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

Author(s):Show less -

Ouellette, Julie ^[1] ; Toussay, Xavier ^[1] ; Comin, Cesar H. ^[2] ; Costa, Luciano da F. ^[3] ; Ho, Mirabelle ^[4] ; Lacalle-Aurioles, Maria ^[5] ; Freitas-Andrade, Moises ^[1] ; Liu, Qing Yan ^{[6, 7]} ; Leclerc, Sonia ^[6] ; Pan, Youlian ^[8] ; Liu, Ziying ^[8] ; Thibodeau, Jean-Francois ^[9] ; Yin, Melissa ^[10] ; Carrier, Micael ^[11] ; Morse, Cameron J. ^[1] ; Van Dyken, Peter ^[1] ; Bergin, Christopher J. ^[12] ; Baillet, Sylvain ^[5] ; Kennedy, Christopher R. ^{[9, 12]} ; Tremblay, Marie-Eve ^[11] ; Benoit, Yannick D. ^[12] ; Stanford, William L. ^{[4, 12]} ; Burger, Dylan ^{[9, 12]} ; Stewart, Duncan J. ^{[4, 12]} ; Lacoste, Baptiste ^{[13, 1, 12]}

Affiliation:Show less -

^[1] Ottawa Hosp, Neurosci Program, Res Inst, Ottawa, ON - Canada

^[2] Univ Fed Sao Carlos, Dept Comp Sci, Sao Carlos - Brazil

^[3] Univ Sao Paulo, Sao Carlos Inst Phys, FCM USP, Sao Paulo - Brazil

^[4] Ottawa Hosp, Regenerat Med Program, Res Inst, Ottawa, ON - Canada

^[5] McGill Univ, Montreal Neurol Inst, Montreal, PQ - Canada

^[6] Natl Res Council Canada, Human Hlth & Therapeut, Ottawa, ON - Canada

^[7] Univ Ottawa, Fac Med, Dept Biochem Microbiol & Immunol, Ottawa, ON - Canada

^[8] Natl Res Council Canada, Digital Technol, Ottawa, ON - Canada

^[9] Ottawa Hosp, Kidney Res Ctr, Res Inst, Ottawa, ON - Canada

^[10] FUJIFILM VisualSon, Toronto, ON - Canada

^[11] Univ Laval, CHU Quebec, Axe Neurosci, Ctr Rech, Quebec City, PQ - Canada

^[12] Univ Ottawa, Fac Med, Dept Cellular & Mol Med, Ottawa, ON - Canada

^[13] Univ Ottawa, Brain & Mind Res Inst, Ottawa, ON - Canada

• Document type: Journal article
• Source: NATURE NEUROSCIENCE; v. 23, n. 9 JUL 2020.
• Web of Science Citations: 0

Abstract

Most studies of autism spectrum disorder (ASD) have focused on neuronal mechanisms. Here, the authors describe vascular impairments in a mouse model of 16p11.2 deletion syndrome using physiological and genetic approaches to examine endothelial-dependent phenotypes. 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 the16p11.2(df/+)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. In16p11.2(df/+)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 primary16p11.2(df/+)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 (16p11.2(Delta EC)) 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. (AU)

• FAPESP's process: 15/18942-8 - Associating Complex Networks with Effective Feature Spaces
• Grantee: Cesar Henrique Comin
• Support type: Scholarships in Brazil - Post-Doctorate
• FAPESP's process: 15/22308-2 - Intermediate representations in Computational Science for knowledge discovery
• Grantee: Roberto Marcondes Cesar Junior
• Support type: Research Projects - Thematic Grants
• FAPESP's process: 11/50761-2 - Models and methods of e-Science for life and agricultural sciences
• Grantee: Roberto Marcondes Cesar Junior
• Support type: Research Projects - Thematic Grants