Long-term potentiation and depression, inferred from analysis on brain slices, are considered the cellular processes underlying learning and memory formation. They have not so far been demonstrated in human stem cell-derived neurons. By expressing channelrhodopsin in hESCs-derived glutamate neurons and co-culturing them with GABA neurons, we found that blue light stimulation increased the frequency of miniature excitatory postsynaptic currents (mEPSCs) and decreased the ratio of paired pulse facilitation (PPF) in non-ChR2-expressing GABA neurons, indicating a facilitating action at the presynaptic terminals. When paired with postsynaptic depolarization, the repetitive stimulation significantly increased the amplitude of light-evoked EPSCs that persisted during the period, indicating long-term potentiation (LTP). In contrast, low-frequency light stimulation induced long-term depression (LTD). These effects were blocked by N-methyl-D-aspartic acid (NMDA) receptor antagonists, suggesting NMDA receptor-mediated synaptic plasticity in human neural networks. Furthermore, induced pluripotent stem cell (iPSC)-derived neurons of patient with Down syndrome showed absence of LTP or LTD. Thus, our platform offers a versatile model for assessing human neural plasticity under physiological and pathological conditions.

从对脑片的分析中推断出的长期增强和抑郁被认为是学习和记忆形成的基础细胞过程。到目前为止，尚未在人干细胞来源的神经元中证实它们。通过在hESCs衍生的谷氨酸神经元中表达通道视紫红质并将它们与GABA神经元共同培养，我们发现蓝光刺激可增加非ChR2的微型兴奋性突触后电流（mEPSCs）的频率并降低配对脉冲促进（PPF）的比率-表达GABA神经元，表明在突触前末端的促进作用。当与突触后去极化配对时，重复刺激显着增加了在此期间持续存在的光诱发的EPSC的幅度，表明长期增强（LTP）。相反，低频光刺激引起的长期抑郁症（LTD）。这些作用被N-甲基-D-天冬氨酸（NMDA）受体拮抗剂所阻断，表明NMDA受体介导的人神经网络中的突触可塑性。此外，唐氏综合症患者的诱导多能干细胞（iPSC）衍生神经元显示缺乏LTP或LTD。因此，我们的平台提供了用于评估生理和病理条件下的人类神经可塑性的通用模型。