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Memory-sustaining Enzyme May Help Treat PTSD, Cognitive Decline

Rat Memory Eraser Study Challenges Prevailing Theories

Science Update

Chemically blocking an enzyme in a specific area in the brain’s cortex, or outer mantle, erased a long-term memory of an aversive event that rats had learned, a study funded in part by NIMH has found. The erasing occurred even if the blocking agent was administered weeks after the event and appeared to be permanent.

This and related discoveries suggest that the enzyme, known as PKMzeta, may be required for sustaining memories throughout the brain. Most current theories instead hold that long-term memories are encoded as enduring structural changes in the connections between neurons – and thus would not be chemically erasable.

“If PKMzeta gives memories their staying power, it might be an ideal target of new therapies for disorders of memory,” suggested NIMH grantee Todd Sacktor, M.D., of the State University of New York Downstate Medical Center. “For example, perhaps traumatic memories associated with post traumatic stress disorder (PTSD) could be selectively erased by blocking the enzyme. Or perhaps boosting the enzyme action could enhance memory generally for those with mild cognitive impairment.” 

Sacktor and colleagues Reut Shema and Yadin Dudai, Ph.D., Weizmann Institute of Science, reported on their discovery in the August 17, 2007, issue of Science.

Last year, Sacktor and colleagues showed that PKMzeta is required for a process underlying initial formation of long-term spatial memory. Blocking this enzyme in the hippocampus, a memory hub, erased rats’ conditioned fear of spaces associated with getting shocked. But little was known about the enzyme’s role in the cortex, where most memories are thought to be stored long-term.

To learn more, the researchers conditioned rats to persistently shun the taste of saccharin by pairing it with lithium, which triggers nausea in the animals. But the rats’ sweet tooth returned within two hours after the researchers infused a PKMzeta-blocking drug called ZIP into the rats’ seat of taste memory, known as the insular cortex. ZIP erased the taste aversion even when it was given 25 days after the rats were conditioned. Also, it worked only retroactively – injecting it before conditioning did not prevent the rats from learning the association later, indicating that the drug did not damage the cortex’s memory-sustaining capacity. However, all long-term association memories in the affected cortex area were likely erased, according to Sacktor.

Until now, enzyme action was thought to play a major role only in the initial making of memories, allowing structural changes in synapses, the connections between neurons, to handle the task of long-term storage. In an earlier study, Sacktor and colleagues found that PKMzeta appeared to work by doubling a type of receptor for the chemical messenger glutamate at synapses. When the enzyme was blocked, the receptors receded, perhaps erasing the memories.

“This provides a clue that the structural changes encoding memories are smaller in scale, more fragile than had been thought, and require continuous enzymatic activity,” said Sacktor.

He added that the new findings suggest a possible way to turn to advantage the counter-intuitive, but well documented, phenomenon that a memory becomes more vulnerable to being lost when it is retrieved from long-term storage.* If storage requires PKMzeta, then blocking the synthesis of specific PKMzeta molecules encoding a retrieved traumatic memory might prevent the memory from re-entering long-term storage and relieve PTSD symptoms, suggested Sacktor.

3D rendering of a PKMzeta molecule.

3D rendering of PKMzeta molecule.

Source: Todd Sacktor, M.D., SUNY Downstate Medical Center

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one day retention ZIP injected rat (shock off)

In an earlier study, injecting the hippocampus with ZIP, an inhibitor of the PKMzeta enzyme, erased memory in rats conditioned to avoid an area (stationary slice of spinning chamber highlighted at top) in which they had received a mild shock. The new study extends this finding to the cortex and suggests that PKMzeta may be required more generally in the brain for sustaining memories. In this video, the rat is first shown prior to training. Next, the animal is conditioned to avoid the highlighted area, which turns red when the shock is on. In the third segment, the conditioned rat avoids the area after a saline solution injection. In the fourth segment, after a ZIP injection erases the memory, the rat enters the shock zone, having forgotten the learned association.

Source: Todd Sacktor, M.D., SUNY Downstate Medical Center

Shema R, Sacktor TC, Dudai Y.  Rapid erasure of long-term memory associations in the cortex by an inhibitor of PKMzeta. Science. 2007 Aug 17;317(5840):951-3. PMID: 17702943

Pastalkova E, Serrano P, Pinkhasova D, Wallace E, Fenton AA, Sacktor TC . Storage of spatial information by the maintenance mechanism of LTP. Science. 2006 Aug 25;313(5790):1141-4. PMID: 16931766

* Doyere V, Debiec J, Monfils MH, Schafe GE, LeDoux JE . Synapse-specific reconsolidation of distinct fear memories in the lateral amygdala. Nat Neurosci. 2007 Apr;10(4):414-6. Epub 2007 Mar 11. PMID: 17351634