Researchers are investigating the role of the histone H2A.Z in memory formation, with an eye on how this might lead to better treatments for memory loss.
The issue of memory loss motivates researchers to try and better understand the workings of the brain, how memories are consolidated, and how and why we lose them.
As being able to keep our memories enables us to maintain a sense of selfhood and orientation in the world, understanding how to prevent chronic loss of memory is a top priority in neuroscience.
Recently, a team of researchers from the University of Toronto Mississauga in Ontario, Canada — in collaboration with colleagues from the United States and the United Kingdom — investigated the role of a particular protein in the formation of memories.
Senior researcher Iva Zovkic and her team conducted their study on mice, focusing specifically on a protein named H2A.Z. This type of protein is called a histone, and it binds to DNA, helping it to keep its structure within cells.
Their results were published in the journal Cell Reports.
H2A.Z and memory formation
Zovkic and team worked with both young and aged mice to understand how the H2A.Z protein was involved with memory formation and suppression.
As a part of their experiment, the researchers placed the mice in a new box, so as to force them to get familiarized with a strange environment. Then, to be able to test how the protein functioned in the context of memory formation, the animals were exposed to a negative stimulus while in the box.
This way, the mice formed an association between the new environment and the bad experience that they had been exposed to. The second time the scientists placed them in the box, the now cautious mice refused to move around and explore, as they normally would have.
Half an hour after the mice had been exposed to the negative stimulus, Zovkic and colleagues assessed the animals' brains for any changes in how H2A.Z bound to DNA.
They revealed that in young mice, fear training was associated with an "overwhelming" reduction of H2A.Z and DNA bonds in 3,048 places on the genes that the proteins normally bind with, as well as an increase in bonds at only 25 places.
The same was true for the older mice, who experienced a reduction in bonds at 2,901 places and an increase at only 9 places in the aftermath of fear training.
This, the researchers explain, means that eviction of H2A.Z (fewer bonds between the protein and DNA) is associated with memory formation, allowing the mice to recall their negative experience.
"We have thousands of experiences each day, but we only remember things that are in some way important to us," Zovkic notes.
"This experiment," she continues, "used a very straightforward learning experience to illustrate that H2A.Z apparently serves to suppress memory, and the removal of this protein appears to [...] allow long-lasting memories to form."
A new therapeutic target?
The researchers also observed that the levels of H2A.Z were dependent on the animals' age. Thus, the protein was found at higher levels in the aged mice's hippocampi, which is a region of the brain strongly associated with memory formation.
Based on these observations, Zovkic and her team inferred that the higher the levels of H2A.Z, the likelier it is that memory formation and retention is hindered. Hence, if advancing in age correlates with more H2A.Z bonds, that might explain age-related memory loss.
"Identifying H2A.Z as a unique protein that is involved with memory and increases with aging could be a big deal for creating genetic or pharmaceutical therapies for age-related cognitive decline and dementia. H2A.Z is a relatively specific therapeutic target."
The next step from here, the researchers say, will be to test their theory on very old mice. Should their ideas be confirmed by further studies, the researchers plan to go forward and study the effects of H2A.Z in humans, whose bodies also produce this protein.
Zovkic and team's ultimate hope is that their research will eventually lead to better therapies to prevent and fight age-relate memory loss.
"We're always trying to find molecular bases for memory, and discovering how genes related to memory are turned on and off is a step in a positive direction," Zovkic concludes.