Cerebrovascular deficits in autism
Bibliographic record
Abstract
Authors: Baptiste Lacoste¹ ¹Ottawa Hospital Research Institute, University of Ottawa Abstract: BACKGROUND AND AIM: Brain development relies on proper maturation of its vascular beds that not only ensure steady supply of oxygen and nutrients, but also support the proliferation and differentiation of neural progenitors. As such, alterations in cerebrovascular processes during development may have long-lasting neurodevelopmental consequences, but direct evidence supporting this concept is missing. Autism spectrum disorders (ASD) are neurodevelopmental conditions that affect attention, memory, learning, motor coordination, language, speech and social interactions. While the neuronal underpinnings of ASD are being extensively studied, whether vascular deficits play a role in ASD onset and/or progression is still unknown. The aim of our study is to address this important knowledge gap. METHODS: We investigated the maturation of cerebrovascular networks in 16p11.2df/+ mice, a robust mouse model of the 16p11.2 deletion ASD syndrome. In addition, we achieved endothelial-specific deletion of the 16p11.2 locus by CRE-mediated recombination under the control of an endothelial promoter (Cdh5-Cretg/+;16p11.2flox/+). Using both constitutive and conditional mutants and their Wild-Type littermates, we quantified neurovascular structure and function in vivo and in vitro, and assessed mouse behavior. RESULTS: We demonstrate that 16p11.2 hemizygosity leads to endothelium-dependent structural and functional neurovascular abnormalities. In 16p11.2df/+ mice, endothelial dysfunction manifested by impaired cerebral angiogenesis at postnatal day (P) 14, and by altered neurovascular coupling and cerebrovascular reactivity at P50. Defective angiogenesis was confirmed in vitro using primary 16p11.2df/+ mouse brain endothelial cells. Finally, we found that mice with endothelium-specific 16p11.2 deletion partially recapitulated ASD behavioral traits, including locomotor hyperactivity and impaired motor learning. CONCLUSIONS: By showing that endothelial 16p11.2 homozygosity is required for normal brain maturation, our findings identify endothelial cells as substantial contributors to ASD, opening new research avenues.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.002 | 0.005 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.007 | 0.005 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; both teacher heads agree on what is shown here.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".