Glutamatergic synapses between neurons and glioma cells can drive the progression and growth of high-grade gliomas, but whether this also applies to GABAergic neurons has remained unclear. Barron et al. now report that GABAergic neurons can form synapses with diffuse midline glioma (DMG) cells. First, analysis of single-cell RNA-sequencing datasets revealed higher expression of GABAA receptor (GABAAR) subunits in H3(K27M)-mutant DMGs than in other high-grade gliomas. Second, after xenografting patient-derived DMG cells into mouse hippocampus or co-culturing them with mouse neurons, the authors observed synapses between GABAergic interneurons and GABAAR-subunit-expressing DMG cells. In slice recordings, local stimulation induced GABAergic currents in xenografted DMG cells; these currents were strongly depolarizing, owing to a high intracellular Cl− concentration mediated by the Na–K–Cl cotransporter NKCCL. Importantly, in mice with patient-derived DMG cells xenografted into CA1, optogenetic stimulation of CA1 interneurons or administration of the GABAAR allosteric modulator lorazepam enhanced the proliferation of the xenografted tumour cells. Lorazepam also increased tumour growth and reduced survival of the mice, but it did not have these effects in mice xenografted with cells of a different type of high-grade glioma. Together, these results show that GABAergic neuronal activity regulates the progression of DMGs and point to important differences between subtypes of high-grade gliomas.
Original reference: Nature https://doi.org/10.1038/s41586-024-08579-3 (2025)
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