protein (gfap) identify different glial populations in the zebrafish brain and document their corresponding relationship with brain blood vessels. Our results demonstrate that olig2 and gfap zebrafish glia have distinct lineages and each interact with brain vessels as previously observed in mouse brain. Additionally, we manipulated these relationships through pharmacological and genetic approaches to distinguish the roles of these cell types during blood vessel development. olig2 glia use blood vessels as a pathway during their migration and Wnt signaling inhibition decreases their single-cell vessel co-option. By contrast, the ablation of gfap glia at the beginning of CNS angiogenesis impairs vessel development through a reduction in Vascular endothelial growth factor (Vegf), supporting a role for gfap glia during new brain vessel formation in zebrafish. This data suggests that zebrafish glia, akin to mammalian glia, have different lineages that show diverse interactions with blood vessels, and are a suitable model for elucidating glial-vascular relationships during vertebrate brain development.

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“…To gain mechanistic insights on the effects of chronic social and variable stress on BBB biology and properties we performed transcriptome-wide gene expression profiling of female PFC endothelial cells. Female mice were subjected to 10-d CSDS, behavioral phenotype was defined using the SI test and PFC punches were collected 24h later and immediately processed through magnetic-activated cell sorting (MACS) which exploits immunomagnetic microbeads to quickly and gently separate cell types 7,25–27 ( Fig.4a, Extended Fig.6a-b ). Enrichment of endothelial cells and genes specific to this cell population were confirmed by fluorescence-activated cell sorting and qPCR, respectively ( Extended Fig.6c ) 7 .…”

Section: Mainmentioning

confidence: 99%

“…Enrichment of endothelial cells and genes specific to this cell population were confirmed by fluorescence-activated cell sorting and qPCR, respectively ( Extended Fig.6c ) 7 . RNA was extracted from female PFC endothelial cells of unstressed CTRL, SS and RES mice ( Fig.4b , P <0.0001) and transcriptome profiles established with the mouse Clariom S assay, which allows measurement of gene expression from >22,000 well-annotated genes 7,25 . Hierarchical clustering of endothelium gene expression variations revealed low overlap between SS and RES groups with fold changes often going in the opposite direction when compared to unstressed CTRL ( Fig.4c ).…”

Section: Mainmentioning

confidence: 99%

Sex-specific blood-brain barrier alterations and vascular biomarkers underlie chronic stress responses in mice and human depression

Dion‐Albert

Cadoret

Doney

et al. 2021

Preprint

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Prevalence, symptoms, and treatment of depression all point toward major sex differences. Social stress-induced neurovascular pathology is associated with depressive symptoms in male mice however it remains unknown if it contributes to this sexual dimorphism. Here, we report that chronic social and subchronic variable stress promoted sex-specific blood-brain barrier (BBB) molecular and morphological alterations in mood-related brain regions. Viral-mediated functional manipulation leading to a targeted disruption of the BBB induced anxiety- and depression-like behaviors including social avoidance and anhedonia. Endothelium cell-specific transcriptomic profiling revealed key pathways and novel genes involved in maladaptive stress responses vs resilience. We also confirmed BBB leakiness in the brain of stressed females which led us to explore and identify circulating vascular biomarkers of chronic stress that could inform on diagnosis and treatment. Importantly, these pre-clinical findings were validated in human blood and postmortem brain samples from depressed women, thus highlighting their translational value. By revealing a sex-specific causal role of BBB dysfunction in stress responses and depression, our results implicate vascular impairment as a major factor underlying mood disorders.

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Vascular contributions to 16p11.2 deletion autism syndrome modeled in mice

Cited by 90 publications

References 71 publications

Distinct Basal Metabolism in Three Mouse Models of Neurodevelopmental Disorders

Distinct Basal Metabolism in Three Mouse Models of Neurodevelopmental Disorders

Using zebrafish to elucidate glial-vascular interactions during CNS development

Sex-specific blood-brain barrier alterations and vascular biomarkers underlie chronic stress responses in mice and human depression

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