Brain Protein That Contributes to Learning and Memory in Mice

Contact: Jennifer BrownHealth Science RelationsUniversity of Iowa(319) 335-9917[email protected]

EMBARGOED UNTIL 12 P.M. (ET) APRIL 24, 2002

IOWA CITY, Iowa -- 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 and is highlighted on the journal's cover.

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 over 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 learned."

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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