Neuronal lactate levels depend on glia‐derived lactate during high brain activity in Drosophila

Abstract

Lactate/pyruvate transport between glial cells and neurons is thought to play an important role in how brain cells sustain the high‐energy demand that neuronal activity requires. However, the in vivo mechanisms and characteristics that underlie the transport of monocarboxylates are poorly described. Here, we use Drosophila expressing genetically encoded FRET sensors to provide an ex vivo characterization of the transport of monocarboxylates in motor neurons and glial cells from the larval ventral nerve cord. We show that lactate/pyruvate transport in glial cells is coupled to protons and is more efficient than in neurons. Glial cells maintain higher levels of intracellular lactate generating a positive gradient toward neurons. Interestingly, during high neuronal activity, raised lactate in motor neurons is dependent on transfer from glial cells mediated in part by the previously described monocarboxylate transporter Chaski, providing support for in vivo glia‐to‐neuron lactate shuttling during neuronal activity.

Mitochondrial Metabolism in Astrocytes Regulates Brain Bioenergetics, Neurotransmission and Redox Balance

“…Accordingly, glucose utilization in neurons is directed to PPP in order to regenerate NADPH for the reductive recycling of GSH upon oxidative stress ( Figure 3.3 ; Delgado-Esteban et al, 2000 ; Vaughn and Deshmukh, 2008 ; Herrero-Mendez et al, 2009 ; Bolanos, 2016 ). The astrocyte-neuron lactate shuttle (ANLS) hypothesis states that a large portion of glucose metabolism in astrocytes is directed to lactate production and this is subsequently shuttled to neurons as fuel for OXPHOS ( Figures 3.2, 3.3 ; Pellerin and Magistretti, 1994 ; Magistretti and Allaman, 2015 ; Machler et al, 2016 ; Gonzalez-Gutierrez et al, 2019 ). This shuttle seems to involve sequestration within the endoplasmic reticulum for its delivery from perivascular endfeet to perisynaptic processes ( Muller et al, 2018 ).…”

Neuronal and astroglial monocarboxylate transporters play key but distinct roles in hippocampus-dependent learning and memory formation

“…In the central nervous system, lactate was long considered as a waste product and its accumulation a sign of tissue suffering. However, lactate is recognized now as a preferred substrate for neuronal oxidative metabolism (Bouzier-Sore et al 2006), and is also crucial for the metabolic coupling between neurons and astrocytes driven by glutamate neurotransmission (González-Gutiérrez et al, 2020;Pellerin & Magistretti, 1994). Furthermore, lactate emerged as a potential neuroprotective agent in pathologies such as neonatal hypoxic-ischemic encephalopathy (Roumes et al, 2020), adult stroke (Castillo et al 2015) or traumatic brain injury (Quintard et al, 2016).…”

Neuron‐glia (mis)interactions in brain energy metabolism during aging

“…Neurons are highly dependent on mitochondrial energy production, which has been proven using toxins and molecular approaches to inhibit mitochondrial function, resulting in neuronal loss and vulnerability (Cleeter et al., 1992; Gubellini et al., 2010; Martinez & Greenamyre, 2012; Sherer et al., 2003; Zolkipli‐Cunningham & Falk, 2017). This lactate‐based energy coupling between neurons and astrocytes was observed in neuron–astrocyte cocultures (Castro et al., 2007; Porras et al., 2004), in ex vivo experiments using acute slices of CA1 and striatal neurons (Acuna et al, 2013; Castro el al., 2007), and using in vivo approaches (Gonzalez‐Gutierrez et al., 2020; Machler et al., 2016; Schurr et al., 1999). Lactate‐based metabolic coupling of astrocytes and neurons is driven by glutamate recycling.…”