Chronic treatment with glutaric acid induces partial tolerance to excitotoxicity in neuronal cultures from chick embryo telencephalons

Publisher Website
Google Scholar
Abstract
Glutaryl‐CoA dehydrogenase deficiency (GDD) is characterized biochemically by an accumulation of glutaric (GA) and 3‐hydroxyglutaric (3‐OH‐GA) acids and clinically by the development of acute striatal degeneration. 3‐OH‐GA was recently shown to induce neuronal damage via N‐methyl‐D‐aspartate (NMDA) receptors. The pathogenetic role of GA, however, remains unclear. We demonstrate that GA exerts a dual action in cultured chick embryo neurons. Short‐term incubation with millimolar concentrations of GA induces a weak neuronal damage, adding to 3‐OH‐GA neurotoxicity. In contrast, chronic treatment with subtoxic, micromolar concentrations of GA results in partial tolerance to 3‐OH‐GA‐ and NMDA‐induced cell damage. A downregulation of NMDA receptors, in particular of the NR2B subunit, is critically involved in this GA‐induced effect, resulting in a reduced Ca2+ increase and generation of reactive oxygen species after acute exposure to NMDA or 3‐OH‐GA. Furthermore, GA decreases Na+/K+‐ATPase activity, which is prevented by glutathione, suggesting a modulation of NMDA receptor function via resting membrane potential and Na+‐dependent glutamate transport. In contrast, GA does not inhibit mitochondrial respiratory chain and β‐oxidation of fatty acids, virtually excluding an activation of NMDA receptors secondary to ATP depletion. These results strongly suggest that GA modulates the NMDA receptor‐mediated neurotoxicity of 3‐OH‐GA, providing an explanatory basis for the non‐linear relationship between organic acid concentrations and disease progression in GDD patients. Furthermore, GA‐induced downregulation of NMDA receptors might be involved in the delayed cerebral maturation of GDD patients, resulting in frontotemporal atrophy and a reduced opercularization, which are common neuroradiological findings in GDD patients.
Funding Information
  • Deutsche Forschungsgemeinschaft (KO 2010/1-1)
  • Medical Faculty of the University of Heidelberg (12/2001)