article published yes Vanessa Goeschl author Matej Hotka author Bernhard Hochreiter author e6cab3de-17f6-11ed-9210-c1e42e045e9d Karlheinz Hilber author Stefan Boehm author Andrey V. Kozlov author Helmut Kubista author Bio department Glutamate excitotoxicity is a cell death mechanism triggered by accumulation of glutamate in the extracellular space. The α-ketoglutarate dehydrogenase complex (αKGDHC), an enzyme of the tricarboxylic acid cycle, represents a branching point controlling glutamate formation and its consumption as a fuel. Hence, modulation of the activity of αKGDHC might alter the amount of glutamate available for excitotoxic effects. To address this hypothesis, hippocampal neurons in primary co-culture with glial cells were exposed to zero-Mg2 buffer to elicit excitotoxicity through N-methyl-D-aspartic acid (NMDA) receptor disinhibition. Pretreatment of the cultures with succinyl phosphonate, to inhibit αKGDHC, enhanced excitotoxity, whereas promotion of αKGDHC activity by pretreatment with thiamine caused an opposite action. Moreover, NMDA receptor currents – but not those mediated by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors – were potentiated in neurons with impaired αKGDHC activity and diminished in neurons with boosted αKGDHC activity. The sensitization of NMDA receptors involved mGluR1 activation and was accompanied by enhanced neuronal discharge activity, elevated basal cytosolic Ca2+ levels, and augmented Ca2+ responses evoked by glutamate application. These results suggest that mGluR1-mediated potentiation of NMDA receptors contributes to a mechanism by which inhibition of αKGDHC might exacerbate glutamate excitotoxicity. https://research-explorer.ista.ac.at/download/21860/21861/2026_JourCellScience_Goeschl.pdf application/pdfno The Company of Biologists2026 eng 0021-9533 1477-9137 4183472410.1242/jcs.264420 1398 V. Goeschl, M. Hotka, B. Hochreiter, K. Hilber, S. Boehm, A.V. Kozlov, H. Kubista, Journal of Cell Science 139 (2026). Goeschl, V., Hotka, M., Hochreiter, B., Hilber, K., Boehm, S., Kozlov, A. V., &#38; Kubista, H. (2026). α-ketoglutarate dehydrogenase complex activity modulates glutamate excitotoxicity via metabotropic regulation of NMDA receptors in primary cultures. <i>Journal of Cell Science</i>. The Company of Biologists. <a href="https://doi.org/10.1242/jcs.264420">https://doi.org/10.1242/jcs.264420</a> V. Goeschl <i>et al.</i>, “α-ketoglutarate dehydrogenase complex activity modulates glutamate excitotoxicity via metabotropic regulation of NMDA receptors in primary cultures,” <i>Journal of Cell Science</i>, vol. 139, no. 8. The Company of Biologists, 2026. Goeschl, Vanessa, Matej Hotka, Bernhard Hochreiter, Karlheinz Hilber, Stefan Boehm, Andrey V. Kozlov, and Helmut Kubista. “α-Ketoglutarate Dehydrogenase Complex Activity Modulates Glutamate Excitotoxicity via Metabotropic Regulation of NMDA Receptors in Primary Cultures.” <i>Journal of Cell Science</i>. The Company of Biologists, 2026. <a href="https://doi.org/10.1242/jcs.264420">https://doi.org/10.1242/jcs.264420</a>. Goeschl, Vanessa, et al. “α-Ketoglutarate Dehydrogenase Complex Activity Modulates Glutamate Excitotoxicity via Metabotropic Regulation of NMDA Receptors in Primary Cultures.” <i>Journal of Cell Science</i>, vol. 139, no. 8, jcs264420, The Company of Biologists, 2026, doi:<a href="https://doi.org/10.1242/jcs.264420">10.1242/jcs.264420</a>. Goeschl V, Hotka M, Hochreiter B, et al. α-ketoglutarate dehydrogenase complex activity modulates glutamate excitotoxicity via metabotropic regulation of NMDA receptors in primary cultures. <i>Journal of Cell Science</i>. 2026;139(8). doi:<a href="https://doi.org/10.1242/jcs.264420">10.1242/jcs.264420</a> Goeschl V, Hotka M, Hochreiter B, Hilber K, Boehm S, Kozlov AV, Kubista H. 2026. α-ketoglutarate dehydrogenase complex activity modulates glutamate excitotoxicity via metabotropic regulation of NMDA receptors in primary cultures. Journal of Cell Science. 139(8), jcs264420. 218602026-05-11T10:52:27Z2026-05-12T06:40:18Z