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In the October 15 issue of Science, Dr. Bai Lu of the National Institutes of Health (NIH) and Dr. Barbara Hempstead of Weill Medical College of Cornell University have teamed up to solve one of the fundamental mysteries of human memory. They have identified the key events and proteins involved in long-term memory. Their findings provide insight into the biochemical basis of memory, and may help in the development of drugs to ameliorate memory disorders.

What is memory, on a biochemical and cellular level? The brain is filled with special cells called neurons — billions of them — and each neuron is connected to literally thousands of other neurons. The connections between neurons are "synapses" — tiny gaps, on one side of which is a "pre-synaptic" neuron and on the other side of which is a "post-synaptic" neuron. At a synapse, the pre-synaptic neuron relays information by releasing chemical messengers (neurotransmitters) to activate the post-synaptic neuron, which can then, in turn, relay signals to any of the thousands of neurons to which it is connected.

The extent to which a post-synaptic neuron is activated generally depends on the amount of neurotransmitter received from a pre-synaptic neuron. If a pre-synaptic neuron releases just a little neurotransmitter across the synapse, the post-synaptic neuron will be moderately activated. But a synapse can actually be made more efficient, so that a small amount of neurotransmitter will cause a greater response from the post-synaptic neuron than would normally occur.

Scientists believe the brain may "learn" by storing information in networks of neurons connected by efficient synapses, and that it may "remember" by activating the proper networks. Forgetting information 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 (thousands per neuron) in the brain.

Scientists have been working for more than a decade 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. A key question has been to identify the exact proteins and the interactions between them that allow a long-term memory to take hold.

Dr. Eric Kandel of Columbia University won a Nobel Prize in 2000 for identifying some of the key proteins in this process. In the course of his work, he found that tissue plasminogen activator (tPA) plays an important, but puzzling, role in memory formation. tPA is best known as a clot-busting drug used to treat stroke and heart attack, but it is normally made by the body to break up clots during wound healing and other normal bodily functions. tPA is an enzyme — a kind of scissor — that cleaves a protein called plasminogen to yield yet another scissor-like enzyme called plasmin, which actually cuts up blood clots. Although all three of these proteins are found in the brain, the role they play in memory formation has been elusive.

At the NIH, Dr. Lu has been studying the effect of certain proteins — neurotrophins — on synaptic efficacy. He has shown that one of the neurotrophins, called brain-derived neurotrophic factor, or BDNF, plays crucial roles in a cellular model of short-term and long-term memory.

Neurotrophins, including BDNF, are made by cells as a larger pro-form, which is cleaved by enzymes to a smaller, "mature" form. The mature form is known to provide signals to cells that help them grow and survive. Until 2001, scientists believed that only the mature forms were biologically active, and that the pro-forms were inactive. But in 2001, Dr. Hempstead discovered that proneurotrophins are biologically active, and that they have functions that are very different from, or even opposite, the actions of mature neurotrophins.

So far, Dr. Hempstead and collaborating scientists have identified only pathological situations in which the proneurotrophins are active — namely stroke, spinal cord injury, and cancer — and up to now, no one has identified a biological system in which the pro-form and mature form each have a normal but distinct physiological role.

In their Science paper, Drs. Lu and Hempstead have demonstrated that certain neurons crucial for memory formation make and release pro-BDNF all the time. When a long-term memory is to be formed, tPA is also released. It cleaves plasminogen to plasmin, which, in turn, cleaves pro-BDNF to BDNF. Through pathways that are not yet fully understood, BDNF 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.

These studies provide insight on how carefully nature regulates this process. For a memory to be formed, a whole chain of events must unfold. tPA, plasminogen, and pro-BDNF must all be present, and interact in just the right way, at the right time, in just the right synapses, to form a long-term memory. These findings also make sense of the previously mysterious role played by tPA, and they identify the first normal physiological role for proneurotrophins.

Perhaps, most importantly, the paper shows that local generation of mature BDNF is the elusive key event that must occur to lock long-term memory in place.

Bai Lu, PhD, is a Senior Investigator in the Section on Neural Development and Plasticity, Laboratory of Cellular and Synaptic Neurophysiology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD.

Barbara Hempstead, MD, PhD, is Co-Chief of the Division of Hematology/Oncology in the Department of Medicine at Weill Cornell Medical College. She is also The O. Wayne Isom Professor of Medicine at Weill Cornell and Attending Physician at NewYork-Presbyterian Hospital/Weill Cornell Medical Center in New York City.

Other authors on the paper from the NIH include Petti T. Pang, Eugene Zaitsev, Newton T. Woo, and Kazuko Sakata. Henry K. Teng, Shushuang Zhen, and Kenneth K. Teng are other collaborators from Weill Cornell Medical College. Dr. Pang has a co-appointment in the Department of Physiology at the Chinese University of Hong Kong, and Wing-Ho Yung, from the same institution, is another co-author.