Blocking this key enzyme can substantially improve memory in older adults

As you age, forgetfulness becomes more common, but the challenge isn't just in recalling new information. It's also in updating memories when new details emerge. This difficulty with memory updating in older adults is a topic that has puzzled scientists for some time. Although much is known about memory formation, the mechanisms behind how memories are updated, and how these processes change with age, are not fully understood.

Recently, researchers at Penn State have identified a specific enzyme that contributes to the challenges older adults face in updating their memories. Their study, published in Frontiers in Molecular Neuroscience, revealed that blocking this enzyme in older mice improved their ability to incorporate new information, making their performance on memory tasks comparable to that of younger mice. These findings open the door to potential therapeutic targets for enhancing cognitive flexibility in aging populations.

“It’s important to understand what’s happening at a molecular level during a memory update because, as humans, most of our memories are updates. We’re constantly building on things we already know and modifying existing memories,” explained Janine Kwapis, assistant professor of biology and the senior author of the study.

Kwapis emphasized the need to differentiate the mechanisms behind memory formation and memory updating, pointing out that this research is a significant step in that direction.

Memory formation involves the brain rewiring itself to retain information through a process known as consolidation. During consolidation, cells express proteins at the synapse—the gap between neurons that facilitates communication—linking together the cells that were activated when the memory was initially formed. When you recall a memory, those same cells fire together, reactivating the memory.

Updating a memory, however, is more complex. “When you’re presented with new information, you have to bring that existing memory out of storage and weaken it so it’s ready to take on new information. Once the new information is learned and those new neurons are incorporated, the updated memory is solidified and stored again,” Kwapis noted. This process, known as reconsolidation, becomes less effective with age, making it harder to update memories as you get older.

The Penn State research team aimed to understand why memory updating becomes more difficult with age and whether enhancing gene expression during reconsolidation could improve this process. To explore this, they focused on histone deacetylase 3 (HDAC3), an enzyme known to regulate gene transcription, which is the process of copying information from DNA into RNA to produce functional proteins.

HDAC3 has been linked to negative effects on memory formation and gene expression during consolidation, but its role in memory reconsolidation had not been thoroughly examined until now.

“HDAC3 typically tightens up the chromatin, a complex of DNA and proteins, and makes it hard for transcription to happen,” explained Chad Smies, a doctoral student in biology and the study’s first author. He further noted that blocking HDAC3 could potentially maintain a more open chromatin state, thereby improving gene expression during memory updating.

In their experiments, the researchers blocked HDAC3 during the reconsolidation phase and found that this intervention prevented the usual age-related decline in memory updating. Older mice that had HDAC3 blocked performed on par with younger mice during memory update tasks, suggesting that this enzyme plays a crucial role in the age-related impairment of memory updating.

To test these effects, the team employed a methodology called the "objects in updated locations paradigm," which was specifically developed by Kwapis to assess memory updating. This paradigm consists of three phases: a training session where mice learn the locations of two identical objects, an update session where one object is moved to a new location, and a test session where objects are placed in four different locations—the original training locations, the updated location, and a novel location.

“Mice like novelty, so if they have good memory for the training session or the update session, they’ll explore the novel object location more,” Smies said. He explained that poor memory would result in the mice exploring all locations equally, rather than showing a preference for the novel location.

By identifying the role of HDAC3 in memory updating, the research team hopes to pave the way for developing treatments that could enhance cognitive flexibility in older adults. Kwapis expressed optimism about the broader implications of their findings, stating, “If these mechanisms improve memory in normal aging, they could potentially help with conditions like Alzheimer’s disease and dementia too.”

These findings are not just a step forward in understanding the molecular underpinnings of memory, but they also hold promise for improving the quality of life for older adults by enhancing their cognitive abilities and potentially offering new avenues for treating neurodegenerative diseases.

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