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

This is the author accepted manuscript. The final version is available from Wiley via the DOI in this record DATA AVAILABILITY STATEMENT: Data available on request from the authors.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.British Heart FoundationBritish Heart FoundationConselho Nacional de Desenvolvimento Científico e TecnológicoNational Institute of HealthNational Institute of HealthNational Institute of HealthNorthcott Devon Medical Trust FoundationNational Institute of Neurological Disorders and Strok