Impaired GABAergic and glutamatergic neurometabolic activity in aged mice brain as measured by 1 H-[13 C]-NMR spectroscopy.

Abstract

Healthy aging is associated with a decline in cognitive function, and is a major risk factor for many neurodegenerative diseases. Although, there are several evidence that brain mitochondrial function is altered with aging its significance at the cellular level is elusive. In this study, we have investigated mitochondrial TCA cycle and neurotransmitter cycle fluxes associated with glutamatergic, GABAergic neurons and astroglia in the cerebral cortex and hippocampus of young (6months) and aged (24months) C57BL6 mice by using 1 H-[13 C]-NMR spectroscopy together with timed infusion of 13 C-labeled glucose and acetate. The ratio VCyc /VTCA was determined from a steady-state [2-13 C]acetate experiment. Metabolic fluxes were obtained by fitting a three-compartment metabolic model to 13 C turnover of amino acids from glucose. Levels of glutamate, aspartate and taurine were reduced in the cerebral cortex, while glutamine and choline were elevated in the hippocampus of aged mice. Interestingly, the rate of acetate oxidation increased in the cerebral cortex, while the flux of mitochondrial TCA cycle of glutamatergic neurons decreased in the cerebral cortex (P<.0001) and hippocampus (P=.025) of aged mice. The glutamate-glutamine neurotransmitter cycle flux was reduced in the cerebral cortex (P<.0001). The GABAergic TCA cycle flux was reduced in the cerebral cortex (P=.0008), while GABA-glutamine neurotransmitter cycling flux was also reduced in the cerebral cortex (P=.011) and hippocampus (P=.042) of aged brain. In conclusion, the reduction in excitatory and inhibitory neurotransmitter activity of glutamatergic and GABAergic neurons in the cerebral cortex and hippocampus correlates qualitatively with declined cognitive function in aged mice.