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How Sea Slugs Make Memories

By Nancy Touchette

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Mad Cow

The sea slug Aplysia is helping researchers understand how memories are stored in the brain.
Researchers studying how memories are made have discovered a protein that is critical to the process. They have also found that the protein works in an unusual way that may help neurons store memories for days or even weeks.

The protein changes its shape in a way similar to the prion protein that has been linked to mad cow disease. But unlike the prion protein, which in its altered state causes brain disease in cows, sheep, and humans, the newly discovered protein does a good thing, by helping nerve cells connect to each other.

Eric Kandel and his coworkers at Columbia University in New York City use a sea slug species known as Aplysia to study memory. The ugly slug uses a relatively simple system of neurons to remember certain stimuli and react to them. For example, the slugs can remember being pinched in the gill, and they learn to react by withdrawing the gill.

Most neurons contain thousands of projections that connect to other neurons in an intricate system, much like a network of interconnected wires. To make sure a signal gets from point A to point B, electrical signals must flow through the right set of wires.

By the same token, in the brain, the trick to storing memories is to strengthen a specific synapse, a small gap between connecting neurons.

Kandel already knew that once a neuron receives a signal through one of its many synapses, that the synapse is somehow “marked.” But he didn’t know whether the proteins and protein precursors needed to strengthen the connection know which synapses to go to—or whether they go to all synapses but are used only where needed.

In new studies reported in Cell, Kausik Si, a member of Kandel’s lab, and his colleagues find that a protein called CPEB gets sent to all the synapses in a neuron. But at synapses that have been stimulated, the protein wakes up other molecules already there to produce new proteins that help strengthen the connection.

“New growth of synapses occurs in front of your eyes over the course of a day,” says Kandel.

For a long-term memory—one that lasts days and not hours—those connections must be maintained. But how does CPEB maintain the synaptic connection?

The researchers noticed that the protein has an unusual structure, similar to a yeast version of the prion protein. They found that when the slug memory protein is produced in yeast, it undergoes a similar change in shape.

“Usually, when these kinds of proteins change shape, they aggregate, and that can cause disease,” says Kandel. “But we found that it is the altered shape of the protein that is active. That was a surprise.”

The CPEB protein is also found in the neurons of humans, mice and fruit flies. Kandel hopes the studies will help researchers eventually understand how humans store long-term memories.

Si, K. et al. A neuronal isoform of the Aplysia CPEB has prion-like properties. Cell 115, 879-891 (December 26, 2003).
Si, K. et al. A neuronal isoform of CPEB regulates local protein synthesis and stabilizes synapse-specific long-term facilitation in Aplysia. Cell 115, 893-904 (December 26, 2003).

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