It can be a good thing to forget, especially when learned information becomes useless or overly troubling. Yet the mechanisms by which we forget are a mystery: Is forgetting a passive reversal of learning, or must the brain make an effort to purge memories? A new study on forgetting in fruit flies suggests the latter. In a paper published in the February 19 issue of Cell, Yi Zhong and colleagues at Cold Spring harbor Laboratory, New York, present evidence that forgetting of newly formed memories is an active process that depends on signaling through the small GTP-binding protein Rac. The researchers show that activating Rac activity can cause flies to forget recently learned odor-stimulus pairs more quickly, while inhibiting Rac causes the memory to linger. Rac is well known for its key role in cytoskeletal organization, and the study points to changes in actin polymerization as an important determinant of the persistence, or loss, of memory.
Although the work was done in flies, the results might have some relevance to humans, perhaps even to Alzheimer disease. Previous studies implicate Rac or its downstream partners in forgetting in mice (see ARF related news story on Sananbenesi et al., 2007 and Meng et al., 2002). Alterations in the Rac signaling pathway induced by Aβ oligomers have been tied to synaptic defects (Ma et al., 2008, and see ARF related news story on Zhao et al., 2006), and lack of Rac activation leads to dendrite loss in cells expressing presenilin mutants (see ARF related news story on Inoue et al., 2009).
To try to understand how flies forget, Zhong and colleagues started by screening for mutants with enhanced early memory (memory that can be measured after a single training session and decays within a few hours), reasoning that these flies might have defects in forgetting. After repeatedly finding genes that converged on the Rac signaling pathway, first author Yichun Shuai and coworkers set out to test the role of Rac itself through targeted expression of dominant mutants of either constitutively active or inactive Rac alleles. They found that inhibiting Rac in a subpopulation of mushroom body neurons could prolong the retention of an odor aversion memory for hours to days. On the flip side, increasing Rac activity accelerated memory decay. Rac had no effect on learning, and it modulated forgetting that occurred by passive decay, or by active training on a new odor. In support of a physiological role for Rac, the researchers showed that endogenous Rac is activated in fly neurons after training with a time course that coincides with forgetting.
Rac regulates many downstream effects in neurons, including cytoskeleton organization, and dendritic spine morphogenesis (Tashiro and Yuste, 2004), a process which may form the anatomical basis of memory (see ARF related news story). To investigate whether the rearrangement of the actin cytoskeleton was critical to Rac’s actions, the authors looked at the effects of mutating cofilin, an actin de-polymerizing factor that sits downstream of Rac. In the pathway, Rac activates the kinase PAK, which activates a second kinase, LIMK, which phosphorylates and inactivates cofilin. Shuai and colleagues showed that expression of a constitutively active cofilin mutant inhibited memory decay, similar to the effect of Rac inhibition. In addition, a Rac mutant that was unable to activate the PAK/LIMK pathway did not affect memory decay. The results argue that the Rac effect is specific, goes through PAK/LIMK/cofilin, and may involve actin-based changes in cell or dendrite morphology.
In an accompanying preview, Ronald Davis of the Scripps Research Institute in Jupiter, Florida, writes that Shuai and colleagues “have ushered in a completely new line of research—the cell biology of active forgetting.” Among the questions the study raises is whether Rac plays a role in forgetting only in transient memory, or in other types as well. Davis points out that the effect of Rac inhibition to increase memory in flies by increasing cofilin activity and thus presumably decreasing actin filament formation goes opposite to accumulated data showing that long-term potentiation and memory consolidation in mammals is promoted through actin polymerization. It remains to be seen if this discrepancy arises because of an incomplete understanding of the signaling systems involved, or because different stages of memory require different cytoskeleton arrangements, he writes.
Zhong says his group is very interested in looking at exactly what is happening at the dendritic level in flies during early memory and its reversal. In addition, he says, they are probing whether Rac can reverse long-term memories by targeting constitutively active Rac to the neurons responsible to see if that will erase consolidated memories. “We think that in neurons for long-term memory, there may be no such mechanism, and that is why the memories stay,” he said.
Greg Cole of the University of California at Los Angeles has studied the Rac/PAK/LIMK pathway in AD. He is not surprised that Rac, a protein that regulates multiple pathways related to synaptic plasticity in neurons, can affect memory, including memory decay rates. “The idea that increased Rac activity can accelerate memory decay is consistent with some Aβ effects where Aβ activates Rac,” he wrote in an e-mail to ARF. However, Cole continues, “I see Rac and downstream PAKs as central to too many processes to be good candidates for direct inhibition. Since Rac is normally inhibited by ser71 phosphorylation by Akt, my lab has looked at treatments like DHA and cocktails that can increase this natural inhibition in a more modulatory way. Other ways of increasing this may include exercise to increase of BDNF or other methods of improving insulin/neurotrophic factor coupling to Akt, which is uncoupled by IRS hyperphosphorylation in AD neurons. What we need is restoration of normal controls on Rac activity, including trophic factor control of inhibitory Akt input and less activation by Aβ.” (See further comment and citations below.)
Zhong reports that his lab is also starting to look at how Rac might affect memory in the context of Alzheimer’s, using their own fly model of Aβ pathology (see ARF related news story on Iijima et al., 2004).—Pat McCaffrey
- Memories—Familiar Kinase, Cdk5, Limits Fear Extinction
- AD Pathology—Loss of Kinase Sends Synapses PAKing
- γ-Secretase Drives Spine Formation Via Novel Substrate
- Persistence of Dendrites Leads to Lifelong Memories
- What the Fly Forgot—Aβ Expression in <i>Drosophila</i>
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