Electrical and synaptic integration of glioma into neural circuits

High-grade gliomas are lethal brain cancers whose progression is robustly regulated by neuronal activity. Activity-regulated growth factor release promotes glioma growth, but this alone is insufficient to explain the effect that activity exerts on glioma progression. Here, we use single-cell transcriptomics, electron microscopy, whole-cell patch-clamp electrophysiology and calcium imaging to demonstrate that neuron-glioma interactions include electrochemical communication through bona fide AMPA receptor-dependent neuron-glioma synapses. Neuronal activity also evokes non-synaptic activity-dependent potassium currents that are amplified through gap junction-mediated tumor interconnections forming an electrically-coupled network. Glioma membrane depolarization assessed with in vivo optogenetics promotes proliferation, while pharmacologically or genetically blocking electrochemical signaling inhibits glioma xenograft growth and extends mouse survival. Emphasizing positive feedback mechanisms by which gliomas increase neuronal excitability and thus activity-regulated glioma growth, human intraoperative electrocorticography demonstrates increased cortical excitability in glioma-infiltrated brain. Together, these findings indicate that synaptic and electrical integration in neural circuits promotes glioma progression.