Published online 3 March 2011 | Nature | doi:10.1038/news.2011.134

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Research paves way to adjusting recall of events.

Boosting an enzyme could help make old memories stronger.

Precious memories need not fade if a report today bears fruit. Neuroscientists have successfully strengthened old memories in rats, according to research published today in Science1.

A handful of substances can strengthen memories as they're being made. But a greater aim for neuroscientists is to learn how to enhance existing, older memories, such as where you live or your grandson's name — memories often lost because of dementia or amnesia.

"Finding out what perpetuates long-term memory has been a real challenge," says Todd Sacktor, a neuroscientist at SUNY Downstate Medical Center in New York and an author on the paper. "What's special here is we've found a way to make old memories stronger without interfering with them as they're formed or recalled."

When a memory is made, new connections, or synapses, form between brain cells. To keep the memory, that synapse must endure. Scientists don't yet know exactly what strengthens these synapses to keep memories stable over time, but there are some clues. In 2007, Sacktor and his colleagues erased long-term memories that rats had formed weeks earlier using a drug that inhibited the enzyme protein kinase Mζ (PKMζ)2.

Doubts laid to rest

In the current study, the researchers alleviated some neuroscientists' concerns about the specificity of the PKMζ-blocking drug by using genetic tools in rats to disrupt PKMζ and also boost the enzyme in the neocortex, a presumed repository for long-term memory storage in the brain.

One week after rats fell ill from drinking sweet, lithium-laced water, they were given injections containing genetic elements that would either block or increase the activity of PKMζ. Rats with abundant PKMζ in their neocortices seemed to remember that sweet water caused illness. They hardly touched the sweet water when they were served it again a week after the injection — far less so than untreated rats. Meanwhile, rats with reduced PKMζ activity drank thirstily. The same thing happened with salty, lithium-laced water given a week before the treatment and again a week after.

"I'm a believer now," says David Glanzman, a neuroscientist at the University of California, Los Angeles. "I was cautious at first, but this study is impressive because they've specifically altered levels of the kinase."

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Lead author Yadin Dudai, a neuroscientist at the Weizmann Institute of Science in Rehovot, Israel, says that PKMζ is persistently active for months — or longer — after animals learn. Without it, memories of those lessons won't stick. The enzyme seems to modify proteins at synapses that receive information from chemical messengers called neurotransmitters. In doing so, says Dudai, PKMζ probably increases the sensitivity of the synapse to neurotransmitters and facilitates memory recall.

Other established memories were probably also strengthened by the PKMζ boost, says Dudai. Thus, targeting the enzyme could one day lead to long-sought treatments for diseases in which established memories grow dim. Conversely, blocking it might help people with post-traumatic stress disorder to forget a damaging experience.

However, neuroscientists must first find ways to target only good memories or only the bad. "Treatments that will enhance or inhibit memories are just around the corner," says Glanzman. "What will be tough is finding the needle of a specific memory in the synaptic haystack of a human brain."