They found that when the functions of normal CBP is suppressed in adult rodents, the animals had trouble forming long-term memories, suggesting that CBP is required for the formation of long-term memory and that defects in CBP are involved in cognitive dysfunction.
Furthermore, the scientists found that they were able to correct this defect by administering a drug that restored CBP's function.
"This is significant," says Mark Mayford, Ph.D., an associate professor of cell biology and a member of the Institute for Childhood and Neglected Diseases at Scripps Research. Before moving to Scripps Research four years ago, Mayford was a faculty member at UCSD, where together with another UCSD scientist Edward Korzus, Ph.D., they initiated the research.
"There is a link between this molecule and very severe problems in humans," Mayford added, noting that the findings may be significant for children with the rare but severe developmental disorder known as Rubinstein-Taybi syndrome, which causes growth and mental retardation and several anatomical abnormalities. These children have mutations in their CBP genes.
Scientists have long known that when laboratory animals are treated with a class of drugs known as protein synthesis inhibitors, which stops the production of proteins in the animals' brains, these animals lose their long-term memory. This observation has led scientists to predict that the formation of long-term memory requires new protein synthesis.
This prediction has since been borne out in experiments repeated in many different species -- from mice to fruit flies.
After this fact was established, a number of scientists around the country began looking for the specific genes and proteins that could stabilize long-term memory.
One such signal had already been discovered by other scientists when they began their work -- the protein CREB. CREB is what is known as a transcription factor, a protein that interacts with the DNA of a gene and controls the early steps in "turning on" the expression of a new protein. Mutations in CREB prevent the activation of certain genes, and animals with defective forms of CREB have problems forming long-term memories.
But, scientists asked, was CREB the only protein that controls memory formation?
A few years ago, Korzus and Mayford were working at the UCSD School of Medicine, where in a collaboration with Michael G. Rosenfeld, M.D., who is a Howard Hughes Medical Institute Investigator and Professor of Medicine at UCSD, they began looking for other signals in neurons that affected the formation of long-term memory. Korzus and Mayford continued their work at Scripps Research, focusing on a mutation in rodents that affected a protein associated with CREB called CREB binding protein (CBP). CBP is what is known as a coactivator of transcription -- it works with CREB to control the expression of genes.
CBP is sort of like a molecular haberdasher. It grooms proteins involved in gene expression by fitting them with chemicals that turn them on or off. Specifically, CBP attaches acetyl groups to other proteins, and these acetyl accoutrements modulate their behavior in the cell.
One of the proteins in neurons that CBP acetylates are histones. Histones are short cylindrical proteins that associate with DNA in the nuclei of cells.
Histones are the fashion mavens of the molecular world. They must be wearing something! Normally, they have an affinity for wrapping themselves with DNA, and so DNA wraps around them in the cell, forming a compact bundle of DNA and protein called chromatin. This allows the DNA in a cell to maintain a compact form. Seen under a microscope, the DNA and histones appear as distinct bundles known as chromosomes.
But when a gene is going to be expressed, such as during the formation of long-term memory, the chromatin must be opened up and the DNA unwound from the histones. CBP plays a critical role in this process because it acetylates amino acids known as lysine on the histones, and this makes the histones lose their affinity for the DNA and facilitates the expression of genes on that DNA.
Losing and Regaining Memory Ability
Korzus and Mayford performed an experiment in which they could turn on a defective form of CBP in adult rodents. They found that the defective CBP cannot acetylate the histones, and this prevents the DNA wound around the histones from releasing. This, in turn, prevents protein synthesis, and that prevents the formation of long-term memory.
Significantly, Korzus and Mayford were able to correct the long-term memory defect in the animals by administering a leukemia drug called histone deacetylase inhibitor Trichostatin A, which put the acetyl group back on the histones.
Their results suggest that remodeling of chromatin is important in learning and memory. It also provides a new mechanism for influencing cognitive function. And it suggests a possible treatment for the mental retardation associated with Rubinstein-Taybi syndrome.
The article, "CBP histone acetyltransferase activity is critical component of memory consolidation" by Edward Korzus, Michael G. Rosenfeld, and Mark Mayford appears in the June 24, 2004 issue of the journal Neuron. See http://www.
This work was supported by the National Institutes of Health, the National Institute of Mental Health, the Howard Hughes Medical Institute, and the Institute for Childhood and Neglected Diseases at Scripps Research.
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