PTSD Treatment Combines Psychotherapy And HDAC2 Inhibitor
January 17, 2014

New Treatment For PTSD

Rebekah Eliason for - Your Universe Online

Approximately eight million Americans are afflicted with post-traumatic stress disorder (PTSD). This condition is characterized by severe anxiety that can be traced back to a traumatic event such as a battle or violent attack.

Because of the difficulties in treating this disorder with behavioral approaches, these traumatic memories often last throughout a lifetime. Although many patients are treated with psychotherapy in order to let them re-experience their traumatic memory to overcome their fear of it, often the memories are so entrenched that the therapy is ineffective.

"Psychotherapy is often used for treating PTSD, but it doesn't always work, especially when the traumatic events occurred many years earlier," says senior study author Li-Huei Tsai of the Massachusetts Institute of Technology.

A new study by MIT neuroscientists has revealed that well-established traumatic memories in mice can be eliminated when administered an HDAC2 inhibitor. With proper conditions, this drug allows the brain’s memories to become malleable. Li-Huei Tsai indicated that giving this type of drug to human patients receiving psychotherapy may be much more effective than psychotherapy alone.

"By inhibiting HDAC2 activity, we can drive dramatic structural changes in the brain. What happens is the brain becomes more plastic, more capable of forming very strong new memories that will override the old fearful memories," says Tsai.

Additionally, this study discovered the molecular mechanism that explains why older memories are more difficult to forget. In previous studies, Tsai’s lab showed that as memories are formed, DNA packaged with proteins, known as neurons’ chromatin, undergo major modifications. As these chromatins are altered, it allows easier activation of the genes required to create new memories.

The chromatin modifications that occurred as previous memories became extinguished were the main focus of this study. First mice were trained to fear a specific chamber through a mild foot shock. Next the researchers attempted to recondition the mice to no longer be of afraid of it by placing them into the chamber again without receiving a shock.

This reconditioning process succeeded for mice when the traumatic event had only occurred 24 hours before. Interestingly, when they attempted to re-condition mice 30 days after experiencing the traumatic event, it was impossible to get rid of the fearful memory.

For the brains of mice with memories that were only 24 hours old, major chromatin alteration occurred during the reconditioning. After the mice were put back into the feared chamber, for several hours there was an enormous increase in histone acetylation of the genes related to memory. This was caused by the protein HDAC2 becoming inactive. To turn on the process necessary to from new memories or overwrite old ones, histone acetylation enables the genes to be more accessible.

When the mice with 30-day-old memories were placed into the feared chamber, there was no change in histone acetylation. According to Tsai, these findings indicate that re-exposure to a fearful memory can be successful in altering the fearful memory but only for recently formed memories.

"If you do something within this window of time, then you have the possibility of modifying the memory or forming a new trace of memory that actually instructs the animal that this is not such a dangerous place," she says. "However, the older the memory is, the harder it is to really change that memory."

In response to these discoveries, researchers administered an HDAC2 inhibitor to the mice with 30-day-old memories right after re-exposure to the feared chamber. After being given this treatment, the mice were able to forget their traumatic memories as easily as the mice with 24-hour-old memories.

HDAC2 was also discovered to turn on a key group of genes called immediate early genes. These types of genes are responsible for activating other genes that are important to form new memories. Also, the researchers say this treatment increased the amount of connection between neurons in the hippocampus, which is where memories are formed, and strengthened the communication among the neurons.

"Our experiments really strongly argue that either the old memories are permanently being modified, or a new much more potent memory is formed that completely overwrites the old memory," Tsai says.

There are some HDAC2 inhibitors that are currently approved to treat cancer. Tsai believes that it is worth trying such drugs to treat PTSD. "I hope this will convince people to seriously think about taking this into clinical trials and seeing how well it works," she says.

In addition, she hypothesized that this treatment could be effective for phobias and other anxiety disorders.

To continue her research, Tsai’s lab is currently studying what occurs when memory traces are re-exposed to traumatic memories at different times. It has already been established that memories form in the hippocampus but are transferred to the cortex for long term storage. Tsai said that it appears the HDAC2 inhibitor treatment may somehow restore the memory to the hippocampus so it can be extinguished.

This study was published January 16, 2014 in the journal Cell.