HDAC3 Inhibition Restores Memory Updating in Aging: A Potential Therapeutic Target for Cognitive Decline

The ability to update our memories with new information is essential for adapting to changing situations and maintaining cognitive flexibility. However, this process tends to decline with age, contributing to the cognitive challenges often seen in older adults. Despite the significance of memory updating, especially as we age, the underlying molecular mechanisms are not well understood. One enzyme that might play a role is histone deacetylase 3 (HDAC3), which is known to suppress memory formation. While HDAC3’s involvement in consolidating memories is well-established, its role in updating memories, particularly in the context of aging, has been less explored. This study sought to fill that gap by examining whether inhibiting HDAC3 could reduce age-related memory updating impairments and potentially offer new therapeutic strategies for combating cognitive decline associated with aging. New study published in Frontiers in Molecular Sciences and conducted by Chad Smies, Lauren Bellfy, Destiny Wright, Sofia Bennetts, Mark Urban, Chad Brunswick, Guanhua Shu, and led by Professor Janine Kwapis from the Pennsylvania State University. The researchers conducted a series of experiments to delve into the role of HDAC3 in memory updating, using both young and older male mice. They applied the Objects in Updated Locations (OUL) paradigm, a task designed to see how well mice can integrate new information into existing memories. In the initial experiments, they focused on 18-20-month-old mice, which typically show age-related challenges in memory updating. These mice were trained to recognize the positions of two identical objects. After the training phase, one of the objects was moved to a new spot, giving the mice a chance to update their memory. Immediately after this update, the researchers administered RGFP966, a selective HDAC3 inhibitor. The next day, they tested the mice to see how well they remembered both the original and updated object locations.

The authors showed that inhibiting HDAC3 in older mice significantly enhanced their ability to remember the updated location, effectively reducing the memory updating deficits that come with age. Importantly, this improvement didn’t diminish their recall of the original location, suggesting that HDAC3 is crucial for memory reconsolidation and that its inhibition can help restore cognitive flexibility in aging.

However, the results were quite different when the researchers conducted similar experiments with young, 3-month-old mice. After these younger mice went through the same OUL paradigm and received the HDAC3 inhibitor post-update, they could remember the new location, but their recall of the original location was impaired. This suggests that in young animals, the original and updated information might compete during memory retrieval, and HDAC3 inhibition tilts this balance in favor of the new information, weakening the original memory. To explore this further, the researchers conducted another experiment with young mice, this time using a subthreshold update—a much shorter update session that, on its own, wasn’t enough to drive successful memory updating. Interestingly, when HDAC3 was inhibited after this brief update, the young mice demonstrated strong memory for the updated location without losing the original memory. This finding indicates that HDAC3 inhibition can strengthen a weak update, allowing it to effectively compete with the original memory during retrieval.

These experiments collectively demonstrate that HDAC3 plays a pivotal role in regulating memory updating. Inhibiting HDAC3 could offer a potential therapeutic approach to reducing age-related cognitive decline. The different effects observed in young and older mice highlight the complexity of memory processes and suggest that HDAC3 might help balance the retention of old and new information, depending on the strength of the memory update. The significance of this study lies in its identification of HDAC3 as a key regulator of memory updating, especially as it relates to aging. By showing that inhibiting HDAC3 can restore cognitive flexibility in older mice, the research opens up new possibilities for therapeutic interventions aimed at reducing age-related memory decline. The findings suggest that targeting HDAC3 could enhance the ability to update memories, which often becomes impaired with age, thereby improving overall cognitive function in the elderly.

The study’s implications are broad, providing a deeper understanding of the molecular mechanisms that contribute to cognitive aging. The varying effects of HDAC3 inhibition in young versus older mice underscore the complexity of memory processes and suggest that epigenetic regulation may play a subtle yet crucial role in balancing old and new memories. These insights could lead to more precise therapeutic strategies tailored to specific cognitive deficits associated with aging. Moreover, Professor Janine Kwapis and colleagues raises important questions about how we can manipulate memory updating without compromising the integrity of existing memories, particularly in younger individuals. This could pave the way for further research into finding the right balance between memory retention and flexibility, ultimately aiming to optimize cognitive health across the lifespan.