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 singlecell 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 gliomainfiltrated brain. Together, these findings indicate that synaptic and electrical integration in neural circuits promotes glioma progression.

Activity-dependent modulation of synaptic efficacy in the brain contributes to neural circuit development and experience-dependent plasticity. Although glia are affected by activity and ensheathe synapses, their influence on synaptic strength has largely been ignored. Here, we show that a protein produced by glia, tumor necrosis factor alpha (TNFalpha), enhances synaptic efficacy by increasing surface expression of AMPA receptors. Preventing the actions of endogenous TNFalpha has the opposite effects. Thus, the continual presence of TNFalpha is required for preservation of synaptic strength at excitatory synapses. Through its effects on AMPA receptor trafficking, TNFalpha may play roles in synaptic plasticity and modulating responses to neural injury.

The endocytosis of AMPA receptors is thought to be important in the expression of long-term depression (LTD) triggered by NMDA receptor activation. Although signaling pathways necessary for LTD induction have been identified, those responsible for the regulated internalization of AMPA receptors are unknown. Here we show that activation of NMDA receptors alone can trigger AMPA receptor endocytosis through calcium influx and activation of the calcium-dependent protein phosphatase calcineurin. A distinct signaling mechanism mediates the AMPA receptor endocytosis stimulated by insulin. These results demonstrate that although multiple signaling pathways can induce AMPA receptor internalization, NMDA receptor activation enhances AMPA receptor endocytosis via a signaling mechanism required for the induction of LTD.

Ts65Dn mice, a model for Down syndrome, have excessive inhibition in the dentate gyrus, a condition that could compromise synaptic plasticity and mnemonic processing. We show that chronic systemic treatment of these mice with GABAA antagonists at non-epileptic doses causes a persistent post-drug recovery of cognition and long-term potentiation. These results suggest that over-inhibition contributes to intellectual disabilities associated with Down syndrome and that GABAA antagonists may be useful therapeutic agents for this disorder.