MCG researchers find clues in process that enables working memory

March 01, 2000

New clues about how the neurotransmitter, dopamine, stimulates brain cells, enabling a person to literally complete a thought, have been identified by researchers at the Medical College of Georgia.

The process of working memory, controlled by the cerebral cortex in the front part of the brain - the part that most distinguishes man from lower vertebrates - is basic to human function, enabling people to converse, process information and plan, said Dr. Clare Bergson, molecular biologist and lead researcher on the study published in the March 3 issue of Science.

Dr. Nelson Lezcano, a postdoctoral fellow working with Dr. Bergson, is a co-investigator on the study along with Dr. Patricia Goldman-Rakic, professor in the Section of Neurobiology at Yale School of Medicine in New Haven, Conn.

Working memory tends to wane with age and can be a major trouble spot for people with schizophrenia and Parkinson's disease, interfering with their ability to work and even maintain personal relationships.

Researchers have identified a protein they named calcyon (for 'calcium on') that appears to regulate how dopamine receptors function in the cerebral cortex and other areas of the brain as well. "This protein may help us understand how dopamine modulates working memory," Dr. Bergson said.

They have found that calcyon directly interacts with dopamine D1 receptors and, in the presence of dopamine, the receptor activates two types of signals, known as second messengers. The researchers' next step is to clarify the role of these messengers in working memory.

Brain cells are constantly bombarded by multiple neurotransmitters, such as glutamate and serotonin, that make it possible for them to communicate and so function; a single cell may respond to several neurotransmitters.

Researchers found that calcyon works to integrate the signals from various neurotransmitters, called cross talk, and so modulate the cell's ultimate response to stimuli. Which receptor is stimulated first also plays a role in determining the cell's ultimate response.

"Calcyon is one of the first molecules discovered that explains how cells might integrate stimuli to come up with a different response. Before this, we had a less interactive view of how cells respond to multiple stimuli," Dr. Bergson said. "Now we have learned something very specific about how dopamine D1 receptors probably work in the brain."

By the same token, the protein may also be a target site for new drugs to treat schizophrenia as well as Parkinson's disease, in which inadequate dopamine levels cause uncontrolled movement. Current drug therapies target a different class of receptors, rather than dopamine D1 receptors.

Dr. Bergson already is looking for other proteins that participate in the communication process that ultimately leads to working memory.

She also is looking to see if mutations in the protein ­ which was identified by researchers in the primate brain ­ may help explain why schizophrenics typically lack normal working memory yet have normal dopamine D1 receptors. "Anything that regulates how the dopamine D1 receptor works could be a candidate for a gene that is defective in schizophrenia," Dr. Bergson said. She also is working on ways to block the newfound protein and see how that affects cells.

"We are developing viruses that we hope can get into the cells and knock out the interaction; we also are trying to do experiments in mice where we knock out the gene for calcyon in cells that make dopamine D1 receptors and see how that changes the dopamine D1 receptor function."

Medical College of Georgia at Augusta University

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