Researchers at Johns Hopkins have figured out how one
particular protein contributes to long-term memory and
helps the brain remember things longer than an hour or two.
The findings are reported in two papers in the Nov. 9 issue
of Neuron.
The protein, called Arc, has been implicated in
memory-linked behaviors ranging from song learning in birds
to rodents being aware of 3-D space. In people, Arc may be
one culprit behind certain long-term memory-based behaviors
like drug addiction, the researchers say.
"We think Arc controls how brain cells learn and
associate behaviors and remember them over a long period of
time," said Paul F. Worley, professor of
neuroscience and
neurology in the School of Medicine and director of
both studies. "For example, the person who quits smoking
can wean himself from cravings at home, at work or outside.
But if you put him in a bar with a drink in his hand, his
brain remembers that former association and suddenly the
craving returns. These types of long-term associations are
memories wired in your brain."
Years ago, Worley and his colleagues, studying
laboratory rats, found that the rats' brains made lots of
Arc protein while the animals were awake and active. In
fact, it has been long known that stimulating individual
nerve cells — by an act as simple as exploring new
environs, for example — causes the cells to make more
Arc protein almost immediately. "Arc is an instant and
reliable readout for active cells in the brain," Worley
said. But although scientists knew that active cells were
making copious amounts of Arc, no one knew exactly what Arc
was doing in those cells until now.
To figure out what Arc was doing, the Johns Hopkins
team looked for other proteins with which Arc "plays."
Using Arc protein as bait, they went on a molecular fishing
expedition in a pond filled with other proteins normally
found in the brain and hooked two known to be involved in
transporting materials into and out of cells.
"Moving things in and out of cells is critical for
normal brain cell function. We were extremely excited that
Arc might somehow be involved in this transport because it
links transport to memory formation," Worley said. "This
brings us one step closer to understanding how the brain
saves memories."
According to Worley, memories form when nerve cells
connect and "talk" to other nerve cells. It's thought that
the stronger these connections are, the stronger the
memory.
Like the childhood game called telephone, in which one
person taps her neighbor and whispers a message that is
passed on in similar fashion to the next person in line,
nerve cells connect and "talk" to each other by relaying
messages — usually by passing small chemicals —
from cell to cell.
When nerve cells connect with each other in the brain,
one cell releases chemicals into the space between it and
its neighbor. The neighboring cell has protein receptors on
its surface that capture the released chemicals. The cell
that captures these chemicals then swallows up the receptor
chemical complexes, removing the receptors from the cell's
surface. The more receptors present, the stronger the
connection between the two cells. New receptors constantly
replace the swallowed-up ones.
The two proteins that came out of the Arc fishing
expedition — known as dynamin and endophilin —
previously were known to be critical for this swallowing
action. And, it turns out that Arc controls these two
proteins and therefore controls how often cells swallow
receptors from their surfaces.
When the researchers altered Arc so that it was unable
to bind these two proteins, cells were unable to "swallow"
and wound up with more receptors than normal on their
surfaces. Adding more Arc to cells caused the opposite to
happen; the cells hyperactively swallowed up too many
receptors, leaving few at the surface.
Unfortunately, it's possible to overexcite a cell to
death, Worley says, and if the excitation controls come
off, the strength of long-term memory is altered.
So what does Arc's control over brain cell receptors
mean for our ability to remember where we put the car keys?
"We know that animals lacking Arc live only in the here and
now. They learn fine in the short term, but tomorrow they
will need to relearn everything," Worley said. And in the
case of long-term memories that are better forgotten, such
as that cigarette craving that occurs while sitting in a
bar, a better understanding of how these memories form
promises hope that there might be a way in the future to
forget them entirely.
Researchers were supported by grants from the National
Institute of Mental Health, the National Institute of
Deafness and Other Communication Disorders, the Howard
Hughes Medical Institute and the Human Frontier Science
Program Organization.
Authors of the two papers are Shoaib Chowdhury, Jason
Shepherd, Gavin Rumbaugh, Hiroyuki Okuno, Gregory Lyford,
Jing Wu, Richard Huganir and Worley, all of Johns Hopkins;
Ronald Petralia, of the National Institute on Deafness and
Other Communication Disorders at the National Institutes of
Health; and Niels Plath and Dietmar Kuhl, of Freie
Universitat Berlin in Germany.
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