Neuronal glucose metabolism is impaired while astrocytic TCA cycling is unaffected at symptomatic stages in the hSOD1G93A mouse model of amyotrophic lateral sclerosis

Although alterations in energy metabolism are known in ALS, the specific mechanisms leading to energy deficit are not understood. We measured metabolite levels derived from injected [1-C-13]glucose and [1,2-C-13]acetate (i.p.) in cerebral cortex and spinal cord extracts of wild type and hSOD1(G93A) mice at onset and mid disease stages using high-pressure liquid chromatography, H-1 and C-13 nuclear magnetic resonance spectroscopy. Levels of spinal and cortical CNS total lactate, [3-C-13]lactate, total alanine and [3-C-13]alanine, but not cortical glucose and [1-C-13]glucose, were reduced mostly at mid stage indicating impaired glycolysis. The [1-C-13]glucose-derived [4-C-13]glutamate, [4-C-13]glutamine and [2-C-13]GABA amounts were diminished at mid stage in cortex and both time points in spinal cord, suggesting decreased [3-C-13]pyruvate entry into the TCA cycle. Lack of changes in [1,2-C-13]acetate-derived [4,5-C-13]glutamate, [4,5-C-13]glutamine and [1,2-C-13]GABA levels indicate unchanged astrocytic C-13-acetate metabolism. Reduced levels of leucine, isoleucine and valine in CNS suggest compensatory breakdown to refill TCA cycle intermediate levels. Unlabelled, [2-C-13] and [4-C-13]GABA concentrations were decreased in spinal cord indicating that impaired glucose metabolism contributes to hyperexcitability and supporting the use of treatments which increase GABA amounts. In conclusion, CNS glucose metabolism is compromised, while astrocytic TCA cycling appears to be normal in the hSOD1(G93A) mouse model at symptomatic disease stages.