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

While the neuronal underpinnings of autism spectrum disorders (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 discovered that 16p11.2 hemizygosity leads to male-specific, endothelium-dependent structural and functional neurovascular abnormalities. In 16p11.2df/+ mice, endothelial dysfunction resulted in impaired cerebral angiogenesis at postnatal day (P) 14, and in altered neurovascular coupling and cerebrovascular reactivity at P50. Moreover, we showed defective angiogenesis in primary 16p11.2df/+ mouse brain endothelial cells and in iPSC-derived endothelial cells from human 16p11.2 deletion carriers. Finally, we found that mice with endothelium-specific 16p11.2 deletion (16p11.2DEC) partially recapitulated some 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. 16 RNA samples (i.e. 16 biological replicates) from 32 mice were produced in total for RNA deep sequencing.尽管自闭症谱系障碍（autism spectrum disorders, ASD）的神经生物学基础正逐步被阐明，但其血管相关致病贡献仍不甚明确。本研究针对16p11.2缺失型自闭症综合征的16p11.2df/+小鼠模型，探究其出生后脑血管的发育进程。研究发现，16p11.2半合子缺失会引发雄性特异性、依赖于内皮细胞的结构与功能神经血管异常：在16p11.2df/+小鼠中，内皮功能障碍会导致小鼠在出生后第14天（P14）的脑血管生成受损，并在出生后第50天（P50）出现神经血管耦合与脑血管反应性的改变。此外，本研究证实，原代16p11.2df/+小鼠脑内皮细胞以及来自人类16p11.2缺失携带者的诱导多能干细胞（induced pluripotent stem cell, iPSC）分化的内皮细胞均存在血管生成缺陷。最后，本研究发现，内皮细胞特异性16p11.2缺失小鼠（16p11.2DEC）可部分重现16p11.2综合征的部分行为学改变，具体表现为活动过度与运动学习能力受损。本研究证实，内皮细胞源性的发育性16p11.2单倍体不足会导致成年个体出现神经血管与行为学改变，上述结果提示内皮功能损伤可能在ASD的发病机制中发挥潜在作用。本研究共从32只小鼠中制备了16份RNA样本（即16个生物学重复）用于RNA深度测序。