Aging and memory are altered by genetically manipulating lactate dehydrogenase in the neurons or glia of flies

The astrocyte-neuron lactate shuttle hypothesis posits that glial-generated lactate is transported to neurons to fuel metabolic processes required for long-term memory. Although studies in vertebrates have revealed that lactate shuttling is important for cognitive function, it is uncertain if this form of metabolic coupling is conserved in invertebrates or is influenced by age. Lactate dehydrogenase (Ldh) is a rate limiting enzyme that interconverts lactate and pyruvate. Here we genetically manipulated expression of Drosophila melanogaster lactate dehydrogenase (dLdh) in neurons or glia to assess the impact of altered lactate metabolism on invertebrate aging and long-term courtship memory at different ages. We also assessed survival, negative geotaxis, brain neutral lipids (the core component of lipid droplets) and brain metabolites. Both upregulation and downregulation of dLdh in neurons resulted in decreased survival and memory impairment with age. Glial downregulation of dLdh expression caused age-related memory impairment without altering survival, while upregulated glial dLdh expression lowered survival without disrupting memory. Both neuronal and glial dLdh upregulation increased neutral lipid accumulation. We provide evidence that altered lactate metabolism with age affects the tricarboxylic acid (TCA) cycle, 2-hydroxyglutarate (2HG), and neutral lipid accumulation. Collectively, our findings indicate that the direct alteration of lactate metabolism in either glia or neurons affects memory and survival but only in an age-dependent manner. Author SummaryThe brain is composed of metabolically demanding cell types that must remain functional throughout life to maintain cognitive tasks like memory formation. How brain metabolism varies between cell-types across the lifespan is uncertain. It has been suggested that in vertebrate brains glia breakdown sugars to produce lactate and shuttle it to neurons to support long-term memory and survival. Yet, this phenomenon has not been directly tested in invertebrates. In Drosophila melanogaster flies, we genetically manipulated lactate dehydrogenase, a central enzyme in lactate metabolism, specifically within the adult brain. We discovered that shifting lactate metabolism to either higher or lower levels in neurons caused decreased survival and worse long-term memory with age. In contrast, we found increased glial lactate metabolism worsened survival, whereas decreased glial lactate metabolism impaired long-term memory in aged flies. Both increased glial or neuronal lactate metabolism led to increased accumulation of metabolites, such as 2-hydroxyglutarate, mitochondrial metabolites, and neutral lipids, in aged fly brains. These findings provide evidence for the first time in invertebrates that lactate and memory are connected and altered lactate metabolism in neurons and glia differentially impact survival and memory, but only in an age-dependent manner. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=83 SRC="FIGDIR/small/512981v1_ufig1.gif" ALT="Figure 1"> View larger version (17K): org.highwire.dtl.DTLVardef@6b34d7org.highwire.dtl.DTLVardef@5a159forg.highwire.dtl.DTLVardef@41a3f6org.highwire.dtl.DTLVardef@17377ea_HPS_FORMAT_FIGEXP M_FIG C_FIG