New Scholar Award in Aging
David G. Wells, Ph.D.
Yale University School of Medicine

Synaptic Plasticity in the Aging Brain: Role of CPE-dependent Protein Synthesis.

The formation and maintenance of memories is one of the brain's most intriguing functions. The human brain has the remarkable ability to store and retrieve past experiences for years and in some instances decades. Changes in memory occur with age and there is increasing evidence that there is a considerable difference between the nature of memory changes in aging and that in disease states like Alzheimer's disease. As individuals age they are not more rapidly forgetting what they learned, but rather they are taking longer to learn new information. This has been especially evident in explicit episodic memory, the recall of information pertaining to people or places. Episodic memory formation is processed through a region of the brain called the hippocampus, and is thought to require the formation of new synaptic connections in the brain. Of late, extensive effort has been put into reducing the process of learning and memory to the cellular and molecular level.

Both memory and the ability of neurons to stably modify synaptic connections are dependent upon new protein synthesis. We have recently described a mechanism by which neuronal mRNA translation can be regulated in an experience-dependent manner by the process of cytoplasmic polyadenylation. This mechanism is regulated by the interaction of an mRNA binding protein (CPEB) to a specific cis-element (CPE) located in the 3'-untranslated region of some mRNA. Importantly, CPE-mediated protein synthesis is likely to occur in neuronal dendrites. Protein synthesis in dendrites is thought to play a critical role in the neuronal changes associated with memory formation. Our lab is examining this CPE-mediated process to address several fundamental questions regarding the molecular changes associated with synaptic plasticity, memory formation and age-related loss of memory. Among these questions are: Where in the brain is CPEB located and does the statement change as a function of age? In two regions of the brain responsible for learning, the hippocampus and the cerebellum, can CPE-mediated translation regulate proteins implicated in synaptic growth? Does the ability to regulate translation of these proteins change with age? In answering these questions we hope to describe a molecular mechanism for the synthesis of new proteins that will contribute to the formation new synaptic connections.

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