Excitatory and Inhibitory Activity Is Differentially Affected in SOD1^G37R Mouse Model of ALS: A ¹H-[¹³C]-NMR Analysis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder marked by the selective degeneration of motor neurons in the central nervous system. In this study, neuronal and astroglial metabolic activities were evaluated in the cerebral cortex and spinal cord of an 18 month-old male SOD1^G37R mouse model of ALS using ¹H-[¹³C]-nuclear magnetic resonance spectroscopy in tissue extracts in conjunction with an infusion of [1,6-¹³C₂]glucose or [2-¹³C]acetate, respectively. The cerebral metabolic fluxes were obtained by fitting a three-compartment metabolic model to the ¹³C turnover of amino acids from ¹³C-glucose. The SOD1^G37R mice exhibited decreased forelimb strength and hindlimb function compared to age-matched controls. The spinal cord of SOD1^G37R mice exhibited a reduction in aspartate, glutamate, <i>N</i>-acetylaspartate, and <i>N</i>-acetylaspartylglutamate levels and an increase in myo-inositol, glutamine, and taurine levels. The increased acetate oxidation rate suggests heightened inflammatory conditions in the cerebral cortex and spinal cord of SOD1^G37R mice. The glutamatergic and GABAergic TCA cycle and neurotransmitter cycle fluxes were reduced in the spinal cord of SOD1^G37R mice. In contrast, glutamatergic fluxes were increased in the cerebral cortex. These data suggest heightened excitatory activity in the cerebral cortex and differential degeneration of excitatory and inhibitory neurons in the spinal cord in advanced conditions of ALS.