A mind-altering mutation in mice results in an enhanced long-term memory, researchers report in the April 6, 2007 issue of the journal Cell, published by Cell Press.
These findings point to a potential target for the development of a drug to treat memory loss, according to the researchers.
The researchers studied a gene that normally increases levels of a natural memory-blocking protein. Animals that carry a defective version of this gene showed improved performance in classical behavioral memory tests, they show. Moreover, animals treated with a small molecule that had the opposite effect, leading ultimately to an increase in the memory-blocker's concentration'showed signs of memory impairment.
"There are very few examples where you can increase memory, especially by deleting genes," said study author Nahum Sonenberg of McGill University in Montreal, Canada. "It's a small, but important part of the big puzzle of how memory works."
"The next step, which is inevitable, is to look for small molecules that mimic this memory-enhancing effect," he continued.
"If such a pill could be generated, it might provide a new method for treating people with memory-related diseases such as Alzheimer's," said Mauro Costa-Mattioli, a senior postdoctoral fellow in Sonenberg's laboratory. "While a drug that worked in this way wouldn't cure the disease itself, it might rescue the symptoms of memory loss."
Memories are formed when the repeated activation of brain cells leads to a strengthening of neural connections, or synapses. This process, considered the cellular basis of learning and memory, is known as synaptic plasticity.
Both memory and synaptic plasticity have two components, the researchers explained. One, which is evoked by weak training protocols, yields only transient phenomena, including short-term memory, lasting for minutes to hours, or the beginning stages of longer-term memory storage, lasting for one to three hours. The second component, which follows strong or repetitive training, activates mechanisms that stabilize the memory and nerve connections, resulting in long-term memory, lasting days, weeks, or years.
"Quite different molecular machineries, widely conserved from sea slugs to rodents, are thought to underlie these two components. While modifications of pre-existing proteins are sufficient for the transient changes, new gene expression is required for those that are sustained," the researchers said, emphasizing that a gene's expression depends on both its transcription into messenger RNA and the translation of that messenger RNA into functional proteins.
Sonenberg and Costa-Mattioli earlier found the first genetic evidence that control over protein synthesis plays an important role in the formation of lasting memories.
"Most of the focus on gene control is at the level of transcription," Sonenberg said. "In contrast, here there is control at the level of translation, in making protein from messenger RNA, a less appreciated mode of regulation."
When the regulatory protein eIF2a is chemically modified with the addition of a phosphate to one of its amino acids, it switches on the protein synthesis of another factor that halts production of genes required for the long-term storage of memories. Sonenberg and his colleagues previously discovered that mice lacking the enzyme that performs the phosphorylation reaction have a superior ability to remember new things under certain training conditions.
"Those results led us to suspect that decreasing the phosphorylation of eIF2a enhanced memory storage," Costa-Mattioli said.