Expression of Nischarin increases with postnatal hippocampal maturation and regulates cofilin phosphorylation

The hippocampus, critical for memory integration and synaptic plasticity, undergoes cytoskeletal reorganization during development and maturation, a process regulated by cofilin phosphorylation dynamics. Nischarin is a tumor-suppressive scaffold protein, yet its role in neurodevelopment remains unexplored. This study investigated the spatiotemporal expression of Nischarin and its effect on cofilin during postnatal hippocampal maturation in rats. Using western blot, quantitative reverse transcription-polymerase chain reaction, and shRNA-mediated knockdown in adult rat hippocampal neurons and Neuro-2a cells, we demonstrated that Nischarin expression progressively increased from postnatal day 7 to P28, inversely correlating with declining phosphorylated cofilin levels. Mechanistically, Nischarin reduced phosphorylated cofilin levels by suppressing PAK1/LIMK1 activity. Immunofluorescence revealed that Nischarin knockdown disrupted the subcellular distribution of phosphorylated cofilin by impeding its translocation from the cytoplasm to the nucleus. These findings indicate Nischarin regulates cofilin activity via dual mechanisms: inhibiting phosphorylation through the PAK1/LIMK1 pathway and modulating phosphorylated cofilin nuclear translocation. The study highlights the role of Nischarin in hippocampal neuronal maturation by orchestrating cytoskeletal remodeling and suggests its therapeutic potential in neurodegenerative diseases linked to cofilin dysregulation.