Cerebral organic acid disorders induce neuronal damage via excitotoxic organic acids in vitro.

Glutaryl-CoA dehydrogenase deficiency (GDD), which is one of the most frequent organic acid disorders, is characterized by a specific age- and regional-dependent neuropathology. We hypothesized that the distinct brain damage in GDD could be caused by the main pathologic metabolites, the organic acids glutaric (GA) and 3-hydroxyglutaric (3-OH-GA) acids, through an excitotoxic sequence. Therefore, we investigated the effects of 3-OH-GA and GA on primary neuronal cultures from chick embryonic telencephalons. Here we report that 3-OH-GA and GA decreased cell viability concentration- and time-dependently, which could be only totally prevented by preincubation with MK-801, ifenprodil and NR2B antibodies. Furthermore, cell viability decreased in parallel with the increasing expression of NR2B subunit on cultured neurons from 2nd to 6th DIV. We conclude that GA and 3-OH-GA act as excitotoxic organic acids (EOA) specifically through NR1/NR2B and that the extent of induced neurotoxicity is dependent on NR1/NR2B expression during maturation.