CONTACT: JENNIFER BROWN
Iowa City IA 52242
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Release: April 24, 2002
UI study identifies brain protein that contributes to learning and memory
Research by University of Iowa scientists is shedding new light on the molecular
basis of learning and memory. In addition to improving understanding of these
vital brain functions, the findings also may point the way to medications
for treating memory disorders or even suggest pharmacological targets to reduce
brain damage caused by stroke and seizures. The UI study is reported in the
April 25 issue of the journal Neuron.
Using a genetically engineered mouse, the UI team has shown that an acid-activated
protein found in brain cells is responsible for acid-generated currents in
the brain, and that these currents play a role in processes responsible for
learning and memory. Mice that lack the protein known as acid sensing ion
channel (ASIC) have a variety of learning impairments, including difficulty
with spatial learning, such as remembering where something is located.
Scientists have known for more than 20 years that brain cells (neurons)
exposed to acid become excited and generate an electrical current. Although
these observations indicated that some type of channel protein was probably
responsible for the current, the molecular identity of the channel remained
a mystery. Without knowing the identity of the channel, researchers have not
been able to investigate why the currents might be important for brain function.
In recent years, a small number of channel proteins, including ASIC, have
been shown to be activated by acid. The UI team reasoned that one or several
of these newly identified genes might be the mystery acid-gated channel protein.
"Our studies show that ASIC is one molecule that is responsible for
acid-activated currents in neurons," said John Wemmie, M.D., Ph.D., UI
assistant professor of psychiatry and lead author of the study. "This
also is the first time anyone has shown that this channel could be involved
in learning. These results extend our understanding of the molecules that
make learning possible."
The researchers found that mice without the ASIC protein had no acid-gated
currents in their neurons. Despite this complete loss of channel function,
the mice looked normal.
"In many ways these animals behave and appear normal, so we were hard-pressed
to figure out what these channels do," said Wemmie, who also is a staff
physician at the Veterans Affairs Medical Center in Iowa City. "It was
not until we started to look at learning and memory and also at synaptic function
in brain samples that we noted a significant problem in the way these animals
The researchers found that the ASIC protein is expressed in the hippocampus,
an area of the brain involved in learning and memory. In particular, the protein
is located at the synapses, where communication between brain cells occurs.
Chemicals called neurotransmitters carry signals across the synaptic cleft
between neighboring brain cells. Heavy usage of a synapse by repeated communication
between its two neurons strengthens the connection, and strengthening of synapses
is one process thought to underlie learning and memory.
"The way that synapses change over time and become stronger through
frequent use is also known as long-term potentiation," Wemmie explained.
"This phenomenon is impaired in the mice that lack the ASIC protein."
The mice showed significant learning and memory deficits as compared to
normal mice. However, the researchers found that the spatial learning deficits
could be reversed with intensive training.
"The most exciting thing about our mice is that rather than a dramatic
effect, there is a subtle disruption of learning and memory function,"
Wemmie said. "The ASIC protein might offer a nice target for medications
to improve memory without grossly affecting brain function. Alternatively,
blocking its action could suppress memory. Damping down memory might be useful
for treating certain psychiatric illnesses such as post-traumatic stress disorder."
In addition to its role in memory and learning, ASIC also may be involved
in brain damage caused by strokes and seizures. During stroke and seizure,
acid levels in brain tissue increase for a short period of time. This increased
acidity has been implicated in brain damage associated with these diseases.
The acid levels also may activate ASIC channels.
Although the researchers have not yet tested the hypothesis, Wemmie speculated
that activation of ASIC by acid produced during a stroke or seizure might
contribute to brain damage associated with those diseases.
Wemmie added that he and his colleagues plan to investigate this theory
and to continue their studies to determine the precise role of the ASIC channel
in brain function.
In addition to Wemmie, the UI researchers involved in the study included
Michael Welsh, M.D., the Roy J. Carver Chair in Physiology and Biophysics,
professor of internal medicine and physiology and biophysics, and a Howard
Hughes Medical Institute (HHMI) investigator; Jianguo Chen, Ph.D., postdoctoral
associate in physiology and biophysics, and pharmacology; Candice Askwith,
Ph.D., and Alesia Hruska-Hageman, Ph.D., both postdoctoral associates in internal
medicine and HHMI associates; Margaret Price, Ph.D., assistant research scientist
in internal medicine; Brian Nolan, graduate student in psychology; Patrick
Yoder, pharmacy student; Ejvis Lamani, research assistant in psychiatry; and
John Freeman, Ph.D., assistant professor of psychology. Toshinori Hoshi, Ph.D.,
a former UI faculty member now in the department of physiology at the University
of Pennsylvania also was part of the research team.
The study was funded by the Howard Hughes Medical Institute, the Veterans
Administration and the National Institutes of Health.
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the UI Roy J. and Lucille A. Carver College of Medicine and UI Hospitals and
Clinics and the patient care, medical education and research programs and
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