Our real-world memories are formed in a particular context and are often not acquired or recalled in isolation. Time is a key variable in the organization of memories, as events that are experienced close in time are more likely to be meaningfully associated, whereas those that are experienced with a longer interval are not. In new research, scientists from the United States and Korea have discovered a key molecular mechanism behind the memory linking, and identified a way to restore this brain function in middle-aged mice — and an FDA-approved drug, maraviroc, that achieves the same thing.
CCR5 expression and activation in the dorsal hippocampus after contextual fear conditioning. Image credit: Shen et al., doi: 10.1038/s41586-022-04783-1.
“Our memories are a huge part of who we are. The ability to link related experiences teaches how to stay safe and operate successfully in the world,” said Professor Alcino Silva, a researcher with the David Geffen School of Medicine at the University of California Los Angeles.
Cells are studded with receptors. To enter a cell, a molecule must latch onto its matching receptor, which operates like a doorknob to provide access inside.
Professor Silva and colleagues focused on a gene called C-C chemokine receptor type 5 (CCR5) that encodes the CCR5 receptor — the same one that HIV hitches a ride on to infect the brain cell and cause memory loss in AIDS patients.
In earlier research, the researchers demonstrated that CCR5 expression reduced memory recall.
In the current study, they discovered a central mechanism underlying mice’s ability to link their memories of two different cages.
A tiny microscope opened a window into the animals’ brains, enabling the scientists to observe neurons firing and creating new memories.
Boosting CCR5 gene expression in the brains of middle-aged mice interfered with memory linking. The animals forgot the connection between the two cages.
When the scientists deleted the CCR5 gene in the animals, the mice were able to link memories that normal mice could not.
They had previously studied a drug called maraviroc, which the U.S. Food and Drug Administration approved in 2007 for the treatment of HIV infection.
They discovered that maraviroc also suppressed CCR5 in the brains of mice.
“When we gave maraviroc to older mice, the drug duplicated the effect of genetically deleting CCR5 from their DNA,” Professor Silva said.
“The older animals were able to link memories again.”
The finding suggests that maraviroc could be used off-label to help restore middle-aged memory loss, as well as reverse the cognitive deficits caused by HIV infection.
“Our next step will be to organize a clinical trial to test maraviroc’s influence on early memory loss with the goal of early intervention,” Professor Silva said.
The study was published in the journal Nature.
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Y. Shen et al. CCR5 closes the temporal window for memory linking. Nature, published online May 25, 2022; doi: 10.1038/s41586-022-04783-1
