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Jan 30, 2014
 |  BC Innovations  |  Targets & Mechanisms

PTSD: rewriting fearful memories

A Massachusetts Institute of Technology-led team has outlined a strategy for addressing the underlying causes of post-traumatic stress disorder.1 The approach centers on blocking histone deacetylase 2, which is the only class I histone deacetylase target with a growing body of evidence suggesting a role in learning and memory.

Future studies will need to identify a selective histone deacetylase 2 (HDAC2) inhibitor and determine its optimal human dosing to avoid unwanted effects on memory.

Post-traumatic stress disorder (PTSD) is caused by a traumatizing event that the individual re-experiences episodically when environmental or situational cues trigger its recollection. Approved PTSD drugs help manage the anxiety associated with the traumatic memory and include antidepressants or anxiolytics, sometimes in combination with atypical antipsychotics.

Behavioral approaches include exposing the patient to the trauma-associated cues in a safe setting. This allows the patient to reinterpret those cues as neutral and thus develop reduced anxiety responses to them-a process known as extinction.

Neither drugs nor behavior therapy alters the underlying memory of the original trauma that triggers PTSD episodes. Moreover, patients may be averse to recalling the traumatic event and thus may not complete the series of exposure therapy sessions needed for extinction.

Over the past seven years, multiple groups have shown that inhibitors of class I HDACs improved the effectiveness of extinction protocols in fear-conditioned mice when given a day after the completion of fear conditioning.2-7

These studies did not examine the effect of combining class I HDAC inhibition and extinction protocols in mice several days or weeks after fear conditioning-an approach that would more closely model human PTSD.

Thus, the role of class I HDACs in the extinction of anxiety responses to long-term traumatic memories was poorly understood.

That began to change in 2009 and 2012 when teams led by Li-Huei Tsai showed that HDAC2-but not other class I HDACs-blocked memory formation in mice8 and contributed to long-term memory impairment in patients with Alzheimer's disease (AD).9

Also in those studies, Hdac2 reduced memory deficits in the normal mice and mouse...

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