Human brain ontogeny is characterized by a considerably prolonged neotenic development of cortical neurons and circuits. Neoteny is thought to be essential for the acquisition of advanced cognitive functions, which are typically altered in intellectual disability (ID) and autism spectrum disorders (ASDs). Human neuronal neoteny could be disrupted in some forms of ID and/or ASDs, but this has never been tested. Here, we use xenotransplantation of human cortical neurons into the mouse brain to model SYNGAP1 haploinsufficiency, one of the most prevalent genetic causes of ID/ASDs. We find that SYNGAP1-deficient human neurons display strong acceleration of morphological and functional synaptic formation and maturation alongside disrupted synaptic plasticity. At the circuit level, SYNGAP1-haploinsufficient neurons display precocious acquisition of responsiveness to visual stimulation months ahead of time. Our findings indicate that SYNGAP1 is required cell autonomously for human neuronal neoteny, providing novel links between human-specific developmental mechanisms and ID/ASDs.

中文翻译：

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SYNGAP1缺陷破坏了体内异种移植人皮层神经元的突触新生


人脑个体发育的特征是皮层神经元和回路的新生发育相当延长。Neoteny 被认为对于获得高级认知功能至关重要，这些功能通常在智力障碍 （ID） 和自闭症谱系障碍 （ASD） 中发生改变。人类神经元新生可能在某些形式的 ID 和/或 ASD 中被破坏，但这从未被测试过。在这里，我们使用人类皮层神经元异种移植到小鼠大脑中来模拟SYNGAP1倍体不足，这是 ID/ASD 最普遍的遗传原因之一。我们发现，SYNGAP1缺陷的人类神经元表现出形态和功能突触形成和成熟的强烈加速，同时突触可塑性被破坏。在回路水平上，SYNGAP1单倍体不足的神经元提前数月表现出对视觉刺激的反应性早熟。我们的研究结果表明，SYNGAP1 是人类神经元新生儿自主需要的细胞，在人类特异性发育机制和 ID/ASD 之间提供了新的联系。