Blocking a protein can erase long-term memory

Prof. Yadin Dudai's research may be the first time memories have been erased so long after their formation.

By JUDY SIEGEL-ITZKOVICH
Elderly 224.88 (photo credit: Sasson Tiram [file])
Elderly 224.88
(photo credit: Sasson Tiram [file])
Are memories recorded in our brains as a stable physical change, like an inscription on a clay tablet? Weizmann Institute of Science neurobiology chairman Prof. Yadin Dudai and colleagues think not. They recently discovered that the storing of long-term memories involves a molecular machine that operates constantly to keep memories going; "jamming" the machine erases memories. Their findings, which appeared recently in Sciencea, may pave the way to treatments for memory problems. Dudai and research student Reut Shema, together with Todd Sacktor, of the State University of New York's Downstate Medical Center, trained rats to avoid certain tastes. They then injected a drug to block a specific protein into the taste cortex - an area of the brain associated with taste memory. They hypothesized, on the basis of earlier research by Sacktor, that this protein (an enzyme called PKMzeta) acts as a miniature memory machine that keeps memory up and running. An enzyme causes structural and functional changes in other proteins: PKMzeta, located in the synapses (the functional contact points between nerve cells) changes some facets of the structure of synaptic contacts. It must be persistently active, however, to maintain this change, which is brought about by learning. Silencing PKMzeta, the scientists theorized, should reverse the change in the synapse. And this is exactly what happened: Regardless of the taste the rats were trained to avoid, they forgot their learned aversion after a single application of the drug. The technique worked as successfully a month after the memories were formed (analogous to years in humans), and all signs so far indicate that the unpleasant memories indeed disappeared. This is the first time memories have been erased so long after their formation. "This drug is a molecular version of jamming," says Dudai. "When the machine stops, the memories stop as well." In other words, long-term memory is not a one-time inscription, but a process that the brain must fuel continuously. These findings raise the possibility of developing drug-based approaches for boosting and stabilizing memory. Dudai notes that the question of how memories are retained over long periods is still unresolved: Most studies on the biological bases of long-term memory storage focused till now mostly either on simple preparations, such as the nervous systems of invertebrates, or on slices taken from a particular brain region called the hippocampus. Most of these studies analyzed cellular changes that take place over days only, and tried to correlate them with memory. However, the Rehovot team proved that new items in memory do not consolidate into an amnesia-resistant form within hours or days after encoding, as was thought so far, but remain sensitive to an amnesic agents long after learning ends. "We also show that an enzyme, PKMzeta, has to remain active for long-term memory to survive. This enzyme can therefore be dubbed 'a memory keeper,'" says Dudai. Shutting off the "memory keeper" in the cortex of a rat seems to rapidly erase long-term memory. "We showed that the inhibitor can disrupt memory, and probably even erase it, at least several weeks after learning," he says. The researchers detected no evidence for memory return, which led them to suggest that inhibition of PKMzeta in the cortex might practically erase memory. However, "we do not yet know whether PKMzeta is a memory eraser after more than a month. All this means that long-term memories are prone to disruption even long after their presumed consolidation window is closed, contrary to what most people thought. Furthermore, our results show that memories require continuous activity of an enzyme; the minute that enzyme is blocked, memory may collapse. What we do with our inhibitor resembles placing a stick in the wheels of a molecular machine; when the machine stops running, the taste associations that rat has learned quickly disappear." The Weizmann studies deal with the rat - and not human - brain. "We usually assume that the basic neural mechanisms in the rat brain and in the human brain are rather similar. But first of all we must probe further the applicability of our findings to other types of memory in the rat and to other areas of the rat cortex. We predict that our results are not confined to taste associations, but in science, the data have the final say. The team's findings," he concludes, "could contribute to a new pharmacology that targets the 'memory keeper' and in doing so, new drugs to repair or enhance memory might be developed in the future." TECHNION EXCELLENCE The Technion-Israel Institute of Technology in Haifa has been rated 38 among the world's best technological and engineering universities by Shanghai Jiao Tong University in China. The Technion thus beat out most universities in Europe except for Cambridge in the UK (#16), Imperial College London (#27) and the Technological University in Lausanne (28). The Haifa institution also came ahead of countries with a long tradition of engineering and technology like Germany, France, Holland and Italy. All the first 15 places are held by universities in the US, with the Massachusetts Institute of Technology chosen for the top place. Stanford and the University of Illinois were second and third, while Harvard - #1 in a separate rating of general universities - was only #35 on the technology/engineering scale. Technion president Prof. Yitzhak Apeloig expressed satisfaction at the institution's being among the top 40. "We reached this despite repeated government budget cuts, to the Technion specifically and to higher education in general. This is thanks mostly to Friends of the Technion around the world, giving us the ability to employ talented young faculty members, to establish the Russell Berrie Center for Nanotechnology Research and the Zisapel Center for Nanoelectronics Research, and others. But this rating reflects mostly the successes of the past; if there is no change in government policy, we will drop out of the Top-40 list. This would have serious effects on the Israeli economy in general and specifically on the hi-tech sector. I hope the government realizes that the future of Israel is in higher education, and that it will adopt the Shochat committee recommendations to restore education budgets to the institutes of higher education and put education at the head of the list of national priorities."