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

Julie Ouellette1, Xavier Toussay1, Cesar H Comin2, Luciano da F Costa3, Mirabelle Ho4, María Lacalle-Aurioles5, Moises Freitas-Andrade1, Qing Yan Liu6,7, Sonia Leclerc6, Youlian Pan8, Ziying Liu8, Jean-François Thibodeau9, Melissa Yin10, Micael Carrier11, Cameron J Morse1, Peter Van Dyken1, Christopher J Bergin12, Sylvain Baillet5, Christopher R Kennedy9,12, Marie-Ève Tremblay11, Yannick D Benoit12, William L Stanford4,12, Dylan Burger9,12, Duncan J Stewart4,12, Baptiste Lacoste13,14,15

  1. Neuroscience Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
  2. Department of Computer Science, Federal University of São Carlos, São Carlos, Brazil.
  3. São Carlos Institute of Physics, FCM-USP, University of São Paulo, São Paulo, Brazil.
  4. Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
  5. Montreal Neurological Institute, McGill University, Montréal, Québec, Canada.
  6. National Research Council of Canada, Human Health and Therapeutics, Ottawa, Ontario, Canada.
  7. Department of Biochemistry Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
  8. Digital Technologies, National Research Council of Canada, Ottawa, Ontario, Canada.
  9. Kidney Research Center, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
  10. FUJIFILM VisualSonics, Toronto, Ontario, Canada.
  11. Axe Neurosciences, Centre de recherche du CHU de Québec, Université Laval, Québec, Québec, Canada.
  12. Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
  13. Neuroscience Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada. blacoste@uottawa.ca.
  14. Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada. blacoste@uottawa.ca.
  15. University of Ottawa Brain and Mind Research Institute, Ottawa, Ontario, Canada. blacoste@uottawa.ca.

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.

Presented By Julie Ouellette

NeuroscienceNicholas Liao2020-09 (Sep)