Originally created 03/03/00

Doctors spot key protein in memory



Researchers at Medical College of Georgia have isolated a protein that may hold the key to how some brain cells process dopamine, an essential neurotransmitter. The findings have implications in "working memory," the ability to store and process immediate information, and for disorders like schizophrenia.

The findings, published today in the journal Science, may lead to new targets for drugs to help patients, said lead author Clare Bergson, a molecular biologist at MCG.

The protein-producing gene, dubbed calcyon, was isolated from millions of genes known to be active in the human brain after researchers noted its interaction with a dopamine receptor called D1. Receptors lie on the cell surface and can bind with specific molecules that then cause a secondary reaction inside the cell.

Studying the interaction under a calcium imaging microscope, the researchers saw calcium flashes within the cells, which signaled activity, Dr. Bergson said. Brain cells can be signaled by many neurotransmitters and in this case the MCG researchers found there was a "cross talk" effect, Dr. Bergson said.

If both a receptor for the neurotransmitter glutamate and the dopamine receptor were activated on the target cell, along with the calcyon, it created the calcium reaction inside the cell that would then activate other cell responses. When the calcyon protein was not present, the dopamine did not create that reaction, Dr. Bergson said.

The next step will be to genetically screen schizophrenics to see if there is a defect in the calcyon gene, Dr. Bergson said. The researchers would also like to create mice where the calcyon gene is "knocked out" in the cells with D1 receptors to see if there is an effect on learning, Dr. Bergson said.

Colleagues at Yale University showed the D1 receptor is involved in cells in the prefrontal cortex of the brain, an area known to be involved in working memory, Dr. Bergson said.

In addition to the more commonly known delusions and hallucinations that can plague schizophrenics, those patients "are known to have difficulties in the control of working memory," said Dr. Jeffrey Rausch, professor and vice chairman of the Department of Psychiatry and Health Behavior. Tests may involve asking them to distinguish between images on cards, and then switching around what they are supposed to identify to see if they can follow the instructions, Dr. Rausch said.

"It's where you have to hold one thing in mind and then do some processing on it," Dr. Rausch said, more of "an executive function."

In tests with primates who watch a brief image on a television screen and then are asked to pinpoint where the image had been, the cells in that area of the brain are firing between the time the image disappears and the primate is asked to perform the task, Dr. Bergson said.

"The cells are actively firing when they seem to be storing some information they will use again," Dr. Bergson said.

Yet testing shows no genetic damage to the D1 receptors in that area of the brain in schizophrenics, Dr. Bergson said.

"So a protein that regulates how the D1 receptor functions could be considered a candidate gene for the disorder," Dr. Bergson said. "One thing that calcyon now gives us is a new route for drug development that would be specific to treating these cognitive developments schizophrenics have."

There are some drugs for schizophrenics with working memory problems that target a receptor for a different neurotransmitter, serotonin, Dr. Rausch said.

"At present we do not have available approved treatments that target the D1 receptor," Dr. Rausch said. "The discovery that these D1 receptors are linked to working memory, and are reduced in schizophrenia and can be modulated by a newly discovered protein may be important for the illness, although we don't know yet."

Reach Tom Corwin at (706) 823-3213.