Abstract

Sialin, a sialic acid transporter encoded by the Slc17a5 gene, plays a critical role in lysosomal function, with complete loss resulting in severe sialic acid storage diseases with profound neurological impairment. However, the consequences of SLC17A5 haploinsufficiency on adult brain function remain largely unknown. Here, we systematically investigated the impact of heterozygous Slc17a5 deletion in adult mice. We found that Slc17a5 +/− mice exhibited a specific working memory deficit, as revealed by the Y-maze test. Hippocampal transcriptomic profiling uncovered widespread dysregulation, with significant enrichment in extracellular matrix (ECM) organization and microtubule-based processes. Protein–protein interaction network analysis identified key hub genes within these dysregulated pathways. Furthermore, we confirmed a significant reduction in the presynaptic protein Synaptophysin, indicating structural compromise at synapses. Our study demonstrates that SLC17A5 haploinsufficiency is sufficient to cause selective cognitive impairment in adult mice, driven by discrete molecular disruptions involving ECM remodeling, intracellular transport deficits, and synaptic damage. These findings provide novel mechanistic insights into the role of Slc17a5 in maintaining brain function and establish a foundation for understanding related neurological disorders