Currently, few molecular targets have been identified to treat age-related memory disorders such as mild cognitive impairment during normal aging, or Alzheimer's disease. We identified an isoform of the Homer1 gene,-Homer1c- that plays an important role in age-related learning. Our goal is to understand the molecular mechanisms of age-related learning and memory formation by studying the role of Homer1c in age-related cognitive decline. Our proposal builds upon earlier work using microarray analysis of the hippocampal CA1 region;we demonstrated that neuronal Homer1c is down-regulated in aged, learning-impaired rats versus superior learners of similar age. We validated microarray data by reversing learning deficits of aged impaired rats with Adeno-associated viral vectors (rAAV) targeting Homer1c to the dorsal hippocampus of these animals. We hypothesize that Homer1c improves memory by enhancing synaptic plasticity through interactions with metabotropic glutamate receptor 5. This interaction activates signaling cascades leading to translational activation important for hippocampal synaptic plasticity and long-term memory formation. We propose to determine mechanisms by which Homer1c regulates learning in the aging hippocampus. Three distinct experimental models will be studied: 1) normal aging, differentiating aged rats into impaired and superior learners to study differences between these groups;2) aged impaired rats over-expressing rAAV-Homer1c to reverse cognitive decline;and 3) environmental enrichment in aged rats to elicit environmentally enhanced cognition. Through studies of these distinct models (of greater or enhanced learning ability), we will identify common cellular and molecular mechanisms preserving or restoring cognitive function. From these studies we hope to define the role of Homer1c in cognitive aging towards finding therapeutic strategies based on gene replacement or pharmaceutical intervention for age-related memory loss.
As the human population becomes older the risk for developing age-related memory impairments such as Alzheimer's has increased. Understanding the role that putative learning and memory genes play in learning and aged-related neurodegeneration will help us understand the causes for memory loss. This project is significant because it will elucidate the role of Homer1c, a neuronal gene that is downregulated in aged individuals with cognitive impairment, and it will provide a characterization important to its future clinical role in the treatment of human mild cognitive impairment associated with aging, and Alzheimer's disease.