IDH Mutated Gliomas Promote Epileptogenesis through D-2-Hydroxyglutarate Dependent mTOR Hyperactivation

Mortazavi A, Fayed I, Bachani M, Dowdy T, Jahanipour J, Khan A, Owotade J, Walbridge S, Inati SK, Steiner J, Wu J, Gilbert M, Yang CZ, Larion M, Maric D, Ksendzovsky A, and Zaghloul KA. 

Neuro-Oncology, 2022.

Bioelectronic assays demonstrate the oncometabolite D-2-HG promotes glioma-associated seizure activity in surrounding neurons.

Patients with glioma brain tumors containing mutations of the metabolic enzyme isocitrate dehydrogenase (IDH) often experience treatment-resistant seizures, but the causative mechanisms are not well understood. In this study, researchers used neuron-glial rat cortical cell culture models and human cortical tissue from patients with IDH-mutant gliomas to demonstrate that D-2-hydroxyglutarate (D-2-HG)—a metabolite produced by the tumor subtype—alters metabolic profiles and upregulates mammalian target of rapamycin (mTOR) signaling in surrounding cortical neurons, which promotes neuronal spiking and seizure activity.

To examine in vitro neural network activity in the presence of glioma metabolites, the researchers used Axion’s Maestro Pro multielectrode array (MEA) platform and custom transwell inserts containing the glioma cultures, which showed increased seizurogenic activity in firing and burstings in neural co-cultures models. The researchers also found that the increases were reversed in the presence of an IDH inhibitor. Overall, the study findings demonstrate that the oncometabolite D-2-HG promotes seizure activity in surrounding neurons by activating the mTOR pathway—an important finding that improves the understanding of epileptogenesis in people with IDH-mutant gliomas and may lead to novel therapeutic approaches.