Health of normal synapses seen to depend on neurotrophin signaling

November 22, 1999

In a new study, researchers at the University of Pennsylvania Medical Center have shown that the long-term health of synapses -- the connections between brain cells -- depends on ongoing signaling by a family of compounds called neurotrophins. Although neurotrophins are known to be critical during development, the current findings are among the first to show the importance of neurotrophin signaling at adult synapses. A report of the study appears in the November 24 issue of Neuron.

The results have implications for understanding how synapses are maintained in development and in adulthood, and suggest that neurotrophins may protect synapses from atrophy in aging and patients with certain neuromuscular diseases or injuries. In their experiments, the scientists used a novel technique borrowed from gene therapy to block normal neurotrophin activity in a type of synapse called the neuromuscular junction. They demonstrated that the synapses of developing and adult mice fall apart in the absence of particular neurotrophins.

The results are evocative of the synaptic changes seen in aging, muscular weakness and other diseases, suggesting that artificially augmenting neurotrophin signaling might someday be used to protect against certain kinds of synaptic failure.

"In aging animals and in aging humans, the synapse we studied -- the neuromuscular junction -- falls apart over time in much the same way it did in our neurotrophin experiments," says Rita J. Balice-Gordon, Ph.D., an assistant professor of neuroscience and senior author on the study. "Below a certain threshold, neurotrophin-deprived synapses begin to lose function. This nerve-signaling failure is one reason for the decrease in muscle strength in old age. So, one question we'll be looking at in the future is whether neurotrophin treatment of aging synapses might slow this process down." "What we've done argues that, in any disease or injury where the neuromuscular junction or other synapse is affected, neurotrophins could play a role in helping to maintain the synapse until the primary problem can be addressed," says Michael Gonzalez, Ph.D., a postdoctoral fellow in Balice-Gordon's lab and lead author on the study.

The synapse investigated by the Penn team is the neuromuscular junction, a type of synapse that connects spinal cord cells called motor neurons and skeletal muscle fibers. The neuromuscular junction is thought by neuroscientists to be similar to synapses in the brain and has long been used as a model system in many studies.

In looking for one of the target receptors for neurotrophins, called trkB receptors, the scientists expected to find the trkB receptors in the endings of the motor neurons at neuromuscular junctions. The working hypothesis of many neuroscientists had been that the muscle fibers provide neurotrophin to the motor neurons to support their endings. What the scientists found, however, was that the great majority of the trkB receptors were clustered in the muscle fiber itself. This suggested that neurotrophins might have a different role at the synapse than previously thought.

To experimentally block the activity of neurotrophins at synapses, the researchers used a gene-therapy vector -- a cold virus stripped of its genes and reloaded with genes of the scientists' choosing -- to flood otherwise normal synapses with many copies of a nonfunctional form of the trkB receptor. The flawed receptors effectively soaked up all available neurotrophin, depriving the synapse of its normal allotment. The result was the disassembly of the entire synapse, starting at the muscle fiber side and progressing to include the loss of motor neuron endings.
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The additional co-authors are Francis P. Ruggiero, [M.S.]; Qiang Chang, [B.S.]; Yi-Jun Shi, [B.S.]; Mark M. Rich, [M.D., Ph.D.]; and Susan Kraner, [Ph.D.]. Funding for the research was provided by the National Institutes of Health.

The University of Pennsylvania Medical Center's sponsored research and training ranks second in the United States based on grant support from the National Institutes of Health, the primary funder of biomedical research and training in the nation - $201 million in federal fiscal year 1998. In addition, the institution continued to maintain the largest absolute growth in funding for research and training among all 125 medical schools in the country since 1991. News releases from the University of Pennsylvania Medical Center are available to reporters by direct e-mail, fax, or U.S. mail, upon request. They are also posted electronically to the medical center's home page (http://www.med.upenn.edu), to EurekAlert! (http://www.eurekalert.org), an Internet resource sponsored by the American Association for the Advancement of Science, and to the electronic news service Newswise (http://www.newswise.com).

University of Pennsylvania School of Medicine

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