Protein stimulates key link between nerve cells, suggesting possible target for mental retardation and nerve regeneration therapies

November 16, 2000

UCSF researchers have exposed a single protein that can stimulate the maturation of the synapses, or junctures, through which nerve cells communicate a key signal to one another. The discovery reveals a mechanism critical for supporting brain development, learning and memory and a possible target for treating mental retardation and nerve damage following stroke and spinal cord injury.

The finding, reported in the November 17 issue of Science, indicates that the protein, PSD-95, helps build the physical scaffolding of the synapse that cells use to transmit the chemical messenger, or neurotransmitter, known as glutamate, to a target cell. The protein also matures other aspects of the synapse -- enhancing the clustering of glutamate receptors on the target cells receiving the chemical messenger, increasing the number and size of the dendritic spines that hold glutamate receptors, and increasing the number of glutamate neurotransmitters emitted from the releasing cell.

The results, says senior author David S. Bredt, MD, PhD, UCSF professor of physiology, indicate that the protein is the cornerstone of physical maturation for both the pre- and post- synaptic structures that allow glutamate to signal from one neuron to another.

The findings are provocative, for glutamate, the major excitatory neurotransmitter in the brain, is the engine behind cellular learning -- including brain development and mental and physical processes. Glutamate is also thought to be the key to plasticity, the brain's ability to relearn mental and physical skills following injury and to adjust to new circumstances. The neurotransmitter acts by stimulating a receptor on target cells containing a protein known as the NMDA receptor, which serves to strengthen, or reinforce, the neural circuits between nerve cells that store memory.

Glutamate enables the brain to develop, language to be learned, a new math equation to be grasped, tennis to be mastered and walking to be relearned following a stroke. But without the synapses that allow the chemical signal's transmission from one nerve cell to the next, glutamate has no more luck in communicating its messages than a train has luck in reaching its destination without tracks to follow.

During synaptic transmission, nerve cells release thousands of neurotransmitters from their nerve terminals at once. The messengers diffuse across a synaptic cleft to corresponding receptors on a target cell, and prompt a response in that cell that is then transmitted to another cell and yet another, ultimately causing a wave of reaction in the brain.

Some neurotransmitters, such as GABA, carry inhibitory signals, reducing excitation and anxiety in the brain, and others, such as dopamine and serotonin, modulate the activity of neural circuits to influence mood and sleep. The millisecond relay of glutamate to thousands of nerve cells sparks the brain into high activity.

Mental retardation is associated with a loss of the dendritic spines on post-synaptic neurons that play a role in receiving glutamate messages. As the study shows that PSD-95 increases the number and size of these spines, gene therapy could prove effective in stimulating the growth of the spines and thus treating the disease. Likewise, using PSD-95 gene therapy to stimulate the maturation of glutamate receptors could be used to regenerate nerves following stroke or spinal cord injury.

On the flip side, when nerve cell receptors that receive glutamate become overactive and thus receive too much glutamate - as occurs following stroke and in such neurodegenerative diseases as Alzheimer's disease -- brain damage occurs.

Much research is aimed at treating this so-called excito-toxicity by blocking the glutamate receptor. But identifying a way to disrupt the synapses that allow communication of glutamate from one nerve cell to another could provide an alternative way of treating these diseases and, again, the PSD-95 protein might prove an effective target.

The UCSF researchers conducted their study in cultured neurons of the hippocampus, a brain structure involved in learning and memory. They over-expressed the PSD-95 protein in their normal location, the post-synaptic membrane of neurons, at an early stage of glutamate synapse development.

They detected enhanced clustering and activity of glutamate synapse development, enhanced clustering and activity of glutamate receptors at the post-synaptic sites and an increase in the number and size of dendritic spines, which contain the receptors that respond to glutamate neurotransmitters.

More surprisingly, they discovered that PDS-95 stimulates maturation of the pre-synaptic terminal, which emits neurotransmitters, presumably by reaching across the synaptic cleft. They also determined the protein increases the release of glutamate neurotransmitters from the pre-synaptic terminal of the emitting neuron.

The findings suggest, says Bredt, that during normal conditions clustering of the protein at the post-synaptic site, which would cause maturation of the glutamate synapse, may be regulated during development and during learning processes and plasticity. The next step in the research, he says, is to try to understand at the molecular level what the PSD-95 protein targets to promote synaptic maturity and plasticity.
Co-authors of the study were Alaa El-Din El-Husseini, PhD, UCSF postdoctoral fellow in physiology, Eric Schnell, BS, a UCSF graduate student in cellular and molecular pharmacology, Dane M. Chetkovich, MD, PhD, clinical instructor in neurology and Roger A. Nicoll, PhD, UCSF professor of cellular and molecular pharmacology. The study was funded by the National Institutes of Health, the Howard Hughes Medical Institute and the National Association for Research on Schizophrenia and Depression.

University of California - San Francisco

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