The glioma metabolite, D-2-hydroxyglutarate (D-2-HG), reduces synaptic transmission and epileptiform bursts in neocortical slices.

80% of patients with low-grade gliomas containing mutations of the metabolic enzyme isocitrate dehydrogenase (IDH) experience seizures, of which nearly half are drug-refractory. Studies in isolated neuronal cultures have led to the hypothesis that the metabolite of the mutant IDH, D-2-hydroxyglutarate (D-2-HG), is epileptogenic by mimicking glutamate and activating NMDA receptors. To test this hypothesis, we used whole-cell patch-clamp techniques to determine the direct effects of D-2-HG on neuronal and synaptic functions and epileptiform activity in neocortical slices that preserve natural and balanced excitatory-inhibitory neural networks. Acute bath application of D-2-HG (10 mM) for 10-30 min did not cause significant neuronal depolarization, induce epileptiform activity, or alter the input-output relationship in layer V pyramidal neurons. D-2-HG slightly lowered action potential (AP) threshold (~2-3 mV) and significantly reduced AP amplitude. In neocortical slices with ongoing epileptiform bursts (induced by 0 Mg2+ plus 4-aminopyridine), addition of D-2-HG reduced the frequency of the bursts (prolonged inter-burst intervals) and seizure burden. Moreover, D-2-HG diminished electrically evoked mono- and poly-synaptic excitatory postsynaptic currents. Together, the results demonstrate that short-term exposure to D-2-HG inhibits seizure-like activity in neocortical slices possibly by suppressing excitatory synaptic transmission. Thus, these data do not support the initial hypothesis that D-2-HG may excite neurons and promote seizures by mimicking glutamate actions.