New Scholar Award in Aging
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.