Evidence Supporting the Existence of an Activity-Dependent Astrocyte-Neuron Lactate Shuttle

Abstract

Mounting evidence from in vitro experiments indicates that lactate is an efficient energy substrate for neurons and that it may significantly contribute to maintain synaptic transmission, particularly during periods of intense activity. Since lactate does not cross the blood-brain barrier easily, blood-borne lactate cannot be a significant source. In vitro studies by several laboratories indicate that astrocytes release large amounts of lactate. In 1994, we proposed a mechanism whereby lactate could be produced by astrocytes in an activity-dependent, glutamate-mediated manner. Over the last 2 years we have obtained further evidence supporting the notion that a transfer of lactate from astrocytes to neurons might indeed take place. In this article, we first review data showing the presence of mRNA encoding for two monocarboxylate transporters, MCT1 and MCT2, in the adult mouse brain. Second, by using monoclonal antibodies selectively directed against the two distinct lactate dehydrogenase isoforms, LDH₁ and LDH₅, a specific cellular distribution between neurons and astrocytes is revealed which suggests that a population of astrocytes is a lactate ‘source’ while neurons may be a lactate ‘sink’. Third, we provide biochemical evidence that lactate is interchangeable with glucose to support oxidative metabolism in cortical neurons. This set of data is consistent with the existence of an activity-dependent astrocyte-neuron lactate shuttle for the supply of energy substrates to neurons.

Neuron-specific deficits of bioenergetic processes in the dorsolateral prefrontal cortex in schizophrenia

“…Glucose is converted to glucose-6-phosphate (G6P) via HXK in the first step of glycolysis, where it may be further converted to other bioenergetic intermediates by highly regulated enzymes, such as phosphofructokinase, ultimately yielding pyruvate and ATP (23). Pyruvate may be converted to lactate by lactate dehydrogenase (LDH) and shuttled via monocarboxylate transporters (MCTs) into neurons, providing energy for receptor trafficking, spine formation and other neurotransmission events (24, 25). In schizophrenia, cognitive impairment correlated with decreases in striatal cytochrome oxidase and cortical glucose utilization (26, 27).…”

Glucose is Necessary to Maintain Neurotransmitter Homeostasis during Synaptic Activity in Cultured Glutamatergic Neurons

“…According to this, uptake of released neurotransmitter glutamate into astrocytes leads to increased glycolysis and production of lactate, which is subsequently exported to neurons (Bittar et al, 1996;Pellerin et al, 1998). Indeed, neurons in culture as well as other brain tissue preparations are able to maintain functional activity using lactate, other monocarboxylates, and certain amino acids as energy substrates (Schurr et al, 1988;Hertz et al, 1988;Brown et al, 2001;Waagepetersen et al, 2005).…”

Brain lactate responses during visual stimulation in fasting and hyperglycemic subjects: A proton magnetic resonance spectroscopy study at 1.5 Tesla

“…However, studies of muscle energy metabolism have established that lactate is almost always produced during intense muscle activity under fully aerobic conditions, and that lactate serves to shuttle energy substrate from one cell or cellular compartment to another (Brooks, 1986;Gladden, 2004). Recent studies have suggested that lactate might serve a similar role in brain energy metabolism (Pellerin et al, 1998;Schurr, 2005). In vivo measures of brain lactate with microsensors in rats (Hu and Wilson, 1997) and with proton magnetic resonance spectroscopy (1H-MRS) in humans (Prichard et al, 1991;Sappey-Marinier et al, 1992;Frahm et al, 1996) have demonstrated brain lactate increases during neuronal activation.…”