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, Michelle Monje
Author Information
- Humsa S Venkatesh: Department of Neurology, Stanford University, Stanford, CA, USA.
- Wade Morishita: Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA.
- Anna C Geraghty: Department of Neurology, Stanford University, Stanford, CA, USA.
- Dana Silverbush: Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
- Shawn M Gillespie: Department of Neurology, Stanford University, Stanford, CA, USA.
- Marlene Arzt: Department of Neurology, Stanford University, Stanford, CA, USA.
- Lydia T Tam: Department of Neurology, Stanford University, Stanford, CA, USA.
- Cedric Espenel: Cell Sciences Imaging Facility, Stanford University School of Medicine, Stanford, CA, USA.
- Anitha Ponnuswami: Department of Neurology, Stanford University, Stanford, CA, USA.
- Lijun Ni: Department of Neurology, Stanford University, Stanford, CA, USA.
- Pamelyn J Woo: Department of Neurology, Stanford University, Stanford, CA, USA.
- Kathryn R Taylor: Department of Neurology, Stanford University, Stanford, CA, USA.
- Amit Agarwal: Department of Neuroscience, Johns Hopkins University, Baltimore, MA, USA.
- Aviv Regev: Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
- David Brang: Department of Psychology, University of Michigan, Ann Arbor, MI, USA.
- Hannes Vogel: Department of Neurology, Stanford University, Stanford, CA, USA.
- Shawn Hervey-Jumper: Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA.
- Dwight E Bergles: Department of Neuroscience, Johns Hopkins University, Baltimore, MA, USA.
- Mario L Suvà: Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
- Robert C Malenka: Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA.
- Michelle Monje: Department of Neurology, Stanford University, Stanford, CA, USA. mmonje@stanford.edu.
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.
Animals
Brain
Cell Membrane
Cell Proliferation
Electrical Synapses
Electrophysiological Phenomena
Gap Junctions
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Glioma
Heterografts
Humans
Mice
Mice, Inbred NOD
Neurons
Optogenetics
Potassium
Synaptic Transmission
Tumor Cells, Cultured
