Despite the long-established therapeutic efficacy of lithium in the treatment of bipolar disorder (BPD), its molecular mechanism of action remains elusive. Newly developed stable isotope-resolved metabolomics (SIRM) is a powerful approach that can be used to elucidate systematically how lithium impacts glial and neuronal metabolic pathways and activities, leading ultimately to deciphering its molecular mechanism of action. The effect of lithium on the metabolism of three different 13C-labeled precursors ([U-13C]-glucose, 13C-3-lactate or 13C-2,3-alanine) was analyzed in cultured rat astrocytes and neurons by nuclear magnetic resonance (NMR) spectroscopy and gas chromatography mass spectrometry (GC-MS). Using [U-13C]-glucose, lithium was shown to enhance glycolytic activity and part of the Krebs cycle activity in both astrocytes and neurons, particularly the anaplerotic pyruvate carboxylation (PC). The PC pathway was previously thought to be active in astrocytes but absent in neurons. Lithium also stimulated the extracellular release of 13C labeled-lactate, -alanine (Ala), -citrate, and -glutamine (Gln) by astrocytes. Interrogation of neuronal pathways using 13C-3-lactate or 13C-2,3-Ala as tracers indicated a high capacity of neurons to utilize lactate and Ala in the Krebs cycle, particularly in the production of labeled Asp and Glu via PC and normal cycle activity. Prolonged lithium treatment enhanced lactate metabolism via PC but inhibited lactate oxidation via the normal Krebs cycle in neurons. Such lithium modulation of glycolytic, PC and Krebs cycle activity in astrocytes and neurons as well as release of fuel substrates by astrocytes should help replenish Krebs cycle substrates for Glu synthesis while meeting neuronal demands for energy. Further investigations into the molecular regulation of these metabolic traits should provide new insights into the pathophysiology of mood disorders and early diagnostic markers, as well as new target(s) for effective therapies.
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Pentose phosphate pathway
Stable isotope resolved metabolomics
Total correlation spectroscopy
Heteronuclear single quantum coherence spectroscopy
Uniformly 13C labeled glucose
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NMR spectra were recorded at the JG Brown Cancer Center NMR facility, and mass spectra were obtained from the Center for Regulatory and Environmental Analytical Metabolomics (CREAM) facility at the University of Louisville. Ioline Henter of NIMH provided invaluable editorial assistance. Financial support: The study was supported in part by NIH Grant Numbers P20RR018733 from the National Center for Research Resources, 1R01CA118434-01A2 (TF, ANL, RMH), 3R01CA118434-02S1 (TF, RMH), and R24GM078233 (RKD, TF) and National Science Foundation EPSCoR grant # EPS-0447479 (TF, ANL).
T. W.-M. Fan and P. Yuan contributed equally to this work.
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Fan, T.W., Yuan, P., Lane, A.N. et al. Stable isotope-resolved metabolomic analysis of lithium effects on glial-neuronal metabolism and interactions. Metabolomics 6, 165–179 (2010). https://doi.org/10.1007/s11306-010-0208-9
- Bipolar disorder
- 13C-labeled tracers
- Pyruvate carboxylation
- Glu/Gln cycling