Pharmacological activation of SERCA2 reverses ER calcium dysregulation and depression-like behaviors in hyperglycemic mice

Chronic hyperglycemia is linked to neuronal dysfunction and mood disorders, but the underlying molecular mechanisms remain unclear. In the present study, we examined the role of sarco/endoplasmic reticulum Ca²⁺-ATPase 2 (SERCA2) in depression-like behaviors induced by hyperglycemia, using in vivo and in vitro models. Streptozotocin (STZ)-induced hyperglycemic mice exhibited elevated glucose levels and depression-like behaviors, along with increased hippocampal endoplasmic reticulum (ER) stress markers such as C/EBP homologous protein (CHOP), neuronal loss, and reduced SERCA2 expression. Human SH-SY5Y neuroblastoma cells exposed to high-glucose (40 mM) similarly showed decreased SERCA2, elevated ER stress markers, and impaired ER calcium homeostasis. Pharmacological activation of SERCA2 by CDN1163 suppressed ER stress and reversed depression-like behaviors in STZ mice; it also restored ER calcium levels in SH-SY5Y cells. Intrahippocampal infusion of SERCA2 inhibitor thapsigargin induced ER stress and depression-like behaviors without changing SERCA2 expression, indicating that SERCA2 dysfunction alone can trigger pathology. Treatment with the ER stress inhibitor tauroursodeoxycholic acid (TUDCA) alleviated both molecular and behavioral alterations in hyperglycemic mice, supporting ER stress as a downstream effect of calcium dysregulation. These findings implicate hippocampal SERCA2 dysfunction as a central mechanism linking hyperglycemia to depression-like behaviors, highlighting SERCA2 as a potential therapeutic target.