title: Disturbance of the glutamatergic system by glutaric acid in striatum and cerebral cortex of glutaryl-CoA dehydrogenase-deficient knockout mice: possible implications for the neuropathology of glutaric acidemia type I.
abstract: The role of excitotoxicity on the neuropathology of glutaric acidemia type I (GA I) is still under debate. Therefore, in the present work, we evaluated glutamate uptake by brain slices and glutamate binding to synaptic membranes, as well as glutamine synthetase activity in cerebral cortex and striatum from glutaryl-CoA dehydrogenase deficient (Gcdh(-/-)) mice along development (7, 15, 30 and 60 days of life) in the hopes of clarifying this matter. We also tested the influence of glutaric acid (GA) added exogenously on these parameters. [(3)H]Glutamate uptake was not significantly altered in cerebral cortex and striatum from Gcdh(-/-) mice, as compared to WT mice. However, GA provoked a significant decrease of [(3)H]glutamate uptake in striatum from both WT and Gcdh(-/-) mice older than 7 days. This inhibitory effect was more pronounced in Gcdh(-/-), as compared to WT mice. The use of a competitive inhibitor of glutamate astrocytic transporters indicated that the decrease of [(3)H]glutamate uptake caused by GA was due to the competition between this organic acid and glutamate for the same astrocytic transporter site. We also found that Na(+)-dependent [(3)H]glutamate binding (binding to transporters) was increased in the striatum from Gcdh(-/-) mice and that GA significantly diminished this binding both in striatum and cerebral cortex from Gcdh(-/-), but not from WT mice. Finally, we observed that glutamine synthetase activity was not changed in brain cortex and striatum from Gcdh(-/-) and WT mice and that GA was not able to alter this activity. It is therefore presumed that a disturbance of the glutamatergic neurotransmission system caused by GA may potentially be involved in the neuropathology of GA I, particularly in the striatum.
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: Estela Natacha Brandt
authors.initials: EN
authors.lastname: Busanello
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: Carolina Gonçalves
authors.initials: CG
authors.lastname: Fernandes
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: Rafael Volter
authors.initials: RV
authors.lastname: Martell
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: Vannessa Gonçalves Araujo
authors.initials: VG
authors.lastname: Lobato
authors.affiliation: School of Medicine, University of Colorado Denver, Aurora, United States.
authors.forename: Stephen
authors.initials: S
authors.lastname: Goodman
authors.affiliation: School of Medicine, University of Colorado Denver, Aurora, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Woontner
authors.affiliation: Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil.
authors.forename: Diogo Onofre Gomes
authors.initials: DO
authors.lastname: de Souza
authors.affiliation: Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil; Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil. Electronic address: mwajner@ufrgs.br.
authors.forename: Moacir
authors.initials: M
authors.lastname: Wajner
mesh_terms: D000592:Amino Acid Metabolism, Inborn Errors / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001928:Brain Diseases, Metabolic / Q000378:metabolism* / Q000473:pathology; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D005974:Glutamate-Ammonia Ligase / Q000378:metabolism; D005977:Glutarates / Q000494:pharmacology*; D050770:Glutaryl-CoA Dehydrogenase / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout
chemical_list: D005977:Glutarates; D050770:Glutaryl-CoA Dehydrogenase; D005974:Glutamate-Ammonia Ligase; C035736:glutaric acid
keywords: Excitotoxicity; Glutamate binding; Glutamate uptake; Glutaric acidemia type I; Glutaryl-CoA dehydrogenase; Knockout mice