Mechanisms underlying Li⁺ effects in glutamatergic and GABAergic neurotransmissions in the adult rat brain and in primary cultures of neural cells as revealed by ¹³C NMR

Abstract

We investigated by (13)C nuclear magnetic resonance (NMR) the mechanisms underlying Li(+) effects on glutamatergic and GABAergic neurotransmission systems in the adult rat brain and in primary cultures of cortical neurons and astrocytes during the metabolism of (1-(13)C) glucose or (2-(13)C) acetate. Adult male rats receiving a single dose of Li(+) intraperitoneally (7 mmol/kg) were infused 2 hr later, for 60 min, with (1-(13)C) glucose (80 mumol/min/kg) or (2-(13)C) acetate (240 micromol/min/kg). High-resolution (13)C NMR spectra of brain extracts prepared after the infusion revealed that Li(+) significantly decreased the incorporation of (13)C in glutamate and GABA (gamma-aminobutyric acid) carbons from (1-(13)C) glucose, but not from (2-(13)C) acetate. To complement the in vivo approach, primary cultures of cortical neurons or astrocytes were incubated with 1 mM uniformly (13)C-labeled glucose or 5 mM (2-(13)C) acetate, in the absence and presence of increasing Li(+) concentrations up to 15 mM. Under these conditions, Li(+) significantly decreased neuronal glucose uptake in a concentration-dependent manner without apparent effects on astrocytic acetate uptake. Extracts prepared at the end of the incubations showed that Li(+) significantly decreased the incorporation of (13)C labeling into GABA carbons from its precursor glutamate in neurons, but such a decrease into glutamine carbons in astrocytes was not statistically significant. Our results indicate that the effects of Li(+) are mediated through a reduction of neuronal glucose uptake, resulting in a decrease of glutamatergic and GABAergic neurotransmission without apparent effects on astrocytic metabolism.

Li+ in Bipolar Disorder – Possible Mechanisms of Its Pharmacological Mode of Action

“…Our results revealed that 15 mmol L -1 Li + caused a statistically significant decrease in glucose uptake by neurons but no apparent effects in glucose or acetate uptake by astrocytes. The decrease in neuronal glucose uptake in the presence of Li + , consistent with an inhibition of the glycolytic flux, was not paralleled by a concomitant significant change in lactate production, indicating that the decreased glucose consumption reflects a net decrease in glucose oxidation and TCA cycle activity (Fonseca et al, 2009). The ability of Li + to decrease glycolytic and TCA cycle fluxes is in agreement with the results obtained for SH-SY5Y cells (Fonseca et al, 2005) and other data in the literature (Abreu & Abreu, 1973;Kajda & Birch, 1981;Nordenberg et al, 1982).…”

“…(Fonseca et al, 2009). Values are means ± SEM for the number (n) of experiments indicated in parentheses.…”

“…Because [1-13 C]glucose is believed to be a universal substrate for neurons and glial cells and [2-13 C]acetate is known to be mainly a glial substrate, our results suggest that the inhibition observed in vivo must occur primarily in the neuronal compartment, at an upstream level of the glutamate-glutamine-GABA cycles. Glucose consumption through glycolysis and the TCA cycle could be a possible target for this upstream Li + action (Fonseca et al, 2005(Fonseca et al, , 2009Nordenberg et al, 1982;Plenge, 1976;Zager & Ames, 1988;). Li + significantly increased the glutamate C3/GABA C3 labelling ratio (p < 0.01), suggesting that Li + may affect the synthesis of GABA from its direct precursor glutamate in the neuronal compartment, in vivo, possibly through the inhibition of glutamate decarboxylase activity (Fonseca et al, 2009).…”

“…. Graphical representation of 13 C NMR signal areas of the metabolites glutamate, glutamine and GABA, as observed in the 13 C NMR spectra obtained form rat brain extracts prepared after saline (control) and Li + administration, and infusion with [1-13 C]glucose (n=3 for both saline-and Li + -treated rats) (A) or [2-13 C]acetate (n=4 for saline-and n=5 for Li + -treated rats) (B) (Fonseca et al, 2009). Tissue wet weight and appropriate correction factor for nuclear Overhauser enhancement and signal saturation were taken into account.…”

“…The results obtained suggested that cell energetic metabolism might be an important target for Li + action. 13 C NMR spectroscopy was also used to investigate Li + effects on glucose and acetate metabolism in primary cell cultures, rat cortical neurons and astrocytes, as well as in rat brain (Fonseca et al, 2009). It was proposed that Li + has an important role on the GABAergic neurotransmitter system as detected in cortical neurons when 13 C-glucose was used as substrate, as well as in rat brain after infusion with [1-13 C]glucose.…”