AbstractGlutaric acidemia type 1 (GA1) is an autosomal recessively inherited deficiency of glutaryl‐CoA dehydrogenase. Accumulating metabolites, 3‐hydroxyglutaric (3‐OH‐GA), glutaric (GA), and trans‐glutaconic (TG) acids, have been proposed to be involved in the development of the striatal degeneration seen in children with GA1 via an excitotoxic mechanism. We have studied the extent to which 3‐OH‐GA, GA, and TG are neurotoxic and whether neurotoxicity is caused by an excitotoxic mechanism in which 3‐OH‐GA, GA, or TG overactivates N‐methyl‐D‐aspartate (NMDA) receptors. In cultured mouse neocortical neurons, all three compounds were weakly neurotoxic, possibly through activation of NMDA receptors. However, further studies in the rat cortical wedge preparation and with NMDA receptors expressed in Xenopus oocytes could not confirm an interaction of the compounds with NMDA receptors. It is concluded that the metabolites 3‐OH‐GA, GA, and TG are only weak neurotoxins and that the neurodegenerative cascade destroying the striatum in patients with GA1 involves mainly mechanisms other than excitoxicity. © 2004 Wiley‐Liss, Inc.