Calbindin regulates Kv4.1 trafficking and excitability in dentate granule cells via CaMKII-dependent phosphorylation

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. Neuroscience: an important buffer for memory-making Regulation of cytosolic calcium in neurons is crucial for normal brain functions. Neuronal signaling is governed in part by dynamiic changes in calcium concentrations, and calbindin acts as a 'buffer' that binds calcium ions to shape the spatiotemporal extent of changes in free calcium concentrations. Prior studies have noted reduced calbindin levels in certain neurological disorders, and researchers led by Won-Kyung Ho at Seoul National University, and Jong-Sun Kang at Sungkyunkwan University, South Korea, have uncovered a potential mechanism underlying these observations. Loss of calbindin in mouse models resulted in excessive firing by certain cells in a brain structure called the dentate gyrus. This structure is important to cognition, and the mice showed impaired performance in discriminating similar contexts, so-called pattern separation, highlighting the critical importance of calcium homeostasis in the brain.

Automated summary

Calbindin plays a crucial role in shaping calcium signals in neurons, with knockout mice showing hyperexcitability and impaired pattern separation due to downregulated K+ current. The reduction of calcium buffering capacity in Tg2576 mice suggests calbindin as a target of oxidative stress. Regulation of CaMKII signaling by calcium buffering is essential for neuronal excitability regulation.