Lactate plays a significant role as an energy supply for neurons and has a neuroprotective effect in hypoglycemia and ischemia (1±5). Further, oligodendrocytes can use lactate for myelination when glucose levels are low. New studies suggest that lactate is not only a metabolic fuel but also a signaling molecule via the lactate receptor hydroxycarboxylic acid receptor 1 (HCAR1), which was recently demonstrated in the brain (6). Lactate is released from cells when glycolytic activity exceeds mitochondrial respiration and can occur in hypoxic as well as normoxic conditions (aerobic glycolysis) (7,8). Lactate-producing aerobic glycolysis takes place in the developing brain (9,10), suggesting that lactate signaling could play a role in glial development and neurogenesis (11). Here we have used HCAR1 KO mice, organotypic brain slice cultures, and immunohistochemistry to examine the role of HCAR1 in the development and survival of neurons and oligodendrocytes in normal conditions and hypoglycemia. We show that young HCAR1 KO mice have a reduced number of neural progenitor cells in the hippocampus and the cerebral cortex, and the average size of cortical axons is smaller in KO compared with WT mice. In organotypic brain slices, hypoglycemia led to a loss of axons, which could be partly rescued by the HCAR1 agonist 3,5-DHBA in WT, but not in HCAR1 KO mice. As previously reported, myelinating oligodendrocytes were more severely affected by hypoglycemia than axons (12). The myelination was not rescued by 3,5-DHBA. However, application of lactate to our cultures completely restored myelination in WT, but only partly in HCAR1 KO mice. Our findings reveal previously unknown receptor-mediated actions of lactate in brain development and neuroprotection and suggest HCAR1 as a new therapeutic target