癫痫是恶性胶质瘤的常见病理生理特征。最近的研究表明，周围肿瘤突触调节失常是大脑高度兴奋和肿瘤进展的驱动因素；然而，引导这些现象的分子机制仍然难以解释。通过单细胞RNA测序和术中患者脑电图记录，我们发现，癫痫患者的肿瘤富含调节突触形成的基因标志物。使用人-鼠体内实现功能化管道筛选这些基因，我们确定IGSF3是介导神经胶质瘤进展和失调的神经回路的中介物，并表现为扩散去极化（SD）。在机制上，我们发现IGSF3与Kir4.1相互作用以抑制钾缓冲，并发现癫痫患者在增殖的肿瘤细胞中表达钾处理器的表达减少。体内成像揭示出失调的突触活动源自肿瘤-神经元界面，我们在患者中也予以证实。我们的研究揭示了离子失调在肿瘤进展和癫痫中的作用，并确定SD是疾病的驱动因素。 版权所有 ©2023 Elsevier Inc.。

Seizures are a frequent pathophysiological feature of malignant glioma. Recent studies implicate peritumoral synaptic dysregulation as a driver of brain hyperactivity and tumor progression; however, the molecular mechanisms that govern these phenomena remain elusive. Using scRNA-seq and intraoperative patient ECoG recordings, we show that tumors from seizure patients are enriched for gene signatures regulating synapse formation. Employing a human-to-mouse in vivo functionalization pipeline to screen these genes, we identify IGSF3 as a mediator of glioma progression and dysregulated neural circuitry that manifests as spreading depolarization (SD). Mechanistically, we discover that IGSF3 interacts with Kir4.1 to suppress potassium buffering and found that seizure patients exhibit reduced expression of potassium handlers in proliferating tumor cells. In vivo imaging reveals that dysregulated synaptic activity emanates from the tumor-neuron interface, which we confirm in patients. Our studies reveal that tumor progression and seizures are enabled by ion dyshomeostasis and identify SD as a driver of disease.Copyright © 2023 Elsevier Inc. All rights reserved.