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J Inherit Metab Dis. 2004;27(6):825-8.

Modulation of glutamatergic and GABAergic neurotransmission in glutaryl-CoA dehydrogenase deficiency.

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Department of Biochemistry, Instituto de Ciências Básicas da Saúde, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil.


Although the precise mechanisms underlying the CNS degeneration of patients with glutaryl-CoA dehydrogenase (GCDH) deficiency are still the subject of intense debate, many studies have highlighted that excitotoxicity plays a fundamental role in the neuropathology of this disease, particularly involving the N-methyl-D-aspartate receptor subtype of ionotropic glutamate receptors. Modulation of the glutamatergic system by these compounds involves an inhibition of glutamate uptake into synaptosomes and synaptic vesicles, and a decrease in glutamate binding. Furthermore, glutaric and 3-hydroxyglutaric acids inhibit glutamate decarboxylase, the key enzyme of GABA synthesis, and striatal GABAergic medium-spiny neurons are highly vulnerable to 3-hydroxyglutaric acid-induced neurotoxicity. In conclusion, glutaric acid and 3-hydroxyglutaric acid induce an imbalance in glutamatergic and GABAergic neurotransmission.

[Indexed for MEDLINE]

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