Memory-Erasing Drug May Help PTSD

Researchers have discovered a drug that may eventually help combat the symptoms of posttraumatic stress disorder (PTSD). Using a combination of re-exposure–based behavioral training and histone deacetylase 2 (HDAC2) inhibitor treatment, they found that it is possible to extinguish remote fear memories in mice. PTSD is an anxiety disorder stemming from a previous traumatic event. Despite the serious nature and high prevalence of this condition, there are limited effective strategies to weaken long-term traumatic memories. Psychotherapy is often used to treat PTSD, but it is not always effective, especially when the traumatic event occurred many years earlier. “Many people suffer from anxiety disorders,” said senior author Li-Huei Tsai, PhD, Massachusetts Institute of Technology, Cambridge, MA. “Our study provides a new target for therapeutic intervention.” Researchers began the process of ascertaining whether traumatic memories could be attenuated with a drug treatment by training mice to fear a specific chamber in their habitat with the administration of a mild electric shock to their feet when they entered that area. Tsai and colleagues attempted to recondition the mice to no longer fear that same chamber when they were placed in it without the administration of the electric shock. The mice with 24-hour-old memories of the electric shock were able to be reconditioned, whereas those whose memories were 30 days old could not be reconditioned. It was also discovered that extensive chromatin remodeling occurred in the brains of mice with 24-hour-old memories while they were being retrained. For several hours after these mice were placed in the chamber with no electric shock, a dramatic increase in histone acetylation of memory-related genes occurred, which was caused by inactivation of the HDAC2 protein. This process is believed to enable a person to overwrite old memories or form new memories. Tsai and colleagues observed that this did not occur in mice with 30-day-old memories of the electric shock, however. “We find that, whereas recent memory recall induces a limited period of hippocampal neuroplasticity mediated, in part, by S-nitrosylation of HDAC2 and histone acetylation, such plasticity is absent for remote memories,” the authors write. Researchers then administered an HDAC2 inhibitor to mice with 30-day-old memories shortly after they were placed in the feared chamber, and they discovered that the traumatic memories were attenuated in this group just as they were in the group with more recent memories of the electric shock. In addition, the HDAC2 inhibitors activated other genes necessary for memory formation and caused an increased number of connections among neurons in the hippocampus. The communication among those neurons was also strengthened. These findings indicate that “using small molecules to modulate chromatin modifying enzymes and neuroplasticity gene expression can be beneficial for relieving the symptoms of fear and anxiety,” explained Tsai. According to Tsai, researchers were surprised by the fact that re-exposure of short-term memories—but not long-term memories—can activate the chromatin and neuroplasticity gene expression and that it is possible to extinguish remote memories following a combination of HDAC2 inhibitor treatment and behavioral training. Although they do not currently know whether similar treatment works in people, this drug may eventually be a treatment option for patients with PTSD. “I hope that the HDAC inhibitor treatment will be evaluated in human patients,” she said. In terms of future research, “We would like to know how HADC inhibitor treatment affects brain regions other than the hippocampus, and we want to evaluate other brain regions including the amygdala and the prefrontal cortex,” noted Tsai. This study is available in Cell. -Meredith Edwards White Reference Gräff J, Joseph NF, Horn ME, et al. Epigenetic Priming of memory updating during reconsolidation to attenuate remote fear memories. Cell. 2014;156(1-2):261-276.