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Researchers report in the October issue of Neuron that they have uncovered a new and unexpected control system for a key receptor of nerve cell signals. This central nervous system receptor mediates intelligence and brain adaptability.
This is one of the first studies to explore receptor control through a mechanism not tied to gene expression. It may lead to "interventions that amplify or maintain this receptor's response," said author Martha Constantine-Paton, professor of biology and brain and cognitive sciences. "This may prove useful in the clinical treatment of a variety of neurological dysfunctions and also help us understand how brain activity controls the plasticity of the developing brain."
Professor Constantine-Paton, who studies the development of brain circuitry in the central nervous system, says the research, conducted with colleagues at Yale and MIT, points to a common enzyme called calcineurin as a potential means for controlling the N methyl D aspartate (NMDA) receptor in the brain.
DR. JEKYLL AND MR. HYDE
The NMDA receptor is the Dr. Jekyll/Mr. Hyde of the central nervous system. Responsible for much of the rapid, intense development of children's brains as they learn and grow, it also leads to some of the devastating and permanent effects of stroke or other brain damage caused by genetics, disease or the environment.
The NMDA receptor is a complex molecule of interest to many researchers because it appears to be related to intelligence. When active, this receptor enhances communications among brain cells. When one of the genes contributing to the NMDA receptor is overexpressed in mice, those mice do better on behavioral tests of learning.
The mechanisms that help modulate NMDA receptor function during development are poorly understood, but if the NMDA receptor could be manipulated, scientists would have a powerful tool for altering brain plasticity or reversing disease. "Control of this receptor's function is centrally important to many aspects of neuroscience," Professor Constantine-Paton said.
Blocking glutamate receptors such as the NMDA receptor has been explored as a possible way to decrease brain damage that can occur in epileptic seizures and stroke.
"Our findings suggest that understanding the control of calcineurin and its effects on NMDA receptor activity could provide important and unexpected insights into the mechanisms" of brain plasticity and neurological disease in both developing and mature brains, wrote Professor Constantine-Paton and her co-authors, Jian Shi of biology and Matthew Townsend of the Interdepartmental Neuroscience Program at Yale.
FINE-TUNING YOUNG BRAINS
As they develop, our brains get "tuned" in several ways: through the expression of genes and through input from our senses and motor activity. Most of this tuning occurs in the first month of life in animals and during the first few years of life in humans.
Neurons in young brains are designed to let in a lot of excitatory electrical current.
Like dams that prevent flooding, however, mechanisms within the cell eventually turn down the receptors that drive the current. Over-excitation -- too much current -- can damage and kill brain cells. Excitotoxicity is believed to contribute to the degeneration of brain cells connected with neurological disorders such as trauma, stroke, epilepsy, Huntington's and Lou Gehrig's disease and AIDS-related dementia.
Once the cell mechanisms that shut down NMDA receptors develop, the brain's rate of adaptive reorganization slows. There is far less plasticity in the adult brain, which is why brain damage in adults is so devastating. Without the ability to shape new circuits, the brain cannot compensate for damaged ones.
The mechanism that shuts down the receptors' activity was thought to involve the expression of new genes. At a certain point in the cell's development, it seemed that a genetic switch was flipped to produce a new protein that turned down NMDA receptor function.
Unlike much other research in this area, Professor Constantine-Paton's work does not focus only on gene activation. She is exploring the role of an enzyme that modifies existing proteins.
Calcineurin is a common calcium-activated protein, one of the most prominent in the brain. Calcium enters neurons through the NMDA receptor. Dr. Constantine-Paton and her colleagues show that blocking calcineurin, which otherwise removes phosphate from certain proteins, can keep the NMDA receptor active at an earlier developmental level. This function of calcineurin is novel because it is very long-lasting and it may play an important role in modulating the plasticity of the developing central nervous system.
The Neuron paper reports that the change in the receptor's efficacy that can be induced with calcineurin is large and much more rapid than that achieved through new gene expression. This leads to the tempting quest to recreate the plasticity of the young brain in an older brain by depressing calcineurin at the receptors of mature cells.
"This is exciting because this effect of calcineurin does not require a new pattern of gene expression," Dr. Constantine-Paton said. "It provides another level of control. Calcineurin is something that is present and active near mature brain receptors, but its effects were believed to be only short-lived, so now there is the potential for manipulating it to create more or less potent neuron signals in regions of the adult brain."
TOO MUCH OF A GOOD THING
In their study of young rats' visual systems, the researchers found that NMDA receptors are still going strong at day 10 after birth. Electrical current is still flooding the cells. Then, between days 10 and 11, calcineurin turns on, stays on and immediately halves the duration of the current.
Prolonged activation of calcineurin could protect neurons from excitotoxicity in the face of seizure, ischemia, trauma or disease-induced increases in NMDA receptor activity, the authors wrote.
"This can give us the potential to intervene and exert a finer level of control over the central nervous system," Dr. Constantine-Paton said. "It also provides clues to how the system regulates itself that go beyond a description of the molecules that make it up.
"This work suggests a role for this enzyme in development and regulation. It can exert control over the NMDA receptor," Dr. Constantine-Paton said. "Now we ask, 'How is it working?'"
This work is supported by the National Institutes of Health and the National Institute of Mental Health.
A version of this article appeared in MIT Tech Talk on October 25, 2000.