Mutations in the IQSEC2 gene are associated with drug-resistant, multifocal infantile and childhood epilepsy; autism; and severe intellectual disability (ID). We used induced pluripotent stem cell (iPSC) technology to obtain hippocampal neurons to investigate the neuropathology of IQSEC2-mediated disease. The neurons were characterized at three-time points during differentiation to assess developmental progression. We showed that immature IQSEC2 mutant dentate gyrus (DG) granule neurons were extremely hyperexcitable, exhibiting increased sodium and potassium currents compared to those of CRISPR-Cas9-corrected isogenic controls, and displayed dysregulation of genes involved in differentiation and development. Immature IQSEC2 mutant cultured neurons exhibited a marked reduction in the number of inhibitory neurons, which contributed further to hyperexcitability. As the mutant neurons aged, they became hypoexcitable, exhibiting reduced sodium and potassium currents and a reduction in the rate of synaptic and network activity, and showed dysregulation of genes involved in synaptic transmission and neuronal differentiation. Mature IQSEC2 mutant neurons were less viable than wild-type mature neurons and had reduced expression of surface AMPA receptors. Our studies provide mechanistic insights into severe infantile epilepsy and neurodevelopmental delay associated with this mutation and present a human model for studying IQSEC2 mutations in vitro.

IQSEC2基因的突变与耐药性、多灶性婴儿和儿童癫痫有关；自闭症；和严重的智力残疾（ID）。我们使用诱导多能干细胞 (iPSC) 技术获得海马神经元，以研究IQSEC2介导的疾病的神经病理学。在分化过程中的三个时间点对神经元进行表征，以评估发育进展。我们发现未成熟的 IQSEC2突变齿状回 (DG) 颗粒神经元极度兴奋，与 CRISPR-Cas9 校正的同基因对照相比，钠和钾电流增加，并显示参与分化和发育的基因失调。不成熟的 IQSEC2突变培养的神经元表现出抑制性神经元数量显着减少，这进一步导致过度兴奋。随着突变神经元老化，它们变得低兴奋，表现出钠和钾电流减少，突触和网络活动率降低，并表现出参与突触传递和神经元分化的基因失调。与野生型成熟神经元相比，成熟的IQSEC2突变神经元的存活率较低，并且表面 AMPA 受体的表达降低。我们的研究提供了对与这种突变相关的严重婴儿癫痫和神经发育迟缓的机制见解，并提出了体外研究IQSEC2突变的人体模型。