Inhibition of Monocarboxylate Transporter 2 in the Retrotrapezoid Nucleus in Rats: A Test of the Astrocyte–Neuron Lactate-Shuttle Hypothesis

Abstract

The astrocyte-neuronal lactate-shuttle hypothesis posits that lactate released from astrocytes into the extracellular space is metabolized by neurons. The lactate released should alter extracellular pH (pHe), and changes in pH in central chemosensory regions of the brainstem stimulate ventilation. Therefore, we assessed the impact of disrupting the lactate shuttle by administering 100 M ␣-cyano-4-hydroxycinnamate (4-CIN), a dose that blocks the neuronal monocarboxylate transporter (MCT) 2 but not the astrocytic MCTs (MCT1 and MCT4). Administration of 4-CIN focally in the retrotrapezoid nucleus (RTN), a medullary central chemosensory nucleus, increased ventilation and decreased pHe in intact animals. In medullary brain slices, 4-CIN reduced astrocytic intracellular pH (pHi) slightly but alkalinized neuronal pHi. Nonetheless, pHi fell significantly in both cell types when they were treated with exogenous lactate, although 100 M 4-CIN significantly reduced the magnitude of the acidosis in neurons but not astrocytes. Finally, 4-CIN treatment increased the uptake of a fluorescent 2-deoxy-D-glucose analog in neurons but did not alter the uptake rate of this 2-deoxy-D-glucose analog in astrocytes. These data confirm the existence of an astrocyte to neuron lactate shuttle in intact animals in the RTN, and lactate derived from astrocytes forms part of the central chemosensory stimulus for ventilation in this nucleus. When the lactate shuttle was disrupted by treatment with 4-CIN, neurons increased the uptake of glucose. Therefore, neurons seem to metabolize a combination of glucose and lactate (and other substances such as pyruvate) depending, in part, on the availability of each of these particular substrates.

In VivoEvidence for Lactate as a Neuronal Energy Source

“…Important roles have been attributed to lactate such as the modulation of CBF (Gordon et al, 2008), as a buffer to sustain neuronal energy supply (Kasischke et al, 2004) and most prominently as a pivotal element in the neuron-glia metabolic cooperation to regulate energy supply in an activity-dependent manner (for review, see Pellerin and Magistretti, 2003;Magistretti, 2006). Furthermore, it has been shown recently that lactate levels are sensed by a specific type of neuron (orexin neurons in the lateral hypothalamus) to coordinate the balancing of brain activity and energy supply (Lam et al, 2005;Shimizu et al, 2007;Erlichman et al, 2008;Parsons and Hirasawa, 2010). Nevertheless, the details of brain energy metabolism in general and of lactate as a cerebral energy substrate in particular are still highly debated.…”

High brain lactate is a hallmark of aging and caused by a shift in the lactate dehydrogenase A/B ratio

“…It is thought that an activity-regulated lactate shuttle from astrocytes to neurons would allow neurons to benefit from lactate (40). Although most recent modeling supports this theory (41-43) and lactate shuttling can be shown in brain slices (44), the neuronglia metabolic interactions are not fully understood. The possibility of intracellular astrocyte and neuron lactate shuttles exists in addition to the potential for an astrocyte-neuron lactate shuttle (38).…”

Lactate dyscrasia: a novel explanation for amyotrophic lateral sclerosis

“…Supporting this, lactate dehydrogenase (LDH) activity is detected in oculomotor neurons (Hayashi, 1987) and in eye muscles (Kahan and Juhasz, 1976). Alternatively, it is possible that lactate is also removed from the nerves/muscles via a lactate shuttle (muscle-neuronal lactate shuttle; MNLS), like the recently proposed astrocyte-neuronal lactate shuttle (Erlichman et al, 2008;Mangia et al, 2009). We therefore propose that an MNLS exists to maintain lactate homeostasis between muscles and motoneurons (the neuromuscular unit) and that dysregulation of the MNLS results in lactate assimilation in the NMJ leading to cellular stress, toxicity, and subsequent degeneration.…”