INTRODUCTION: Presenilin (PS) gene mutations cause memory impairment in early-onset familial Alzheimer's disease (FAD), but the underlying mechanisms remain unclear. METHODS: We examined the effects of the PS1 M146V FAD mutation on motor learning, motor learning-related changes in neuronal Ca(2+)activity and CREB phosphorylation in the primary motor cortex. RESULTS: We found that PS1 M146V knock-in mice displayed long-term deficiencies in motor skill learning. Ca(2+) levels are altered in a cortical layer and neuron type-specific manner in PS1 mutant mice as compared to WT control mice. Notably, while running caused a significant increase of CREB phosphorylation in WT mice, it led to a significant decrease of CREB phosphorylation in layer 5 neurons of mutant mice. DISCUSSION: These findings suggest that alterations of Ca(2+) activity and CREB phosphorylation in deep cortical layers are early events leading to memory impairment in the PS1 mutation-related familial form of AD.