ST3 beta-galactoside alpha-2,3-sialyltransferase 4 (St3gal4) deficiency reveals correlations among alkaline phosphatase activity, metabolic parameters, and fear-related behavior in mice

ST3 beta-galactoside alpha-2,3-sialyltransferase 4 (ST3GAL4) is a sialyltransferase involved in the biosynthesis of alpha2,3-sialic acid on glycoproteins and glycolipids. In mice, St3gal4 gene expression plays a crucial role in modulating epilepsy and anxiety/depression through its expression in thalamic neurons. Genome-wide association studies (GWAS) have identified several peripheral metabolic traits strongly associated with ST3GAL4 in humans. However, whether the symptoms observed in mice are associated with metabolic changes remains unclear. This study investigated the effects of St3gal4 deficiency on the same metabolic parameters in mice as those in humans. The parameters examined included body weight, plasma biochemistry, specifically alkaline phosphatase (ALP), protein, and cholesterol levels, and free amino acids profiles, resulting in elevated ALP and reduced tryptophan and total cholesterol (T-Cho) levels in St3gal4-knockout (KO) mice. Additionally, clearance of blood glucose was delayed in KO male mice. These findings suggest mouse St3gal4 deficiency correlated with modulated ALP, tryptophan, and T-Cho levels in the plasma. Next, brain ALP activity was compared between St3gal4-KO mice and wild-type (WT) mice, focusing on the thalamus. Fear conditioning tests assessed the relationship between behavior and ALP activity in plasma and brain. In KO mice, the enhanced tone freezing positively correlated with plasma ALP levels. Conversely, thalamic ALP activity was greatly reduced in KO mice, negatively correlating with plasma ALP. These findings suggest that mouse St3gal4 deficiency influences ALP activity in both thalamus and plasma, associating with emotional behaviors and metabolic changes.