Modulation of glutamatergic and GABAergic neurotransmission in glutaryl-CoA dehydrogenase deficiency.
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.
Wajner
M
M
Department of Biochemistry, Instituto de Ciências Básicas da Saúde, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil. mwajner@vortex.ufrgs.br
Kölker
S
S
Souza
D O
DO
Hoffmann
G F
GF
de Mello
C F
CF
D000592:Amino Acid Metabolism, Inborn Errors / Q000503:physiopathology*; D000818:Animals; D018698:Glutamic Acid / Q000502:physiology*; D050770:Glutaryl-CoA Dehydrogenase; D006801:Humans; D009498:Neurotoxins / Q000378:metabolism; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000172:deficiency*; D009435:Synaptic Transmission / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
D009498:Neurotoxins; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D044925:Oxidoreductases Acting on CH-CH Group Donors; D050770:Glutaryl-CoA Dehydrogenase