α-ketoglutarate dehydrogenase complex activity modulates glutamate excitotoxicity via metabotropic regulation of NMDA receptors in primary cultures Goeschl, Vanessa Hotka, Matej Hochreiter, Bernhard Hilber, Karlheinz Boehm, Stefan Kozlov, Andrey V. Kubista, Helmut ddc:570 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. The Company of Biologists 2026 info:eu-repo/semantics/article doc-type:article text http://purl.org/coar/resource_type/c_2df8fbb1 https://research-explorer.ista.ac.at/record/21860 https://research-explorer.ista.ac.at/download/21860/21861 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> eng info:eu-repo/semantics/altIdentifier/doi/10.1242/jcs.264420 info:eu-repo/semantics/altIdentifier/issn/0021-9533 info:eu-repo/semantics/altIdentifier/e-issn/1477-9137 info:eu-repo/semantics/altIdentifier/pmid/41834724 info:eu-repo/semantics/openAccess