Calbindin, a major Ca²⁺ buffer in dentate granule cells (GCs), plays a critical role in shaping Ca²⁺ signals, yet how it regulates neuronal function remains largely unknown. Here, we found that calbindin knockout (CBKO) mice exhibited dentate GC hyperexcitability and impaired pattern separation, which co-occurred with reduced K⁺ current due to downregulated surface expression of Kv4.1. Relatedly, manipulation of calbindin expression in HT22 cells led to changes in CaMKII activation and the level of surface localization of Kv4.1 through phosphorylation at serine 555, confirming the mechanism underlying neuronal hyperexcitability in CBKO mice. We also discovered that Ca²⁺ buffering capacity was significantly reduced in the GCs of Tg2576 mice to the level of CBKO GCs, and this reduction was restored to normal levels by antioxidants, suggesting that calbindin is a target of oxidative stress. Our data suggest that the regulation of CaMKII signaling by Ca²⁺ buffering is crucial for neuronal excitability regulation.

钙结合蛋白是齿状颗粒细胞 (GC) 中的主要 Ca ²⁺缓冲剂，在形成 Ca ²⁺信号中发挥着关键作用，但它如何调节神经元功能仍然很大程度上未知。在这里，我们发现钙结合蛋白敲除 (CBKO) 小鼠表现出齿状 GC 过度兴奋和模式分离受损，同时由于 Kv4.1 表面表达下调而导致 K ⁺电流减少。相关地，操纵HT22细胞中的钙结合蛋白表达导致CaMKII激活的变化以及通过丝氨酸555磷酸化的Kv4.1表面定位水平的变化，证实了CBKO小鼠神经元过度兴奋的机制。我们还发现，Tg2576 小鼠GC 中的Ca ²⁺缓冲能力显着降低至CBKO GC 的水平，并且这种降低可通过抗氧化剂恢复到正常水平，表明钙结合蛋白是氧化应激的目标。我们的数据表明，Ca ²⁺缓冲对 CaMKII 信号传导的调节对于神经元兴奋性调节至关重要。