Electrical and synaptic integration of glioma into neural circuits

Humsa S. Venkatesh, Wade Morishita, Anna C. Geraghty, Dana Silverbush, Shawn M. Gillespie, Marlene Arzt, Lydia T. Tam, Cedric Espenel, Anitha Ponnuswami, Lijun Ni, Pamelyn J. Woo, Kathryn R. Taylor, Amit Agarwal, Aviv Regev, David Brang, Hannes Vogel, Shawn Hervey-Jumper, Dwight E. Bergles, Mario L. Suvà, Robert C. Malenka and Michelle Monje ()
Additional contact information
Humsa S. Venkatesh: Stanford University
Wade Morishita: Stanford University
Anna C. Geraghty: Stanford University
Dana Silverbush: Massachusetts General Hospital and Harvard Medical School
Shawn M. Gillespie: Stanford University
Marlene Arzt: Stanford University
Lydia T. Tam: Stanford University
Cedric Espenel: Stanford University School of Medicine
Anitha Ponnuswami: Stanford University
Lijun Ni: Stanford University
Pamelyn J. Woo: Stanford University
Kathryn R. Taylor: Stanford University
Amit Agarwal: Johns Hopkins University
Aviv Regev: Broad Institute of Harvard and MIT
David Brang: University of Michigan
Hannes Vogel: Stanford University
Shawn Hervey-Jumper: University of California, San Francisco
Dwight E. Bergles: Johns Hopkins University
Mario L. Suvà: Massachusetts General Hospital and Harvard Medical School
Robert C. Malenka: Stanford University
Michelle Monje: Stanford University

Nature, 2019, vol. 573, issue 7775, 539-545

Abstract: Abstract High-grade gliomas are lethal brain cancers whose progression is robustly regulated by neuronal activity. Activity-regulated release of growth factors promotes glioma growth, but this alone is insufficient to explain the effect that neuronal activity exerts on glioma progression. Here we show that neuron and 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 by gap junction-mediated tumour interconnections, forming an electrically coupled network. Depolarization of glioma membranes assessed by in vivo optogenetics promotes proliferation, whereas pharmacologically or genetically blocking electrochemical signalling inhibits the growth of glioma xenografts and extends mouse survival. Emphasizing the positive feedback mechanisms by which gliomas increase neuronal excitability and thus activity-regulated glioma growth, human intraoperative electrocorticography demonstrates increased cortical excitability in the glioma-infiltrated brain. Together, these findings indicate that synaptic and electrical integration into neural circuits promotes glioma progression.

Date: 2019
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DOI: 10.1038/s41586-019-1563-y

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