Altered cerebral glucose and acetate metabolism in succinic semialdehyde dehydrogenase-deficient mice: evidence for glial dysfunction and reduced glutamate/glutamine cycling.
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 gamma-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-(13)C(2)]glucose or [2-(13)C]acetate for different periods. Cortical extracts were prepared and measured using high-resolution (1)H-[(13)C] 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. (13)C Labeling from [1,6-(13)C(2)]glucose, which is metabolized in neurons and glia, was significantly lower (expressed as mumol of (13)C 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. (13)C Labeling from [2-(13)C]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.
Chowdhury
G M I
GM
Department of Diagnostic Radiology, Magnetic Resonance Research Center, Yale University School of Medicine, New Haven, Connecticut, USA. golam.chowdhury@yale.edu
Gupta
M
M
Gibson
K M
KM
Patel
A B
AB
Behar
K L
KL
D000085:Acetates / Q000097:blood*; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001786:Blood Glucose / Q000378:metabolism*; D002247:Carbon Isotopes / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism*; D005974:Glutamate-Ammonia Ligase / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D005973:Glutamine / Q000378:metabolism*; D007091:Image Processing, Computer-Assisted / Q000379:methods; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D051379:Mice; D018345:Mice, Knockout; D009457:Neuroglia / Q000502:physiology; D012978:Sodium Oxybate / Q000378:metabolism; D050644:Succinate-Semialdehyde Dehydrogenase / Q000172:deficiency*; D013997:Time Factors; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D000085:Acetates; D000596:Amino Acids; D001786:Blood Glucose; D002247:Carbon Isotopes; D005973:Glutamine; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D012978:Sodium Oxybate; D050644:Succinate-Semialdehyde Dehydrogenase; D005974:Glutamate-Ammonia Ligase