Homer-1a immediate early gene expression correlates with better cognitive performance in aging.

The molecular mechanisms underlying cognitive decline during healthy aging remain largely unknown. Utilizing aged wild-type C57BL/6 mice as a model for normal aging, we tested the hypothesis that cognitive performance, memory, and learning as assessed in established behavioral testing paradigms are correlated with the differential expression of isoforms of the Homer family of synaptic scaffolding proteins. Here we describe a loss of cognitive and motor function that occurs when Homer-1a/Vesl-1S protein levels drop during aging. Our data describe a novel mechanism of age-related synaptic changes contributing to loss of biological function, spatial learning, and memory formation as well as motor coordination, with the dominant negative uncoupler of synaptic protein clustering, Homer-1a/Vesl-1S, as a potential target for the prophylaxis and treatment of age-related cognitive decline.