UTM researchers identify protein that could lead to future PTSD treatments for women

Post-traumatic stress disorder, or PTSD, doesn’t affect only men. In fact, although it has long been associated with male soldiers returning from traumatizing experiences in war zones, women have double the risk of developing the disorder. One in 10 women will experience PTSD in her lifetime, following a trauma such as domestic violence, sexual assault or childhood abuse, and in women the condition is more debilitating and prolonged than in men. In trying to understand why, a team at U of T Mississauga’s department of psychology has found a possible clue – a link between fear memories and a certain protein in the brain that affects males and females differently.

This protein, a histone variant called H2A.Z, has been implicated in memory, so the team decided to test how lowering H2A.Z might affect accompanying fear responses. Under the supervision of assistant professor Iva Zovkic, the researchers conducted a series of experiments with male and female mice, some of whom had been modified to have the H2A.Z in their brains reduced or deleted.

After being put in a chamber and allowed to explore, the mice received a mild stressor. The next day, when put back in the same chamber, all the mice showed a fear response, freezing in place instead of doing their usual exploring, suggesting that they remembered the previous day’s stressor. The male mice who’d had their H2A.Z knocked out showed greater fear responses than the control male mice, but there was no difference between the two female groups.

The team was intrigued. “We weren’t initially planning to look at PTSD specifically,” says postdoctoral fellow Firyal Ramzan, who conducted the experiments, which stemmed from her PhD work. “But when we saw the initial sex differences between males and females with the simple fear conditioning test, we thought, ‘Hey, maybe there’ll be a difference if we were to make the stimulant more aversive, using a PTSD paradigm.’” They ramped up the stressors to create a mouse model of a PTSD-triggering situation, so the mice now received multiple mild stressors, spaced randomly over the course of an hour. Returned to the same chamber the next day, researchers measured the mice’s fear response based on their activity levels.

While there was no difference among the male mice between the lower-H2A.Z group and the control group, there was a significant difference in the females: those who’d had their H2A.Z knocked out showed markedly reduced fear responses compared to the controls.

“We think that removing H2A.Z may act as a protective factor in females, but not in males,” says Ramzan. That protective effect extended to pain sensitivity too; the low-H2A.Z female mice had higher pain thresholds, an effect not shown in the males. The researchers had expected to see a difference between the sexes but were surprised to see how stark the differences were.

The female mice’s brains showed increased H2A.Z binding at specific genes in the hippocampus region, an indicator that there may be more H2A.Z in female brains in general. The researchers are now investigating how the protein interacts with estrogen and other sex hormones. Understanding more about those interactions could lead to future PTSD therapeutics that specifically target H2A.Z.

“This was super exciting to see how removing H2A.Z had such a beneficial effect on the females,” Zovkic says. “And we saw no long-term negative effects.” The study was recently published in the journal Nature.

“To me, the most exciting thing is knowing, even at the molecular level, that sex differences exist and can affect behaviour,” says Ramzan. “It really speaks to the importance of needing to study both males and females at the animal level, and multiple genders in human studies.”

This research was supported by NSERC Discovery Grant, NSERC Discovery Accelerator Supplement, and CIHR PJT-156414 to IBZ and NSERC Postgraduate Doctoral Scholarship to FR.