Reducing l‐lactate release from hippocampal astrocytes by intracellular oxidation increases novelty induced activity in mice

Abstract

Astrocytes are in control of metabolic homeostasis in the brain and support and modulate neuronal function in various ways. Astrocyte‐derived l‐lactate (lactate) is thought to play a dual role as a metabolic and a signaling molecule in inter‐cellular communication. The biological significance of lactate release from astrocytes is poorly understood, largely because the tools to manipulate lactate levels in vivo are limited. We therefore developed new viral vectors for astrocyte‐specific expression of a mammalianized version of lactate oxidase (LOx) from Aerococcus viridans. LOx expression in astrocytes in vitro reduced their intracellular lactate levels as well as the release of lactate to the extracellular space. Selective expression of LOx in astrocytes of the dorsal hippocampus in mice resulted in increased locomotor activity in response to novel stimuli. Our findings suggest that a localized decreased intracellular lactate pool in hippocampal astrocytes could contribute to greater responsiveness to environmental novelty. We expect that use of this molecular tool to chronically limit astrocytic lactate release will significantly facilitate future studies into the roles and mechanisms of intercellular lactate communication in the brain.

l-Lactate: Food for Thoughts, Memory and Behavior

“…Mice expressing LOx exhibited improved performance in the Y-maze task, which tests spatial recognition memory, but not in the Y-maze spontaneous alternation task or the NOR test. They concluded that a selective decrease in intracellular lactate pool in hippocampal astrocytes contributes to increased responsiveness to novel stimuli [ 113 ].…”

Expression of Microbial Enzymes in Mammalian Astrocytes to Modulate Lactate Release

“…For experiments in HEK293, expression plasmids were transfected using TransIT-293 (Mirus, MIR 2700). To enable assessment of changes in intracellular lactate or pyruvate, AVVs for CMVdriven expression of the FRET-based reporters for lactate and pyruvate, Laconic and Pyronic, respectively, were used [5,18,19]. To enable assessment of changes in intracellular lactate or pyruvate, AVVs for CMVdriven expression of the FRET-based reporters for lactate and pyruvate, Laconic and Pyronic, respectively, were used [5,18,19].…”

“…Our aim was to decrease intra-astrocytic lactate pools that can be released to the extracellular space, constitutively or in response to local signals, and consequently to reduce lactate action. We recently reported that viral vector-mediated expression of bacterial lactate oxidase (LOx) in hippocampal astrocytes modulates behaviour in the context of environmental novelty in mice [5]. Here we expand the novel toolset by two further constructs, lactate 2-monooxygenase (LMO) and D-lactate dehydrogenase (DLDH) and compare the properties between these and LOx when expressed in rodent astrocytes.…”

“…The glycolysis product L-lactate (lactate) in the brain has been receiving increasing attention as a growing number of studies suggest its roles in the modulation of neuronal circuit function as diverse as memory, decision making, response to environmental novelty, depression, central arousal, or autonomic regulation [1][2][3][4][5][6][7]. Likewise, where the mechanisms of lactate actions have been investigated, these, too, are diverse and are discussed in the context of meeting metabolic demands by intercellular energy substrate shuttling, or receptor-mediated signalling, or modulation of gene expression [4,[8][9][10][11].…”

“…Astrocytic lactate dehydrogenase (LDH) converts pyruvate from glycolytic activity to lactate. Lactate is irreversibly oxidised by transgenic LMO of microbial origin to acetate, or to pyruvate by LOx (as previously described in [5]). This decreases the intracellular lactate pool and limits lactate release from astrocytes.…”