Research may help prevent loss of brain synapses

By discovering one of the first mechanisms through which brain synapses are dismantled, an MIT neuroscientist has shed new light on how our brains eliminate connections between neurons. The work was reported Thursday, Oct. 23 on Science magazine's Science Express web site.

Co-author Morgan Sheng, the Menicon Professor of Neuroscience in MIT's Picower Center for Learning and Memory, says this information may lead to drugs that could prevent or minimize synapse loss associated with neurodegenerative disease such as Alzheimer's.

Sheng, a Howard Hughes Medical Institute investigator, studies the structural and functional connections in the brain and how they are altered during development and by experience. Synapses are eliminated all the time, especially in young developing brains, to balance out new synapses that form in response to experience and learning. The number of synapses in the adult brain stays pretty constant; there is less turnover than in the young brain. But exactly how the brain accomplishes this paring process is not well-understood.

"We focus on synapses because that is where information is processed and stored in the brain," Sheng said.

Synapse loss also is the hallmark of many neurodegenerative diseases. "If there were a way to prevent synapse loss, it could be quite useful," Sheng said. Sheng worked on this study with MIT postdoctoral fellow Daniel T.S. Pak, now assistant professor in Georgetown University's pharmacology department.

Synapse demolition is the job of proteins. Many proteins are made up of modules strung together like beads on a string. When proteins communicate with each other to form multi-protein complexes, the modules on one protein bind to short sequences on other proteins.

Often, this type of binding only occurs when the short sequences have been chemically changed by the addition of a phosphate group. A family of enzymes called protein kinases sticks these phosphates on the short sequences in a process called phosphorylation.

Serum-inducible kinase (SNK) is involved in cell cycle control in dividing cells. In the brain, cells do not divide, but SNK has taken on the function of degrading the proteins that make up synapses. Neurons talk to each other through electrical signals transmitted by synapses. When neurons are stimulated by electrical activity, SNK is produced and targeted to synapses, where it degrades certain synaptic proteins and severs the connection between adjacent neurons.

By inhibiting SNK, Pak and Sheng made neurons grow more synapses than normal. "When we used a molecular trick to inhibit function of the SNK protein kinase, neurons sprouted a lot more synapses. It's doable in a culture dish in the laboratory, but whether it's doable in the living brain, I'm not sure," Sheng said.

This work is supported by Howard Hughes Medical Institute and RIKEN-MIT Neuroscience Research Center.

A version of this article appeared in MIT Tech Talk on October 29, 2003.

Topics: Neuroscience

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