Regional cerebral metabolism in mouse under chronic manganese exposure: Implications for Manganism

Chronic manganese (Mn) exposure in rodents, non-human primates and humans has been linked to Parkinson’s disease like condition known as Manganism. Mn being a cofactor for many enzymes in brain has been known to be accumulated in various regions differentially and thus exert toxic effect upon chronic overexposure. In present study, neuropathology of Manganism was investigated by evaluating regional neuronal and astroglial metabolism in mice under chronic Mn exposure. Male C57BL6 mice were treated with MnCl2 (25 mg/kg, i.p.) for 21 days. Cerebral metabolism was studied by co-infusing [U-13C6]glucose and [2-13C]acetate, and monitoring 13C labeling of amino acids in brain tissue extract using 1H–[13C] and 13C–[1H]-NMR spectroscopy. Glutamate, choline, N-acetyl aspartate and myo-inositol were found to be reduced in thalamus and hypothalamus indicating a loss in neuronal and astroglial cells due to Mn neurotoxicity. Reduced labeling of GluC4 from [U-13C6]glucose and [2-13C]acetate indicates an impairment of glucose oxidation by glutamatergic neurons and glutamate–glutamine neurotransmitter cycle in cortex, striatum, thalamus–hypothalamus and olfactory bulb with chronic Mn exposure. Additionally, reduced labeling of GlnC4 from [2-13C]acetate indicates a decrease in acetate oxidation by astroglia in the same regions. However, GABAergic function was alleviated only in thalamus–hypothalamus. Our findings indicate that chronic Mn impairs excitatory (glutamatergic) function in the majority of regions of brain while inhibitory (GABAergic) activity is perturbed only in basal ganglia.

► Chronic Mn exposure decreases glutamate, NAA and choline in thalamus–hypothalamus.
► Striatal GABA level is elevated with Manganism.
► Glutamatergic (excitatory) activity is impaired in various brain regions.
► GABAergic (inhibitory) function is alleviated only in thalamus–hypothalamus.