CNCR scientists find cellular mechanism shaping fear memories

12 September 2011

PhD students Priyanka Rao-Ruiz and Diana Rotaru from the MCN and INF departments (CNCR, NCA) publish their findings about the molecular and cellular mechanism of dynamic memory processing in Nature Neuroscience.

Brain receptor availability allows memory adaptation
Upon retrieval, memories, including those of fearful occurrences, return to a receptive state of several hours that allows memories to be “rewritten‚, namely altered in strength and even content for future retrieval. This feature can be exploited in psychotherapy aimed at treating disorders related to traumatic memories. PhD students Priyanka Rao-Ruiz and Diana Rotaru discovered a prime molecular and cellular mechanism that underlies this adaptive process of fear memory in mice. “We show that precise levels of a specific glutamate receptor in the hippocampus, the brain area involved in the encoding of memory, explains that memories are not graved in stone, but rather that they are adapted every time you remember them‚ says Sabine Spijker, head of the research team.

Molecular mechanism of fear expression
As behavioral-read out for memory they used the fear response of mice that previously had learned to associate their presence in a specific box with an aversive stimulus. When placed back in the box, mice retrieve this fear memory and show this by periods of total lack of movement, so called ‘freezing’ behavior. The researchers measured post-synaptic AMPA receptor expression after such a memory recall and showed that during a period of only four hours, hippocampal AMPA receptors are gradually internalized from post-synaptic membranes. This causes a change in the efficacy of synaptic communication, a process known to be part of the cellular analogies of learning and memory. Spijker: “The period of AMPA receptor internalization mirrors the time window in which the memory is susceptible to modification. The next step was to prevent AMPA receptor internalization and to see the consequences for behavior. When doing so, this results in enhanced expression of this ‘freezing’ behavior during the following hours to days after memory recall, showing the involvement of the AMPA receptor in this process.‚

Permanent erasure of fear
Moreover, the researchers showed that the glutamate receptor internalization, provoked by retrieval of the memory can also adapt the memory in the long-term. A major obstacle in behavioral therapy is the spontaneous return of fear after months or years. Recently, a new form of behavioral therapy was discovered that specifically utilizes such a short memory recall session in conjunction with conventional therapy sessions to successfully treat both rodents and humans from fearful memories. Spijker: “We now show that the AMPA receptor internalization is key to allow for such a form of therapy to take place. Mice in which AMPAR internalization was prevented show a spontaneous return of fear after weeks. Thus, timing and place of a few glutamate receptor proteins might make the difference between a normal life, and a life in permanent fear.‚

Together, this study shows that precisely timed synaptic plasticity, in the form of internalization of AMPA receptors, causally underlies the adaptive nature of fear memory processing. Spijker: “Understanding the biological underpinnings of memory dynamics, and of this adaptive process in particular, could possibly be further exploited to treat disorders related to traumatic memories.‚

AMPA receptors are dynamically regulated after memory recall in the hippocampus. Shown here is the amount of protein expression (immunoblot; left), as well as function (miniature evoked post-synaptic currents; right).

Retrieval-specific endocytosis of GluA2-AMPARs underlies adaptive reconsolidation of contextual fear
Priyanka Rao-Ruiz, Diana C. Rotaru, Rolinka J. van der Loo, Huibert D. Mansvelder, Oliver Stiedl, August B. Smit, Sabine Spijker

Kevin Janssen