The formation of memories has been a popular research topic among the science community. They occur by a familiar stimulus reactivating a specific group of neurons, but not much else is known about the exact logistics involved in how a memory is created and retained. Many memory-related disorders like Alzheimer’s and PTSD directly affect a person’s brain chemistry and are undoubtedly detrimental to their character and mental health.
In a recent study published in the Journal of Neuroscience, researchers from the University of Alabama at Birmingham set out to elaborate on understanding how memories form and are stimulated. They found that major translational modifications occur to the genes in the memory-related portion of the brain, and epigenetics may play a large role in how these genes are expressed
The research team, led by Dr. Farah Lubin, explored the phenomena of memory reconsolidation, which is the retrieval and stabilization of recent memory. They hoped to gain insight on the complex processes in order to develop preventative and active cures for psychiatric disorders.
To accomplish this, they studied the effects that epigenetic changes had on the memory reconsolidation process in the contextual fear memory located in the hippocampus of rats. Particularly, they examined a gene called PTEN, which is responsible for regulating the downstream translation in neurons during fear memory reconsolidation. PTEN is a known inhibitor of a memory associated pathway called AKT-mTOR, making it the ideal gene target for this study. Little is known about how the AKT-mTOR pathway is activated, and learning to inhibit its activation could provide relief to people suffering from PTSD.
The researchers found that when a stimulus reactivated the fear memory in rats, there was an increase in levels of the enzyme EZH2, a histone methyltransferase enzyme associated with the silencing of gene expression. EZH2 has been previously demonstrated to be an epigenetic switch in the formation of cancer cells, as well as a potential main factor in the formation of ischemic cardiomyopathy.
Upon further examination, the researchers also found an increase in H3K27me3 marks on the DNA, as well as an increased level of DNA methylation at the promotor and coding regions of the PTEN gene. With these three epigenetic factors combined, the activity level of the PTEN enzyme became diminished, ultimately silencing the transcriptional activity of the gene. Since PTEN is an inhibitor of the AKT-mTOR pathway, the combination of these repressive epigenetic marks allowed the AKT-mTOR pathway to activate, stimulating the recollection and formation of the fear memory.
To further understand this newly discovered mechanism, the team used small interfering RNA (siRNA) to knock down the EZH2 enzyme responsible for the increased methylation in the hippocampus, and found that PTEN levels were maintained and the AKT-mTOR pathway remained inactive. When both EZH2 and PTEN were completely knocked out, H3K27me3 methylation was prevented, resulting in the AKT-mTOR pathway remaining active, confirming the idea that these two genes most likely control the memory-forming pathway.
The discoveries made in this study highlight the significance of memory-related research. Figuring out how to deactivate the AKT-mTOR pathway would hinder the fear memory response and provide relief for many patients suffering.
“These findings could be critical in treatment of memory disorders, such as post-traumatic stress disorder,” said Lubin. “PTSD is thought to be caused by the lack of extinction of a fear memory. Altering this memory during the reconsolidation process could help in re-associating the memory with a less traumatic context.”
Source: Lubin, F. et al. (2018). EZH2 Methyltransferase Activity Controls Pten Expression and mTOR Signaling during Fear Memory Reconsolidation. Journal of Neuroscience, 38 (35): 7635-7648.
Reference: Jeff Hansen. “Novel epigenetic control mechanism found for critical brain proteins in memory strengthening” UAB News. 6 Sep 2018. Web.