Persistent memories are doubly paradoxical. They are stable because they are built on physical connections that are dynamically maintained. Also, long-term memories are maintained through the work of prion-like proteins, even though prions are notorious for their contribution to neurodegenerative diseases—Alzheimer's, Parkinson's, and Huntington's—and the destruction of memory.
Prion-like proteins, assert researchers at Columbia University, can have a functional role within neurons instead of contributing to disease. These researchers first identified a functional prion within Aplysia, a giant sea slug. Then they found a similar prion within mice. And now, in a new study, the researchers have proposed a mechanism for how this prion maintains long-term memories.
The new study—“The Persistence of Hippocampal-Based Memory Requires Protein Synthesis Mediated by the Prion-like Protein CPEB3”—appeared June 17 in the journal Neuron. It explains how CPEB3, which stands for cytoplasmic polyadenylation element-binding protein, can account for the persistence of memory even though memories are built on molecular substrates that undergo rapid turnover.
A similar protein exists in humans, suggesting that human memories, too, rely on functional prions. This protein, said Eric Kandel, M.D., the leader of the Columbia team, may have the same role in memory. “Until this has been examined,” he prudently added, “we won't know.”
When disease-causing prions form within a neuron, they cause damage by grouping together in sticky aggregates that disrupt cellular processes. Prion aggregates are highly stable and accumulate in infected tissue, causing tissue damage and cell death. The dying cell releases the prion proteins, which are then taken up by other cells—and are thus considered infectious.
Surprisingly, the very features that make prions so dangerous—the ability to self-propagate and the ability to induce other proteins to take on their alternative shape—can serve useful ends. To show how, the Columbia team challenged mice to repeatedly navigate a maze, allowing the animals to create a long-term memory. But when the researchers knocked out the animal's CPEB3 gene two weeks after the memory was made, the memory disappeared.
“Both memory storage and its underlying synaptic plasticity are mediated by the increase in level and in the aggregation of the prion-like translational regulator CPEB3,” the authors of the Neuron study wrote. “Genetic ablation of CPEB3 impairs the maintenance of both hippocampal long-term potentiation and hippocampus-dependent spatial memory.”
“Like disease-causing prions, functional prions come in two varieties, a soluble form and a form that creates aggregates,” commented Dr. Kandel. “When we learn something and form long-term memories, new synaptic connections are made [and] the soluble prions in those synapses are converted into aggregated prions. The aggregated prions turn on protein synthesis necessary to maintain the memory.”
As long as these aggregates are present, Dr. Kandel added, long-term memories persist. Prion aggregates renew themselves by continually recruiting newly made soluble prions into the aggregates.
“This ongoing maintenance is crucial,” noted Dr. Kandel. “It's how you remember, for example, your first love for the rest of your life.”
