Imagine if increasing a certain type of epigenetic enzyme could ease anxiety or cure post-traumatic stress disorder (PTSD) by simply erasing troubling memories? What if it could also enhance cognitive abilities and improve long-term memory and learning? In previous blog articles, researchers found that an immune-suppressing drug that inhibits HDACs could stop aversive memories and the epigenetic mechanism known as histone acetylation might play a role in memory plasticity. Although we are far from developing epigenetic therapies to erase traumatic memories or improve cognitive ability, a study conducted by researchers at the Interdisciplinary Center for Neurosciences of Heidelberg University continues to expand on our knowledge of the possibility. Instead of looking at histone acetylation or HDAC inhibitors, however, the team, led by Professor Hilmar Bading, Ph.D., focused on an epigenetic player involved in DNA methylation. They found that the level of a key DNA methyltransferase (DNMT) known as DNMT3A2 could improve cognitive ability and significantly impact memory formation as well as memory extinction.
In a previous study, the scientists at Heidelberg investigated elderly mice brains and discovered that the level of the DNMT3A2 protein was significantly reduced. However, the mice’s memory capacity received a boost when the scientists injected them with special viruses that produced the DNMT3A2 protein. In the current study, Professor Bading and his team of neurobiologists expanded on these findings and discovered that increasing the level of DNMT3A2 in the brains of younger mice could also improve their cognitive ability. The group utilized several long-term memory tests, such as classic Pavlovian conditioning, to show that mice with extra DNMT3A2 were significantly better at performing these tasks.
DNA methyltransferases are critical components to the cycle of the epigenetic modification known as DNA methylation, which can change the expression of genes without altering the underlying genetic sequence. DNMTs are a family of enzymes that catalyze this process by adding a methyl group to DNA, relying on S-adenosyl methionine (SAM) as the methyl donor. DNA methyltransferases can be de novo, such as DNMT3A2, which newly methylate cytosines. Alternatively, some DNA methyltransferases maintain methylation by adding a methyl group to DNA when a strand is already methylated. DNMT3A2 can epigenetically modify the DNA and activate gene transcription, thereby synthesizing proteins that play a role in memory consolidation as well as memory elimination.
The researchers reported that DNMT3A2 “overexpression in the hippocampus of young adult mice induced memory enhancements.” For example, the excess DNA methyltransferase “converted a weak learning experience into long-term memory, enhanced fear memory formation and facilitated fear memory extinction.” The overexpression of DNMT3A2 was also linked to an increased expression of genes related to plasticity.
The scientists then conducted “erasure” investigations using methods similar to those in confrontational therapy for patients. This therapy is carried out to treat PTSD and tries to interrupt or erase disturbing associations. Mice with greater levels of DNMT3A2 in their brains could erase negative connections between a certain place and a painful stimulus with substantial efficiency. “Furthermore, the knockdown of DNMT3A2 expression impaired the animals’ ability to extinguish memories, identifying DNMT3A2 as a key player in extinction.”
Although these findings are only preliminary, they offer valuable insight into the role DNA methyltransferases may play in treating cognitive decline and impaired memory. “They could be used to develop new medications to improve memory in senile dementia or in patients suffering from neurodegenerative diseases like Alzheimer’s,” Professor Bading said. The team also believes that there is potential to create novel treatments for disorders related to anxiety. Ideally, medications could be developed to enhance the activity or production of DNMT3A2, which could be given in conjunction with confrontational therapy to fight these disorders.
On the other hand, Professor Bading also noted that these results could lead healthy individuals to misuse any potential drug that uses the DNA methyltransferase to enhance their mental capabilities. Further research would need to be conducted and numerous pre-clinical tests would have to be carried out before a drug could be deemed a safe treatment option for anxiety and fear-related disorders. Nonetheless, this fascinating evidence brings us that much closer to understanding the epigenetic possibilities of improving cognitive ability.
Source: Oliveira, A.M., Hemstedt, T.J., Freitag, H.E., Bading, H. (2015). Dnmt3a2: a hub for enhancing cognitive functions. Molecular Psychiatry, doi: 10.1038/mp.2015.175.
Reference: Heidelberg, University. Protein That Boosts Memory Identified. 21 Dec 2015. Web.