title: Succinic semialdehyde dehydrogenase deficiency: GABAB receptor-mediated function.
abstract: The succinic semialdehyde dehydrogenase (SSADH) null mouse (SSADH(-/-)) represents a viable animal model for human SSADH deficiency and is characterized by markedly elevated levels of both gamma-hydroxybutyric acid (GHB) and gamma-aminobutyric acid (GABA) in brain, blood, and urine. In physiological concentrations, GHB acts at the GHB receptor (GHBR), but in high concentrations such as those observed in the brains of children with SSADH deficiency, GHB is thought to be a direct agonist at the GABABR receptor (GABABR). We tested the hypothesis that both GHBR and GABABR-mediated function are perturbed in SSADH deficiency. Therefore, we examined the high affinity binding site for GHB as well as the expression and function of the GABABR in mutant mice made deficient in SSADH (SSADH(-/-)). There was a significant decrease in binding of the specific GABABR antagonist, [3H]CGP-54626A at postnatal day (PN)7 and PN14 in SSADH(-/-) when compared to wild type control animals (SSADH(+/+)), particularly in hippocampus. GABABR-mediated synaptic potentials were decreased in SSADH(-/-). Immunoblot analysis of GABABR1a, R1b, and R2 in SSADH(-/-) indicated a trend towards a region-specific and time-dependent decrease of GABABR subunit protein expression. There was no difference between SSADH(-/-) and wild type in binding of either [3H]GHB or a specific GHBR antagonist to the GHBR. These data suggest that the elevated levels of GABA and GHB that occur in SSADH(-/-) lead to a use-dependent decrease in GABABR-mediated function and raise the possibility that this GHB- and GABA-induced perturbation of GABABR could play a role in the pathogenesis of the seizures and mental retardation observed in SSADH deficiency.
authors.affiliation: Brain and Behavior Program, Faculty of Medicine, University of Toronto, ON, Canada.
authors.forename: Andrea
authors.initials: A
authors.lastname: Buzzi
authors.forename: Ying
authors.initials: Y
authors.lastname: Wu
authors.forename: Marina V
authors.initials: MV
authors.lastname: Frantseva
authors.forename: Jose L
authors.initials: JL
authors.lastname: Perez Velazquez
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Cortez
authors.forename: Chun C
authors.initials: CC
authors.lastname: Liu
authors.forename: Li Q
authors.initials: LQ
authors.lastname: Shen
authors.forename: K Michael
authors.initials: KM
authors.lastname: Gibson
authors.forename: O Carter
authors.initials: OC
authors.lastname: Snead
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000235:genetics; D001921:Brain / Q000201:enzymology* / Q000503:physiopathology; D001923:Brain Chemistry / Q000235:genetics*; D020739:Brain Diseases, Metabolic, Inborn / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D004195:Disease Models, Animal; D018756:GABA Antagonists / Q000494:pharmacology; D006885:Hydroxybutyrates / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D021122:Protein Subunits / Q000235:genetics; D018080:Receptors, GABA-B / Q000235:genetics / Q000378:metabolism*; D050644:Succinate-Semialdehyde Dehydrogenase / Q000172:deficiency* / Q000235:genetics*; D009435:Synaptic Transmission / Q000187:drug effects / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D018756:GABA Antagonists; D006885:Hydroxybutyrates; D021122:Protein Subunits; D018080:Receptors, GABA-B; C111420:4-hydroxybutyric acid; D005680:gamma-Aminobutyric Acid; D050644:Succinate-Semialdehyde Dehydrogenase