Glioma regulates GABAergic signaling to drive hyperactivity and tumor progression

Recent studies have identified bi-directional communication between neurons and glioma tumors as a key driver of hyperexcitability and malignant progression. Although much of this work has focused on the activity of excitatory neurons, the roles of inhibitory neurons remain poorly defined. Using in vivo screening approaches in autochthonous glioma models, we found that the loss of a γ-aminobutyric acid (GABA) transporter (Slc6a1) enhanced glioma progression, promoted network hyperactivity, and influenced tonic GABA release by tumors. Mechanistically, we show that glioma tumors influence the activity of inhibitory neurons and that their subsequent stimulation suppresses tumor growth. Further screening of these phenomena identified diazepam binding inhibitor (DBI), a secreted negative allosteric modulator of GABA-A, as a link between glioma-related hyperexcitability and proliferation that functions through modulating inhibitory neuronal signaling. Collectively, our findings indicate that glioma tumors utilize multiple mechanisms to manipulate the activity of inhibitory neurons as a means to drive network hyperactivity, which ultimately facilitates malignant progression.