Naofumi Uesaka, Kohei Kumegawa, Takaki Watanabe, Miwako Yamasaki, Zhize Xiao, Shaoai Zheng, Mariko Sekiguchi, Weida Wu, Xianzhi Shao, Wanchen Wang, Kyosuke Goda, Fumitaka Osakada, Hiroyuki Kato, Satoru Takahashi, Shigeo Ohba, Masahiko Watanabe, Masanobu Kano, Yonehiro Kanemura, Reo Maruyama, Daisuke Kawauchi
Neuronal activity is known to promote glioma growth, yet whether inhibitory circuits can oppose this effect has remained unclear. Here, we show that adult gliomas receive functional γ-aminobutyric acid (GABAergic) synaptic input from local inhibitory interneurons and that this input acts as a tumor-suppressive circuit signal. Enhancing inhibitory tone, genetically or pharmacologically, restrains tumor proliferation and prolongs survival, whereas disrupting inhibitory synaptic output accelerates tumor growth. Mechanistically, inhibitory circuit activation suppresses tumor calcium dynamics, and calcium gain- and loss-of-function experiments establish these dynamics as causal regulators of proliferation and survival. Yes-associated protein 1 (YAP1) and mechanistic target of rapamycin (mTOR) emerge as calcium-coupled oncogenic programs attenuated by inhibitory activation. Thus, adult glioma progression is governed not simply by neuronal activity but by a balance between growth-promoting and growth-restraining circuit influences. These findings define inhibitory input as a suppressive component of the glioma ecosystem and suggest that strengthening inhibitory tone may offer a therapeutic strategy.