Researchers led by Ludwig Stanford’s Michelle Monje have previously shown that neural activity drives high grade gliomas (HGGs), aggressive, incurable cancers that include pediatric diffuse midline gliomas (DMGs) such as H3K27M-driven diffuse intrinsic pontine glioma, and glioblastomas (GBMs). Those studies revealed that excitatory glutamatergic synapses between neurons and glioma cells as well as paracrine signaling from neurons stimulate the proliferation of the cancer cells. Michelle and her colleagues explored how another class of neural synapses that form with glioma cells—GABAergic synapses—influence tumor growth. Employing electrophysiology, optogenetics and mouse models of HGGs, the researchers discovered that GABAergic synapses, though ordinarily hyperpolarizing and inhibitory, actually stimulate growth of DMG tumors—but not of GBM—in mouse models of the cancer. This, they reported in a February paper in Nature, is because DMGs, but not GBMs, express the NKCC1 chloride transporter. NKCC1 abnormally boosts chloride levels in DMG cells, making GABA depolarize the cancer cells. In line with this finding, the benzodiazepine drug lorazepam, which augments GABA signaling, accelerates DMG growth in mice and shortens their survival. The study points to new approaches to developing therapies for these cancers and suggests that DMG patients should probably avoid taking benzodiazepine drugs.
GABAergic neuron-to-glioma synapses in diffuse midline gliomas
Nature, 2025 February 19