Smart Genes?

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What's happening when the brain forms memories--and what fails with aging, injury and disease--involves a phenomenon known as "plasticity." It's obvious that something in the brain changes as we learn and remember new things, but it's equally obvious that the organ doesn't change its overall structure or grow new nerve cells wholesale. Instead, it's the connections between new cells--and particularly the strength of these connections--that are altered by experience. Hear a word over and over, and the repeated firing of certain cells in a certain order makes it easier to repeat the firing pattern later on. It is the pattern that represents each specific memory.

How this reinforcement happens was a puzzle for much of this century, until 1949, when Canadian psychologist Donald Hebb came up with a related notion: since most memories consist of a group of disparate elements coming together--the hammer again--something more must be happening than just an electrical signal in one brain cell setting off a response in another. Something in the brain must be acting as a "coincidence detector," taking biochemical note that two nerve cells are firing simultaneously and coordinating two different sets of information.

Over the past decade or so, neurophysiologists have been focusing in on a particular molecule they believe could well be at least one version of Hebb's coincidence detector. Called N-methyl D-aspartate, or NMDA, this substance sits at the ends of the dendrites, the branchlike projections that protrude from nerve and brain cells, waiting to respond to incoming signals. Like other receptor molecules, NMDA reacts to a chemical cue--in the case of learning and memory formation, glutamate--emitted by the axon from a neighboring cell.

But unlike other receptors, NMDA doesn't find this signal sufficient. It must also receive an electrical discharge from its own cell. Only when both cells are talking at once does the NMDA receptor turn on. It then permits calcium ions to flow into the host cell, which somehow--no one knows the details yet--makes the cell easier to turn on next time around. This phenomenon, known as long-term potentiation, is believed to be the essence of one type of memory formation.

NMDA's role in learning and memory isn't just theoretical. It has been known for years that blocking NMDA receptors with drugs, or knocking them out completely at the genetic level, makes animals learning-disabled, even amnesiac. Administering drugs that stimulate the receptor, conversely, tends to improve memory.

Tsien and his team took the next logical step. "A decade ago," says Stanford neuropsychiatrist Dr. Robert Malenka, "if you had asked, Would it be possible to manipulate a higher cognitive function like learning and memory by changing a single molecule? most scientists would have looked at you as if you were crazy."