SA supplementation during lactation promotes learning and memory by reducing H3K27me3 levels.

INTRODUCTION: Sialic acid (SA) is an essential nutrient for brain development and cognition. Infants lack the capacity to synthesize sufficient SA independently, requiring reliance on maternal or exogenous sources. For early nutritional supplementation, elucidating how SA affects learning and memory is necessary. OBJECTIVES: This study aimed to elucidate the critical time window for SA supplementation that best supports cognitive functions and hippocampal neural mechanisms. METHODS: The MWM experiment was conducted to elucidate the critical time window and dose of SA supplementation. Morphological and electrophysiological studies were used to observe the structural and functional responses of hippocampal neurons that are exposed to SA. RNA sequencing, Western Blot, immunofluorescence, and electrophysiology were used to screen and validate possible neural mechanisms. RESULTS: Our results show that SA supplementation during, but not after, the lactation period significantly improves learning and memory. SA promotes neurite outgrowth and increases synaptic transmission without affecting the intrinsic membrane properties of hippocampal CA1 neurons. The effect of SA on CA1 neuronal function is independent of the DG-CA3-CA1 loop. Also, long-term effects on synaptic plasticity are primarily due to intracellular epigenetic changes of H3K27me3 rather than direct binding of extracellular SA to membrane proteins. Consequently, our study indicates that decreased H3K27me3 promotes the glutamate-glutamine cycle under SA, thereby contributing to enhanced learning and memory. CONCLUSION: Consequently, our study finds that decreased H3K27me3 promotes the glutamate-glutamine cycle under the influence of SA, thereby contributing to enhanced learning and memory. The potential implication of our findings is that SA in early life may contribute to the optimization of children's comprehensive cognitive function.