Astrocyte MCT1 Expression Does Not Contribute to the Axonal Degenerative Phenotype Observed With Ubiquitous MCT1 Depletion.

We recently reported that the loss of oligodendrocyte metabolic support through the lactate and pyruvate transporter Monocarboxylate Transporter 1 (MCT1) is well tolerated into adulthood. Only with advanced aging did we observe axonal degeneration and hypomyelination due to the loss of MCT1 from oligodendroglia lineage cells. MCT1 is also expressed by other glial subtypes, such as astrocytes and endothelial cells where it has been suggested to be essential for learning and memory tasks. However, the importance of MCT1 in these cell types for long-term axonal metabolic support is still unknown. We therefore addressed whether the conditional loss of MCT1 from either of these cell types would lead to widespread axonal degeneration with aging. Using a conditional null approach, similar to what was used for oligodendrocyte MCT1 depletion, we observed that the conditional knockout of MCT1 from either astrocytes or endothelial cells did not cause neuronal injury. On the other hand, inducible ubiquitous depletion of MCT1 causes late-onset axonal degeneration, comparable with what was observed in our previous study using the oligodendrocyte lineage MCT1 null mice. Notably, the loss of astrocytic MCT1 does not cause late-onset neurodegeneration. Ubiquitous MCT1 deletion, however, causes axonal degeneration, suggesting that oligodendrocytes and potentially other cells are more prominent drivers of MCT1-mediated metabolic support of neurons. In summary, we conclude that unlike oligodendrocyte MCT1, astrocyte MCT1 is not an essential driver of astrocyte-mediated axonal energy homeostasis with aging.