Brain development and function rely on vascular features that ensure adequate supply of oxygen and nutrients from the blood stream. These features consist of a well-established vascular network, a functional blood-brain barrier, as well as cerebral blood flow regulation. Early life impairments in these features can lead to neurodevelopmental defects. Very few studies have considered the contribution of the brain vasculature to autism spectrum disorders (ASD). A recent postmortem study in young ASD brains suggested an impairment in angiogenesis, a process through which new vessels are formed. A possible link between ASD and altered cerebral perfusion has also been suggested by functional imaging studies. Yet, contribution of cerebrovascular deficits to ASD physiopathology remains elusive, hence a detailed analysis of these deficits is needed. ASD are viewed as neurodevelopmental conditions associated with genetic origins. Mutations identified as a possible cause for ASD include the common 16p11.2 deletion, which leads to the haploinsufficiency of approximately 30 highly-conserved genes. In this thesis, we are using a multidisciplinary approach in order to decipher the cerebrovascular underpinnings of ASD in a mouse model of the 16p11.2 deletion syndrome (16p11.2df/+ mice). We have identified functional and structural cerebrovascular deficits during postnatal development in constitutive 16p11.2df/+ mutants. In particular, 16p11.2df/+ mice display a significant decrease in microvascular branching and density in the cerebral cortex at P14 when compared to age-matched WT littermates. In addition, 16p11.2df/+ mice display a collection of functional abnormalities at P50 when compared to WT mice, such as altered neurovascular coupling in vivo and altered vascular reactivity ex vivo. Notably, we demonstrated a defective endothelium-dependent vasodilation in 16p11.2df/+ mice, while smooth muscle function is unaffected. Furthermore, we generated mice harboring the endothelial-specific 16p11.2 haploinsufficiency (Cdh5-Cretg/+;16p11.2flox/+) in order to dissect the endothelial contribution to ASD phenotypes. These mice underwent behavioral testing to assess whether they display 16p11.2 syndrome -related characteristics. We demonstrated that these conditional mutant mice show home cage hyperactivity in the beam break test, repetitive behaviors in the marble burying test, as well as motor coordination deficits in the rotarod test. Our findings thus establish endothelial cells as key contributors to the pathophysiology of the 16p11.2 deletion syndrome, and provide novel insight into how the cerebral endothelium fine-tunes brain maturation.

Background: Prevalence of metabolic disturbances is higher among individuals with neurodevelopmental disorders (NDDs), yet this association has been poorly studied. Investigation into human disease remains challenging, as a complete pathophysiological understanding relies on accurate modeling and highly controlled variables. As such, genetically engineered mouse models are increasingly used to gain insight into the biology of human NDDs, but preclinical research focus has been mainly on behavioral and neurophysiological abnormalities. Mouse models engineered to embody human-equivalent genetic variations can display discrepancies to human phenotypes, therefore a thorough characterization of mouse phenotypes must be conducted in order to evaluate how accurately a mouse model embodies a human phenotype. Also, mouse models can help discover unsuspected abnormalities that can be further validated in humans. Objective: In this study, we sought to investigate the metabolic alterations derived from NDD-associated genetic polymorphisms in previously-validated genetic mouse models. Due to the similarities in NDD-associated phenotypic expression, we hypothesized that our NDDs of interest would express similar metabolic signatures. Further, we anticipated that we might uncover unknown metabolic anomalies, and that sex may alter these differences. Methods: We used the Comprehensive Lab Animal Monitoring System coupled to EchoMRI, as well as quantification of key plasma metabolites by liquid chromatography-mass spectrometry to characterize and compare basal metabolism in three mouse models of NDDs, namely Down syndrome (Dp(16)Yey/+ mice), 16p11.2 deletion syndrome (16p11.2df/+ mice) and Fragile X syndrome (Fmr1-/- KO mice) and their wild-type (WT) counterparts. Results: Our study reveals that each mouse model expresses a unique metabolic signature that is sex-specific, independent of the amount of food consumed and minimally influenced by physical activity. We found striking differences in body composition, respiratory exchange ratio, caloric expenditure and concentrations of circulating plasma metabolites related to mitochondrial function. Conclusion: Providing novel insight into NDD-associated metabolic alterations provides a basis for future studies aimed at understanding physiological mechanisms and provides a point of reference for research aimed at detecting changes in response to intervention.