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Research Reveals Key Molecular Players in the Erasure of Fear Memories

Summary

Research in mice suggests that manipulating a single molecule might help eliminate fears that have been etched into memory.

The ability to erase certain memories—even traumatic ones—may seem like something out of a science fiction movie, but new research in mice suggests that manipulating a single molecule might help eliminate fears that have been etched into memory.

The finding suggests that a combination of behavioral and pharmacological therapies aimed at that molecular target might one day be used to help people who suffer from post-traumatic stress syndrome. The new study is published online October 28, 2010 in Science Express, and conducted by Howard Hughes Medical Institute investigator Richard Huganir and postdoctoral fellow Roger Clem at the Johns Hopkins University School of Medicine.

We have some ideas about how to reopen that window even though it's months after they've been exposed to the trauma.

Richard L. Huganir

In the study, Huganir and Clem created a fearful memory in healthy mice by playing an audible tone that was immediately followed by a brief electric shock to the mouse’s feet. After a day of training, the animals had learned to respond to the tone alone with a fearful freezing response.

When Huganir and Clem examined the brains of the trained mice, they found that neurons in the animals’ amygdala—a brain area that controls fear and anxiety—showed some intriguing features. As expected, connections between neurons appeared to strengthen soon after the fearful memory formed. But the researchers also found that a specific receptor, called calcium permeable AMPA, was more active in the amygdala for a short window of time.

In particular, beginning about 24 hours after the fearful memory is created, the calcium permeable receptors replace a more common type of AMPA receptor in the amygdala are in the newly strengthened connections, or synapses, between neurons. "Remarkably, the synaptic strength remains the same but the receptors have just exchanged," Huganir says. Seven days after the initial memory develops, the calcium permeable AMPA receptors disappear although the synapses remain strong.

No one had observed calcium permeable receptors in these particular neurons before, but Huganir's team had been studying them for years in other regions of the brain. AMPA receptors—which help neurons receive excitatory signals from their neighbors—are prevalent throughout the brain, but only five to 10 percent of them are calcium permeable AMPA receptors. In a separate line of work, Huganir's team had studied their role in regulating synapses in brain areas that are involved in motor control and the sense of touch.

While Huganir and Clem were investigating the appearance of the calcium permeable receptors, another group of scientists published a potential behavioral therapy for eliminating fear memories in rodents. In those experiments, timing was critical: The researchers exposed the animals to the tone without the shock a day after creating the initial fear memory, and found that they could eliminate the fearful freezing response in mice.

Huganir and Clem hypothesized that the behavioral therapy might work by eliminating calcium permeable AMPA receptors, and indeed, they were correct. The presence of the receptors hints that there's a window of time in which the brain is especially sensitive to behavioral therapy.

In the study published in Science Express, Huganir’s team also found that removing the receptors and erasing memories during behavioral therapy requires activation of a related receptor called metabotropic glutamate receptors or mGluR1, which processes excitatory signals between neurons. It might be possible to combine behavioral therapy with drugs that enhance mGluR1 activity, Huganir says. Drugs that target metabotropic glutamate receptors are being developed by pharmaceutical companies to treat a variety of conditions, and some appear relatively specific and non-toxic, he adds.

Huganir and Clem are now working to sort out whether they can expand or reactivate the short time window of vulnerability for the formation of fearful memories—by recreating the context in which the memory was formed, for example. This approach might yield insights that could help in cases where soldiers returning home from a long tour of duty start to show symptoms of PTSD. "We have some ideas about how to reopen that window even though it's months after they've been exposed to the trauma," Huganir says.

Scientist Profile

Investigator
The Johns Hopkins University

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Jim Keeley
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