For the new study, the EPFL scientists investigated just that. In a common test for associative memory, the team used a contextual fear conditioning method to teach mice to fear a certain trigger. When the mice were given CI-994, they doubled their memory capacity for the task as compared to mice that learned without the drug.
But how did it work? The team examined a hypothesis that the HDACis were operating through a process called epigenetic priming – essentially, changing the expression of certain genes. In this case, the affected genes are related to learning and memory.
And sure enough, RNA sequencing techniques showed that the drug was acting on specific genes that control synaptic plasticity, the process that allows neurons to form stronger connections to facilitate memory and learning. On these key genes, the drug was making DNA packages called chromatin more accessible, easing their expression.
“The drug supports very specific genes, the ones that are already engaged in learning, and it doesn’t affect much other genes, for example genes that could have unwanted side-effects,” said Johannes Gräff, lead author of the study.
Understanding how these HDACis function is important for potentially putting them to work on improving memory and learning in humans. Thankfully they’ve already been approved for use in humans and shown to be safe, which speeds up the process of adapting them for new purposes. Two other clinical trials are already underway, exploring the use of the drug in improving memory in Alzheimer’s patients, and to help unlearn a fear of spiders.
The research was published in the journal PNAS.
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