Weill-Cornell scientists solve mystery of long-term memory

By Bruce Toman

NEW YORK -- Scientists at Cornell's medical college and at the National Institutes of Health have solved one of the mysteries of human memory by identifying key events involved in turning short-term memory into long-term memory. Their findings could help in the development of drugs to ameliorate memory disorders.

Hempstead

The research was published in the Oct. 15 issue of Science by Dr. Barbara Hempstead, co-chief of the Division of Hematology/Oncology in the Department of Medicine at Weill Cornell Medical College in New York City, and by Dr. Bai Lu of the NIH. Hempstead also is the O. Wayne Isom Professor of Medicine at Weill Cornell and attending physician at New York-Presbyterian Hospital/Weill Cornell.

The paper shows that local generation of a protein called brain-derived neurotrophic factor, or BDNF, is the elusive key event that must occur to lock long-term memory in place.

What is a memory? When a long-term memory is formed, researchers believe that certain synapses -- the connections between neurons -- are made more efficient. The brain probably "learns" by storing information in networks of neurons connected by efficient synapses, and it probably "remembers" by activating the proper networks. Forgetting information most likely happens when synapses become less efficient so that the network holding that information ceases to exist -- it becomes indistinguishable from the vast number of potential networks created by the billions of neurons and synapses in the brain.

For more than a decade, researchers have been seeking to understand how a synapse can become more or less efficient and to understand how a brief increase in synapse efficiency can become permanent -- in other words, how short-term memory becomes long-term memory.

Several streams of research came together in the Science paper.

Eric Kandel of Columbia University won a Nobel Prize in 2000 for his work on identifying proteins that play important roles in memory. Of the many he identified, the most puzzling was the enzyme called tissue plasminogen activator (tPA). Kandel found that it must be present for a long-term memory to form, but no one understood what the protein was doing in the brain. Best known as a clot-busting drug used to treat stroke and heart attack, tPA is normally made by the body to break up clots during wound healing and other normal bodily functions. Why would this protein be involved in memory?

At the NIH, Lu has been studying the effect of certain proteins called neurotrophins on synaptic efficacy. He has shown that the neurotrophin BDNF plays a crucial role in making synapses more efficient.

Hempstead also studies neurotrophins. Like many proteins, neurotrophins are made by cells in a large "pro-form," which is then cut by enzymes into smaller pieces. Most scientists thought that only the smaller, or mature neurotrophins were biologically active. In 2001 Hempstead published a paper in Science showing that the pro-forms also are biologically active and often signal very differently from the mature forms. She also showed that cleavage of proneurotrophins often functions like a switch: The outcomes vary according to whether the pro-form is cleaved or not.

In their latest Science paper, Lu and Hempstead discovered that certain neurons crucial for memory formation regularly make and release pro-BDNF. When a long-term memory is to be formed, tPA is also released. It cleaves another protein, called plasminogen, to yield an enzyme called plasmin, which, in turn, cleaves pro-BDNF to BDNF. BDNF then causes the post-synaptic neuron to respond more strongly to a given amount of neurotransmitter, and so the synapse is made more efficient. With the tPA-plasmin-BDNF cascade serving to amplify the synaptic circuitry, long-term memory is locked into place.

Of the millions of things we experience each day, we want to remember only a select few. The Science paper reveals just how intricately regulated memory is -- all those proteins must be in the right place, at the right time -- and could provide some crucial clues for the development of drugs to arrest memory loss.