Can Experimental Conditions Explain the Discrepancy over Glutamate Stimulation of Aerobic Glycolysis?

Abstract

Uncertainty reigns over whether or not glutamate uptake in astrocytes leads to strong stimulation of glucose utilization, measured as accumulation of radioactive deoxyglucose-6-phosphate. This is an important issue, not only because glutamate is the major excitatory transmitter, but also because it has been postulated that glutamate-induced stimulation of glycolysis links brain excitation with activation of energy production. The effect of glutamate on deoxyglucose utilization in cultured rat and mouse astrocytes grown in different media and incubated under various conditions during the deoxyglucose assay has, therefore, been studied. Under most conditions, no stimulation occurred but rather a decrease in deoxyglucose utilization during exposure to glutamate; under certain conditions, the contribution of non-metabolized deoxyglucose to the intracellular ¹⁴C signal was significant.

Oxidative Metabolism in Cultured Rat Astroglia: Effects of Reducing the Glucose Concentration in the Culture Medium and of D-Aspartate or Potassium Stimulation

“…However, L-glutamate, which is released from neurons, is taken up by astrocytes as an oxidizable substrate (Hertz et al, 1998b). Thus, L-glutamate oxidation may meet some fractions of the increased energy demand during neuronal activation.…”

“…However, reports from other laboratories disagree with this concept (Hertz et al, 1998b;Chih and Roberts, 2003;Dienel and Cruz, 2004;Hertz, 2004). Based on the hypothesis of lactate shuttling between neurons and astrocytes, neurons have been suggested to have a larger capacity for oxidizing lactate and glucose to CO 2 than astrocytes (McKenna et al, 2001;Itoh et al, 2003).…”

Brain Lactate Metabolism: The Discoveries and the Controversies

“…Discordant metabolic effects of glutamate on cultured astrocytes, complex biochemical and cellular responses to activation, oxidation of lactate by both neurons and astrocytes in vitro and in vivo, and rapid, substantial lactate release from the brain during in vivo activation have been cited as evidence against the brain's use of lactate as a major fuel during normal adult brain activation under physiologic conditions (Hertz et al, 1998(Hertz et al, , 2004(Hertz et al, , 2007Chih et al, 2001;Chih and Roberts, 2003;, 2004, 2008 Hertz, 2001, 2005;Mangia et al, 2009a;Zielke et al, 2009). In addition, major metabolic responses to activation of the cerebellum in vivo are linked to postsynaptic events, with no detectable effect of blockade of astrocytic glutamate uptake on evoked metabolic activity.…”

“…Brain growth and metabolic and functional development have enormous spurts between 10 and 21 days, with slower increases thereafter (Baquer et al, 1975 Yu et al (1984)), and cerebellar granule neurons obtained from B7-day-old postnatal rodents are used as a model system for glutamatergic neurons (Schousboe et al (1985); Hertz et al (1988) and cited references). Harvest age, culture duration, conditions, medium composition, and cellular development during culturing influence characteristics of cultures (Hertz et al (1998), Hertz (2004) and cited references), as well as any acquired pathophysiology during culturing (e.g., 15 to 30 mmol/L glucose causes diabetic complications; Gandhi et al (2010)). The capacity to use glucose or lactate by cultured astrocytes and neurons grown for < 2 weeks in vitro need not be equivalent to the adult brain.…”

“…Cerebral cortical neuronal cultures obtained from B15-day-old embryos are used as a model system for GABAergic neurons, and cerebellar granule neurons obtained from B7 day-old postnatal rodents are used as a model system for glutamatergic neurons (Yu et al (1984); Schousboe et al (1985); Hertz et al (1988) cited references). It must be noted that culture conditions and duration, composition of the culture medium, and cellular development during time in culture influence characteristics of the cultures (e.g., Hertz et al (1998);Hertz (2004) cited references). b Magnitude of response is expressed as approximate percentage change owing to treatment, 100[(treatedÀcontrol)/control)].…”