Why Some Mice Are Smarter Than Others: The Impact of Bone Morphogenetic Protein Signaling on Cognition.

Inbred mice (C57Bl/6) display wide variability in performance on hippocampal-dependent cognitive tasks. Examination of micro-dissected dentate gyrus (DG) after cognitive testing showed a highly significant negative correlation between levels of bone morphometric protein (BMP) signaling and recognition memory. Cognitive performance decline during the aging process, and the degree of cognitive decline is strongly correlated with aging-related increases in BMP signaling. Further, cognitive performance was impaired when the BMP inhibitor, noggin, was knocked down in the DG. Infusion of noggin into the lateral ventricles enhanced DG-dependent cognition while BMP4 infusion led to significant impairments. Embryonic overexpression of noggin resulted in lifelong enhancement of recognition and spatial memory while overexpression of BMP4 resulted in lifelong impairment, substantiating the importance of differences in BMP signaling in wildtype mice. These findings indicate that performance in DG-dependent cognitive tasks is largely determined by differences in levels BMP signaling in the dentate gyrus. Significance Statement Throughout life, the generation of new neurons in the brain, or neurogenesis, are known to be important for helping to maintain cognitive abilities. The current study describes a significant mechanism contributing to the changes in neurogenesis in aging and provides a specific molecular target for intervention for aging-related changes in cognitive function.