Scientists Identify Protein Believed to Control Formation
of Memory
By Jason Socrates
Bardi
Scientists at The Scripps Research Institute and the University
of California, San Diego (UCSD) School of Medicine have demonstrated
that the action of a protein called CBP is essential for the
stabilization of long-term memory, a discovery that may help
children with a rare but debilitating developmental disorder.
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, 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.
Protein Memories
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.neuron.org.
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.
Send comments to: jasonb@scripps.edu
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