Abnormal calcium activity and CREB phosphorylation are associated with motor memory impairment in presenilin-1 mutant knock-in mice.

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 Caactivity 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 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 activity and CREB phosphorylation in deep cortical layers are early events leading to memory impairment in the PS1 mutation-related familial form of AD.