News Release

Researchers Identify Function Of Brain Receptor Subunit Linked To Memory, Stroke, Dementia

Peer-Reviewed Publication

Harvard Medical School

BOSTON--May 26, 1998--Researchers at Brigham and Women's Hospital and Harvard Medical School have characterized the function of a subunit of the NMDA receptor, a specialized molecule on nerve cells that admits calcium when activated by the neurotransmitter glutamate. The subunit, dubbed NR3A, appears to regulate the activity of the NMDA receptor in ways that may protect nerve cells from damage. Their findings are published in the May 28 Nature.

NMDA receptors are important in nerve cell migration and synapse formation during development. Later, they are essential for the synaptic plasticity?a change in connections between synapses--thought to underlie learning and memory. Paradoxically, NMDA receptors are also responsible for nerve cell injury in a variety of neurologic diseases, including stroke, head and spinal cord trauma, and various forms of dementia, including AIDS dementia.

In 1995, Stuart Lipton, HMS associate professor of neuroscience at Brigham and Women's Hospital, and his colleagues cloned a gene that he and Nobuki Nakanishi, HMS assistant professor of neurobiology, and his colleagues now show is an NMDA receptor subunit, dubbed NR3A. Nakanishi's lab also produced mice that lack the NR3A subunit.

Mice that do not have the NR3A subunit appear normal and lack apparent behavioral abnormalities. When Lipton's laboratory conducted electrophysiological tests, however, they found heightened NMDA receptor activity in the nerve cells of these mice. Ionic current was 2.8-fold higher than in neurons containing the NR3A subunit, increasing the amount of calcium entering nerve cells. In anatomical studies, Nakanishi and his colleagues found a striking increase in the number of dendritic spines--sites where synapses are formed--on the nerve cells of mice lacking NR3A compared with normal mice.

These findings suggest that the NR3A subunit may play a protective role, inhibiting the ionic current passed through the NMDA receptor and reducing the amount of calcium entering the nerve cell. NR3A is expressed very early in life when brain cells are extremely sensitive to glutamate toxicity. The subunit also appears to be involved in synaptic plasticity by regulating the development of dendritic spines.

"Our findings point to a paradigm shift in how NMDA receptors work," says Lipton. "We want to learn more about the NR3A subunit with the hope of possibly developing drugs or gene therapy to protect nerve cells from injury caused by neurological diseases."

For Nakanishi, the knockout mouse holds promise as the first animal model for synaptic plasticity. Activation of the NMDA receptor determines whether neuronal activity is worthy of memory. He plans to further study the role of NMDA receptors in synaptic plasticity and memory formation.

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