加拿大渥太华大学Baptiste Lacoste研究组近日取得一项新成果。他们提出了血管对16p11.2缺失的自闭综合征小鼠模型的贡献。这一研究成果发表在2020年7月13日出版的《自然-神经科学》上。

他们研究了16p11.2df / +小鼠的出生后脑血管发育，16p11.2缺失会导致自闭症谱系障碍（ASD综合征）。他们发现，16p11.2半合子导致雄性特异性、内皮依赖的结构性和功能性神经血管异常。在16p11.2df / +小鼠中，内皮功能障碍导致出生后第14天的脑血管生成受损，并在出生后第50天导致神经血管耦合和脑血管应答性改变。

此外，他们显示，16p11.2缺失的人类原发性16p11.2df / +小鼠脑内皮细胞和人多能干细胞来源的内皮细胞，血管生成存在缺陷。最后，他们发现内皮特异性16p11.2缺失（16p11.2ΔEC）的小鼠部分表现出16p11.2综合征中的某些行为变化，特别是活动过度和运动学习受损。通过展现来自内皮细胞的发育性16p11.2单倍体不足能够导致成人的神经血管和行为发生变化，他们的结果表明了ASD中内皮损伤的潜在作用。

研究人员表示，ASD的神经元基础尚不清楚，同时血管对ASD的贡献亦未知。

附：英文原文

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

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

Issue&Volume: 2020-07-13

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.

DOI: 10.1038/s41593-020-0663-1

Source: https://www.nature.com/articles/s41593-020-0663-1