Glioma epileptiform activity and progression are driven by IGSF3-mediated potassium dysregulation

Neuron. 2023 Mar 1;111(5):682-695.e9. doi: 10.1016/j.neuron.2023.01.013. Epub 2023 Feb 13.


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.

Keywords: brain hyperactivity; glioma; glioma-related epilepsy; potassium dysregulation; spreading depolarization.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Brain / metabolism
  • Brain Neoplasms* / pathology
  • Glioma* / metabolism
  • Humans
  • Immunoglobulins / metabolism
  • Membrane Proteins / metabolism
  • Mice
  • Potassium
  • Seizures


  • Potassium
  • IGSF3 protein, human
  • Immunoglobulins
  • Membrane Proteins