title: Increased glutamate receptor and transporter expression in the cerebral cortex and striatum of gcdh-/- mice: possible implications for the neuropathology of glutaric acidemia type I.
abstract: We determined mRNA expression of the ionotropic glutamate receptors NMDA (NR1, NR2A and NR2B subunits), AMPA (GluR2 subunit) and kainate (GluR6 subunit), as well as of the glutamate transporters GLAST and GLT1 in cerebral cortex and striatum of wild type (WT) and glutaryl-CoA dehydrogenase deficient (Gchh-/-) mice aged 7, 30 and 60 days. The protein expression levels of some of these membrane proteins were also measured. Overexpression of NR2A and NR2B in striatum and of GluR2 and GluR6 in cerebral cortex was observed in 7-day-old Gcdh-/-. There was also an increase of mRNA expression of all NMDA subunits in cerebral cortex and of NR2A and NR2B in striatum of 30-day-old Gcdh-/- mice. At 60 days of life, all ionotropic receptors were overexpressed in cerebral cortex and striatum of Gcdh-/- mice. Higher expression of GLAST and GLT1 transporters was also verified in cerebral cortex and striatum of Gcdh-/- mice aged 30 and 60 days, whereas at 7 days of life GLAST was overexpressed only in striatum from this mutant mice. Furthermore, high lysine intake induced mRNA overexpression of NR2A, NR2B and GLAST transcripts in striatum, as well as of GluR2 and GluR6 in both striatum and cerebral cortex of Gcdh-/- mice. Finally, we found that the protein expression of NR2A, NR2B, GLT1 and GLAST were significantly greater in cerebral cortex of Gcdh-/- mice, whereas NR2B and GLT1 was similarly enhanced in striatum, implying that these transcripts were translated into their products. These results provide evidence that glutamate receptor and transporter expression is higher in Gcdh-/- mice and that these alterations may be involved in the pathophysiology of GA I and possibly explain, at least in part, the vulnerability of striatum and cerebral cortex to injury in patients affected by GA I.
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil.
authors.forename: Valeska Lizzi
authors.initials: VL
authors.lastname: Lagranha
authors.affiliation: Centro de Terapia Gênica, Centro de Pesquisas Experimental, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil.
authors.forename: Ursula
authors.initials: U
authors.lastname: Matte
authors.affiliation: Centro de Terapia Gênica, Centro de Pesquisas Experimental, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil.
authors.forename: Talita Giacomet
authors.initials: TG
authors.lastname: de Carvalho
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil.
authors.forename: Bianca
authors.initials: B
authors.lastname: Seminotti
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil.
authors.forename: Carolina Coffi
authors.initials: CC
authors.lastname: Pereira
authors.affiliation: Departments of Pediatrics, Molecular and Medical Genetics, Oregon Health & Science University, Portland, Oregon, United States of America.
authors.forename: David M
authors.initials: DM
authors.lastname: Koeller
authors.affiliation: School of Medicine, University of Colorado at Denver, Aurora, Colorado, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Woontner
authors.affiliation: School of Medicine, University of Colorado at Denver, Aurora, Colorado, United States of America.
authors.forename: Stephen I
authors.initials: SI
authors.lastname: Goodman
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil.
authors.forename: Diogo Onofre Gomes
authors.initials: DO
authors.lastname: de Souza
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil; Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil.
authors.forename: Moacir
authors.initials: M
authors.lastname: Wajner
mesh_terms: D000592:Amino Acid Metabolism, Inborn Errors / Q000201:enzymology / Q000473:pathology*; D027322:Amino Acid Transport System X-AG / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001928:Brain Diseases, Metabolic / Q000201:enzymology / Q000473:pathology*; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology; D004032:Diet; D005260:Female; D005786:Gene Expression Regulation; D050770:Glutaryl-CoA Dehydrogenase / Q000172:deficiency* / Q000378:metabolism; D008239:Lysine / Q000378:metabolism; D008297:Male; D051379:Mice; D017072:Neostriatum / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017470:Receptors, Glutamate / Q000235:genetics / Q000378:metabolism*
chemical_list: D027322:Amino Acid Transport System X-AG; D012333:RNA, Messenger; D017470:Receptors, Glutamate; D050770:Glutaryl-CoA Dehydrogenase; D008239:Lysine