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

J Inherit Metab Dis. 2004;27(6):825-8. doi: 10.1023/B:BOLI.0000045765.37043.fb.


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.

Publication types

  • Review

MeSH terms

  • Amino Acid Metabolism, Inborn Errors / physiopathology*
  • Animals
  • Glutamic Acid / physiology*
  • Glutaryl-CoA Dehydrogenase
  • Humans
  • Neurotoxins / metabolism
  • Oxidoreductases Acting on CH-CH Group Donors / deficiency*
  • Synaptic Transmission / physiology*
  • gamma-Aminobutyric Acid / physiology*


  • Neurotoxins
  • Glutamic Acid
  • gamma-Aminobutyric Acid
  • Oxidoreductases Acting on CH-CH Group Donors
  • Glutaryl-CoA Dehydrogenase