Although β-amyloid precursor protein (APP) has been suggested to play a role in neuronal survival and plasticity, the mRNA expression of APP has not been studied in terms of neuronal activity. In cultures of mouse cerebellar granule cells, we found that the levels of APP mRNA increased when a high concentration of potassium was present in the medium. A deprivation of membrane depolarization caused by lowering the K+ concentration decreased both mRNA expression and protein synthesis of APP. Increasing the concentration, however, restored mRNA expression, which was driven by the influx of Ca2+ through L-type voltage-dependent calcium channels and mediated by de novo protein synthesis. Thus, APP mRNA expression is controlled in an activity-dependent manner in neurons.