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- Title
Altered cerebral glucose and acetate metabolism in succinic semialdehyde dehydrogenase-deficient mice: evidence for glial dysfunction and reduced glutamate/glutamine cycling.
- Authors
Chowdhury, G. M. I.; Gupta, M.; Gibson, K. M.; Patel, A. B.; Behar, K. L.
- Abstract
Succinic semialdehyde dehydrogenase (SSADH) catalyzes the NADP-dependent oxidation of succinic semialdehyde to succinate, the final step of the GABA shunt pathway. SSADH deficiency in humans is associated with excessive elevation of GABA and γ-hydroxybutyrate (GHB). Recent studies of SSADH-null mice show that elevated GABA and GHB are accompanied by reduced glutamine, a known precursor of the neurotransmitters glutamate and GABA. In this study, cerebral metabolism was investigated in urethane-anesthetized SSADH-null and wild-type 17-day-old mice by intraperitoneal infusion of [1,6-13C2]glucose or [2-13C]acetate for different periods. Cortical extracts were prepared and measured using high-resolution 1H-[13C] NMR spectroscopy. Compared with wild-type, levels of GABA, GHB, aspartate, and alanine were significantly higher in SSADH-null cortex, whereas glutamate, glutamine, and taurine were lower. 13C Labeling from [1,6-13C2]glucose, which is metabolized in neurons and glia, was significantly lower (expressed as μmol of 13C incorporated per gram of brain tissue) for glutamate-(C4,C3), glutamine-C4, succinate-(C3/2), and aspartate-C3 in SSADH-null cortex, whereas Ala-C3 was higher and GABA-C2 unchanged. 13C Labeling from [2-13C]acetate, a glial substrate, was lower mainly in glutamine-C4 and glutamate-(C4,C3). GHB was labeled by both substrates in SSADH-null mice consistent with GABA as precursor. Our findings indicate that SSADH deficiency is associated with major alterations in glutamate and glutamine metabolism in glia and neurons with surprisingly lesser effects on GABA synthesis.
- Subjects
GLUCOSE; DEHYDROGENASES; NEUROGLIA; GLUTAMIC acid; GABA; GLUTAMINE; NUCLEAR magnetic resonance spectroscopy; LABORATORY mice
- Publication
Journal of Neurochemistry, 2007, Vol 103, Issue 5, p2077
- ISSN
0022-3042
- Publication type
Article
- DOI
10.1111/j.1471-4159.2007.04887.x