Altered neural stem/progenitor cell (NSPC) activity and neurodevelopmental defects are linked to intellectual disability. However, it remains unclear whether altered metabolism, a key regulator of NSPC activity, disrupts human neurogenesis and potentially contributes to cognitive defects. We investigated links between lipid metabolism and cognitive function in mice and human embryonic stem cells (hESCs) expressing mutant fatty acid synthase (FASN; R1819W), a metabolic regulator of rodent NSPC activity recently identified in humans with intellectual disability. Mice homozygous for the FASN R1812W variant have impaired adult hippocampal NSPC activity and cognitive defects because of lipid accumulation in NSPCs and subsequent lipogenic ER stress. Homozygous FASN R1819W hESC-derived NSPCs show reduced rates of proliferation in embryonic 2D cultures and 3D forebrain regionalized organoids, consistent with a developmental phenotype. These data from adult mouse models and in vitro models of human brain development suggest that altered lipid metabolism contributes to intellectual disability.

改变的神经干/祖细胞 (NSPC) 活动和神经发育缺陷与智力残疾有关。然而，目前尚不清楚改变的新陈代谢（NSPC 活动的关键调节剂）是否会破坏人类神经发生并可能导致认知缺陷。我们研究了小鼠和人类胚胎干细胞 (hESCs) 中脂质代谢和认知功能之间的联系，这些细胞表达突变脂肪酸合酶 (FASN;R1819W)，这是最近在智障人类中发现的啮齿动物 NSPC 活动的代谢调节剂。由于 NSPC 中的脂质积累和随后的脂肪生成 ER 应激，FASN R1812W 变体纯合小鼠的成年海马 NSPC 活动和认知缺陷受损。纯合 FASN R1819W hESC 衍生的 NSPC 在胚胎 2D 培养物和 3D 前脑区域化类器官中的增殖率降低，与发育表型一致。这些来自成年小鼠模型的数据和人类大脑发育的体外模型表明，脂质代谢的改变会导致智力残疾。