Enzyme may have key dual role in memory formation

Enzyme may have key dual role in memory formation

That a protein molecule common in the brain turns out to have two roles isn't surprising.

"If nature invents it once, you'll find it again and again and again," University of Illinois Professor David Clayton said recently.

What's surprising is the additional role UI researcher Graham Huesmann in Clayton's lab has identified for caspase-3, an enzyme, or catalyst protein.

The protein is well-known for its role in controlled cell death. But it also may be a key player in the formation of memories, according to a report by Huesmann and Clayton in the journal Neuron.

The two roles may be more similar than they sound.

When caspase-3 sets off a chemical cascade that kills cells, it's generally in the context of apoptosis – that is, controlled cell death the body employs for good purposes, for instance to make room for new growth or to stop cancer cells from proliferating.

Similarly, Huesmann and Clayton think the protein drives the pruning of synapses – connections between neurons, or brain cells – when memories are formed.

They admitted that the notion runs counter to scientific dogma, which has the brain adding structure when forming memories.

But Huesmann likened the idea that caspase-3 removes structure to create memories to a bas-relief sculpture created by chipping away pieces of stone. Clayton said Huesmann's insight led to the discovery of the protein's role in memory formation.

Huesmann, who did his doctoral thesis on the research, used the example of remembering someone's face. We take in a lot of other information in the process, maybe the color of the shirt the person was wearing, the pattern of the wallpaper behind them, people passing by whom we're not intent on remembering. It's this background material that gets discarded in the process of carving out the memory.

The UI researchers identified the cell-killing protein's presence in memory formation by teaching songbirds, zebra finches in this case, new songs.

Clayton said the birds are a well-characterized model for studying memory function in the brain because they're among the few animals that communicate vocally – through song – and they can learn new songs. His lab had already identified "dynamic learning-associated changes" in gene activity in the birds' brains when they're in a learning mode.

"We know where to look, when to look, and we can manipulate it with a natural stimulus," said Clayton, a cell and developmental biology professor who's also affiliated with the UI neuroscience and bioengineering programs and the Beckman Institute and Institute for Genomic Biology.

Similarly, the researchers identified the influence of caspase-3 by exposing the birds to tape recordings of other birds singing, then examining their brains at a molecular level. When the birds were exposed to unfamiliar songs, they found an increased concentration of the protein in its active state. Familiar songs caused no significant increase in the enzyme.

The UI researchers also could block the learning process by introducing an enzyme inhibiter to prevent the protein from acting, Clayton said.

He said there are indications from research done elsewhere that the protein is at work during learning in rats' brains as well. Meanwhile, it's also found in human brains, and while humans are obviously different from zebra finches, the hope is that understanding how things work at the molecular level may ultimately provide insight into maladies such as Alzheimer's disease, autism and dementia.

"There's certainly evidence that this is not unique to songbirds," Clayton said.

Huesmann, who has finished his doctorate in neuroscience and is finishing his medical degree through the UI Medical Scholars Program, didn't really expect caspase-3 to be a big player in memory formation.

In controlled cell death, the protein activates itself, works with a lack of subtlety more akin to a jack hammer than the fine strokes of a sculptor's chisel, and is hard to stop.

But in memory formation, it appears to be held in check by a natural inhibiter until a signal to carve out a memory frees it. Once the sculpture is finished, the inhibiter may reattach, leaving the protein inert again and ready for the next round of memory making.

"I think you can actually recycle it," Huesmann said.

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