The Astrocyte—Neuron Lactate Shuttle: A Debated but still Valuable Hypothesis for Brain Imaging

Ten years ago, Luc Pellerin and Pierre Magistretti in Lausanne (Switzerland) made the first observation that glutamate stimulates, in a dose-dependent manner, glucose uptake into cultured astrocytes. The second observation was that glucose was mainly metabolized to lactate, indicating net aerobic glycolysis. The last set of data defined the signaling pathway: glutamate was acting via its transporter not its receptors (Pellerin and Magistretti, 1994). As such, these data do not appear so revolutionary. So what are the reasons for the long-standing and often emotional debate on this issue (Gjedde et al, 2002; Chih and Roberts, 2003; Dienel and Cruz, 2004; Hertz, 2004)?Undoubtedly, the main reason arises from the hypothesis that was put forward by Pellerin and Magistretti: ‘glutamate uptake-induced aerobic glycolysis into astrocytes is the cellular mechanism coupling neuronal activity to glucose utilization‘. What a gap it seems from data obtained on cultured astrocytes to a well-known physiologic response of the brain! In a timely manner, their work came at a moment of increasing interest in the general cell biology underlying the brain imaging signals and they should be recognized for proposing the first cellular hypothesis about neurometabolic coupling. It should be emphasized that until now, and despite the intense debate of their hypothesis, there is no alternative signaling pathway that links neuronal glutamatergic activity to glucose use that would fit with what has been observed using in vivo brain imaging. We still do not know with certainty which signaling pathway enables a tight adjustment of glucose use to meet the increasing needs of the glutamatergic synapse but the great advantage of the aforementioned hypothesis is that it paved the way for a large body of fundamental research on this topic.