Genetic disruption of the core circadian clock impairs hippocampus-dependent memory

Abstract

Perturbing the circadian system by electrolytically lesioning the suprachiasmatic nucleus (SCN) or varying the environmental light:dark schedule impairs memory, suggesting that memory depends on the circadian system. We used a genetic approach to evaluate the role of the molecular clock in memory. Bmal1 ^−/− mice, which are arrhythmic under constant conditions, were examined for hippocampus-dependent memory, LTP at the Schaffer-collateral synapse, and signal transduction activity in the hippocampus. Bmal1 ^−/− mice exhibit impaired contextual fear and spatial memory. Furthermore, LTP in hippocampal slices from Bmal1 ^−/− mice is also significantly decreased relative to that from wild-type mice. Activation of Erk _1,2 MAP kinase (MAPK) during training for contextual fear memory and diurnal oscillation of MAPK activity and cAMP in the hippocampus is also lost in Bmal1 ^−/− mice, suggesting that the memory defects are due to reduction of the memory consolidation pathway in the hippocampus. We conclude that critical signaling events in the hippocampus required for memory depend on BMAL1.