Neuronal and astroglial monocarboxylate transporters play key but distinct roles in hippocampus-dependent learning and memory formation

Brain lactate formation, intercellular exchange and utilization has been implicated in memory formation. However, the individual role of either neuronal or astroglial monocarboxylate transporters for the acquisition and consolidation of information remains incomplete. Using novel transgenic mice and a viral vector approach to decrease the expression of each transporter in a cell-specific manner within the dorsal hippocampus, we show that both neuronal MCT2 and astroglial MCT4 are required for spatial information acquisition and retention (at 24 h post-training) in distinct hippocampus-dependent tasks. Intracerebral infusion of lactate rescued spatial learning in mice with reduced levels of astroglial MCT4 but not of neuronal MCT2, suggesting that lactate transfer from astrocytes and utilization in neurons contribute to hippocampal-dependent learning. In contrast, only neuronal MCT2 was shown to be required for long-term (7 days post training) memory formation. Interestingly, reduced MCT2 expression levels in mature neurons result in a heterologous effect as it blunts hippocampal neurogenesis associated with memory consolidation. These results suggest important but distinct contributions of both neuronal MCT2 and astroglial MCT4 in learning and memory processes, going beyond a simple passive role as alternative energy substrate suppliers or in waste product disposal.