IDH-mutated gliomas promote epileptogenesis through d-2-hydroxyglutarate-dependent mTOR hyperactivation

Area of Science:

• Neuroscience
• Oncology
• Metabolic Disorders

Background:

• Gliomas often cause uncontrolled seizures, impacting patient quality of life.
• The precise mechanisms linking gliomas to seizures are not fully understood.
• The metabolite d-2-hydroxyglutarate (d-2-HG), produced by IDH-mutant enzymes, is implicated.

Purpose of the Study:

• To investigate the hypothesis that d-2-HG causes metabolic disruptions in cortical neurons, leading to seizures.
• To elucidate the role of d-2-HG in epileptogenesis associated with IDH-mutant gliomas.

Main Methods:

• Utilized in vitro neuron-glial cultures and human cortical tissue from glioma patients.
• Employed micro-electrode arrays for electrophysiological studies.
• Conducted pharmacological and biochemical analyses to assess d-2-HG's impact on neuronal activity and metabolism.

Main Results:

• d-2-HG increased neuronal spiking activity and altered neuronal metabolism.
• Observed distinct metabolomic shifts, increased LDHA expression, and mTOR signaling upregulation.
• Neuronal activity increases were mediated by mTOR activation and reversed by mTOR inhibition.

Conclusions:

• Metabolic disruptions in the cortex induced by d-2-HG may drive epileptogenesis in IDH-mutant glioma patients.
• d-2-HG's role in altering neuronal metabolism and activity highlights a potential therapeutic target.