March 4, 2011 | 3
It has happened to everyone. You can’t recall a name or you forget your credit card PIN number. Rather than waiting two weeks for a new one to arrive in the mail, wouldn’t it be great if there were a pill you could swallow to pop that lost memory back into your head? That is essentially what a team of neurobiologists from The Weizmann Institute of Science in Israel and SUNY Downstate Medical Center in Brooklyn have been able to accomplish in experiments on rats—enhance a dim memory by boosting an enzyme in the rat’s brain called protein kinase M zeta (PKM zeta).
Memory is easily disrupted—a bump on the head will do it. Despite the need for a drug to treat amnesia and memory loss accompanying many forms of dementia, scientists have been stymied to find a way to strengthen the formation of new memories or to improve recall of memories that have faded. Many drugs prevent memories from sticking, and there are even drugs to "erase" powerful memories of traumatic events, but so far the highly desired "smart pill" has remained elusive. Scientists reporting in the March 4, 2011 edition of Science claim to have found a new way to boost the formation of memories and to enhance recall of existing memories that have weakened.
The scientists began with a previous finding that when memories are formed, the enzyme PKM zeta is synthesized in the appropriate neurons storing the memory. They knew that if this enzyme was disrupted, memory formation was impaired. This made the researchers wonder whether increasing the amount of this enzyme in neurons could improve memory.
The memory test the scientists used in their experiments, called conditioned taste aversion, is familiar to everyone. If you should become ill after drinking a certain substance, say rum and Coke, you will develop a very strong aversion to the taste of it afterward. Such memories can last a very long time, and you don’t need to repeat the unpleasant experience to form this strong memory. The neuroscientists flavored the rat’s water with saccharin and then injected them with a harmless drug that made the rats feel ill. A few days later, when the rats were given a choice to drink the saccharin-flavored water or sip pure water, the rats strongly avoided drinking water with the sweet taste they had learned to associate with becoming ill.
Using a virus to deliver the gene that makes PKM zeta in the proper neurons, the scientists increased the amount of the enzyme in rats before training them in the taste aversion test. When tested a week later, these rats had a much stronger aversion to drinking the flavored water, indicating that they had a stronger learned association between the taste of the water and the memory of becoming ill afterward. Extrapolated to humans, a pill to boost PKM zeta levels in the human brain before studying for an exam could make it easier to learn and remember the material. But this would be of no help to people suffering amnesia, whose memories have already been lost. Could boosting PKM zeta levels after a memory had been formed and started to fade enhance recall?
To find out, the scientists increased levels of PKM zeta in the rats’ brain a week after training them to avoid the saccharine flavored water. They found that when tested a week later (two weeks after training), these rats had a much stronger aversion to the flavored water than rats that did not receive the PKM zeta after training. This is the first report of enhancing memory by a treatment given after a memory has formed.
To understand how this works, it is helpful to appreciate what memories are and how they form at a cellular level. Memories are the formation or strengthening of connections between neurons, such as connections between neurons conveying the taste of saccharine and neurons conveying the sensation of becoming ill. In learning, synaptic connections between neurons can be strengthened temporarily by chemical reactions in the synapses that make them more sensitive to stimulation, but these memories, like a phone number retained long enough to place a call, are lost rapidly. Long-term memories require building new synaptic structures, including making existing synapses more sensitive to neurotransmitter by simply adding more and different kinds of neurotransmitter receptors to the synapses. This construction job is not performed by PKM zeta, however. Instead, PKM zeta acts like a job foreman at a construction site, directing the actions of other proteins that build the cellular structures strengthening synapses.
The researchers tested the possibility that only the most recent memory was strengthened by increasing levels of PKM zeta, by training rats to avoid saccharine flavored water and then training them to avoid salt flavored water. The result was that both memories were enhanced by increasing levels of PKM zeta after training. This suggests the possibility that increasing the amount of this enzyme in neurons would strengthen every synapse on the neuron. But if every memory, no matter how important or trivial, stuck to our brain like flypaper, this could lead to chaos.
PKM zeta [yellow, image left] goes only to certain synapses (green knob-shaped structures in the figure), presumably because it is preferentially attracted to synapses storing memories temporarily, where it acts to permanently strengthen those connections and the specific memories that they hold.
This does not seem to be the case, however. By labeling PKM zeta with a fluorescent molecule, neuroscientists are able to watch through a microscope and see where the newly synthesized enzyme goes in the neuron. "What they are doing is seeing if PKM zeta goes to the specific synapses that form connections for the specific new memory," Dr. Sacktor told me referring to his future research. The preliminary results indicate that PKM zeta does not go to every synapse (see figure). The results suggest that PKM zeta goes to the particular synapses storing a memory temporarily, presumably because the chemical reactions that temporarily strengthen the appropriate synapse, tag the synapse in a way that attracts PKM zeta to it, so that PKM zeta can direct other proteins to make that memory stick.
Like a Midas, cursed by having his wish granted that everything he touched would turn to gold, permanent retention of memories could be debilitating. This is because forgetting is just as important for learning as memory. Bad habits could not be overcome; skills would not be improved, information, such as an old address or phone number, could not be updated, and traumatic events would never fade from the horror that overwhelms a person immediately after the trauma.
"We don’t know what negative consequences there would be [for a drug that would enhance memory]," Dr. Todd Sacktor, one of the corresponding authors of the paper told me. "For patients with amnesia, such as in neurodegenerative disease, the benefits might outweigh the negatives."
Although there are many different kinds of memories, which are stored in different ways and housed in different places in the brain, Dr. Sacktor sees this approach as potentially useful for all kinds of memory, not just the memory of aversive events. "Because inhibiting PKM zeta disrupts many forms of memory, I imagine it would enhance many as well."
The findings raise the age-old question of whether forgetting is the result of the record of the memory being destroyed or whether it still exists but can’t be found. "The study certainly doesn’t answer that question," Dr. Sacktor replied. "My view is that as we understand more about the molecules that participate in memory storage and recall, this argument will fade away."
The discovery of a way to enhance memory could help many people, especially those later in life experiencing cognitive decline and severe forgetfulness that can be debilitating. Many others suffer amnesia after brain injury, but drug development is not what is motivating this research. "The point of this study is to understand better how memories are stored, which is one of the most fundamental mysteries in biology."
Shema, R. (2011). Enhancement of Consolidated Long-Term Memory by Overexpression of Protein Kinase Mζ in the Neocortex Science Vol. 331 no. 6021 pp. 1207-1210 DOI: 10.1126/science.1200215
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About the Author: R. Douglas Fields, PhD, is the Chief of the Nervous System Development and Plasticity Section at the National Institute of Child Health and Human Development and Adjunct Professor at the University of Maryland, College Park. Fields, who conducted postdoctoral research at Stanford University, Yale University, and the NIH, is Editor-in-Chief of the journal Neuron Glia Biology and member of the editorial board of several other journals in the field of neuroscience. He is the author of the new book The Other Brain (Simon and Schuster), about cells in the brain (glia) that do not communicate using electricity. His hobbies include building guitars, mountain climbing, and scuba diving. He lives in Silver Spring, Md.
The views expressed are those of the author and are not necessarily those of Scientific American.