Objective: Because the d-2-hydroxyglutarate (D2HG) product of mutant isocitrate dehydrogenase 1 (IDH1^mut) is released by tumor cells into the microenvironment and is structurally similar to the excitatory neurotransmitter glutamate, we sought to determine whether IDH1^mut increases the risk of seizures in patients with glioma, and whether D2HG increases the electrical activity of neurons. Methods: Three WHO grade II-IV glioma cohorts from separate institutions (total N = 712) were retrospectively assessed for the presence of preoperative seizures and tumor location, WHO grade, 1p/19q codeletion, and IDH1^mut status. Rat cortical neurons were grown on microelectrode arrays, and their electrical activity was measured before and after treatment with exogenous D2HG, in the presence or absence of the selective NMDA antagonist, AP5. Results: Preoperative seizures were observed in 18%–34% of IDH1 wild-type (IDH1^wt) patients and in 59%–74% of IDH1^mut patients (p < 0.001). Multivariable analysis, including WHO grade, 1p/19q codeletion, and temporal lobe location, showed that IDH1^mut was an independent correlate with seizures (odds ratio 2.5, 95% confidence interval 1.6–3.9, p < 0.001). Exogenous D2HG increased the firing rate of cultured rat cortical neurons 4- to 6-fold, but was completely blocked by AP5. Conclusions: The D2HG product of IDH1^mut may increase neuronal activity by mimicking the activity of glutamate on the NMDA receptor, and IDH1^mut gliomas are more likely to cause seizures in patients. This has rapid translational implications for the personalized management of tumor-associated epilepsy, as targeted IDH1^mut inhibitors may improve antiepileptic therapy in patients with IDH1^mut gliomas.

Mouse models have been indispensable for elucidating normal and pathological processes that influence learning and memory. A widely used method for assessing these cognitive processes in mice is the Morris water maze, a classic test for examining spatial learning and memory. However, Morris water maze studies with mice have principally been performed using adult animals, which preclude studies of critical neurodevelopmental periods when the cellular and molecular substrates of learning and memory are formed. While weanling rats have been successfully trained in the Morris water maze, there have been few attempts to test weanling mice in this behavioral paradigm even though mice offer significant experimental advantages because of the availability of many genetically modified strains. Here, we present experimental evidence that weanling mice can be trained in the Morris water maze beginning on postnatal day 24. Maze-trained weanling mice exhibit significant improvements in spatial learning over the training period and results of the probe trial indicate the development of spatial memory. There were no sex differences in the animals’ performance in these tasks. In addition, molecular biomarkers of synaptic plasticity are upregulated in maze-trained mice at the transcript level. These findings demonstrate that the Morris water maze can be used to assess spatial learning and memory in weanling mice, providing a potentially powerful experimental approach for examining the influence of genes, environmental factors and their interactions on the development of learning and memory.