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

Julie Ouellette, Xavier Toussay, Cesar H. Comin (ORCID), Luciano Da F. Costa, Mirabelle Ho, María Lacalle-Aurioles, Moises Freitas-Andrade, Qing Yan Liu, Sonia Leclerc, Youlian Pan, Ziying Liu, Jean-François Thibodeau, Melissa Yin, Micael Carrier, Cameron J. Morse, Peter Van Dyken, Christopher J. Bergin, Sylvain Baillet, Christopher R. Kennedy, Marie-Ève Tremblay, Yannick D. Benoit, William L. Stanford, Dylan Burger, Duncan J. Stewart, Baptiste Lacoste

Nature Neuroscience, 23(9): 1090-1101. . DOI: 10.1038/s41593-020-0663-1.

Abstract

While the neuronal underpinnings of autism spectrum disorder (ASD) are being unraveled, vascular contributions to ASD remain elusive. Here, we investigated postnatal cerebrovascular development in the 16p11.2df/+ mouse model of 16p11.2 deletion ASD syndrome. We discover that 16p11.2 hemizygosity leads to male-specific, endothelium-dependent structural and functional neurovascular abnormalities. In 16p11.2df/+ mice, endothelial dysfunction results in impaired cerebral angiogenesis at postnatal day 14, and in altered neurovascular coupling and cerebrovascular reactivity at postnatal day 50. Moreover, we show that there is defective angiogenesis in primary 16p11.2df/+ mouse brain endothelial cells and in induced-pluripotent-stem-cell-derived endothelial cells from human carriers of the 16p11.2 deletion. Finally, we find that mice with an endothelium-specific 16p11.2 deletion (16p11.2ΔEC) partially recapitulate some of the behavioral changes seen in 16p11.2 syndrome, specifically hyperactivity and impaired motor learning. By showing that developmental 16p11.2 haploinsufficiency from endothelial cells results in neurovascular and behavioral changes in adults, our results point to a potential role for endothelial impairment in ASD.

Citation

@article{Ouellette2020Vascular,
  title   = {Vascular contributions to 16p11.2 deletion autism syndrome modeled in mice},
  author  = {Ouellette, Julie and Toussay, Xavier and Comin, Cesar H. and Costa, Luciano Da F. and Ho, Mirabelle and Lacalle-Aurioles, María and Freitas-Andrade, Moises and Liu, Qing Yan and Leclerc, Sonia and Pan, Youlian and Liu, Ziying and Thibodeau, Jean-François and Yin, Melissa and Carrier, Micael and Morse, Cameron J. and Dyken, Peter Van and Bergin, Christopher J. and Baillet, Sylvain and Kennedy, Christopher R. and Tremblay, Marie-Ève and Benoit, Yannick D. and Stanford, William L. and Burger, Dylan and Stewart, Duncan J. and Lacoste, Baptiste},
  journal = {Nature Neuroscience},
  year    = {2020},
  volume  = {23},
  number  = {9},
  pages   = {1090--1101},
  doi     = {10.1038/s41593-020-0663-1}
}