Bad memories

Good memory could have a downside, as US researchers have found that genetically-engineered "smart mice" are more sensitive to chronic pain.

The mice had their genes tweaked and appeared to learn faster and remember better. Their creators dispute the discovery of increased pain sensitivity, arguing that the animals just remember injuries for longer.

Neuroscientist Ted Abel, from the University of Pennsylvania, says it is hard to tell who is right. He points out that it's even possible that the smart mice are not smarter at all, just more sensitive to pain.

"In the test they learn to avoid an electric shock," he says. "If they respond to pain more, the shock will be more effective and so they will appear smarter."

The confusion illustrates the problems associated with trying to improve memory in humans. Abel says Vietnam war veterans with post-traumatic stress disorder show the harm caused by an overly vivid memory. "The war was 25 years ago but when they see a helicopter they run for cover," he explains. "Their memory is extremely good, but it's pathological."

Opening the gate

The smart mice were originally created by Joe Tsien and his colleagues from Princeton University in New York. They engineered the animals to make extra copies of a brain receptor subtype called NMDA.

Memories in the brain are thought to consist of clusters of neurons that activate simultaneously when the memory is recalled. NMDA acts like a gate, only activating the neurons if it receives at least two signals from other neurons. The most common subtype of NMDA in adult mouse brains is NR2A, but new-borns have mostly NR2B and this holds the gate open for longer.

Tsien's smart mice have extra copies of NR2B, and perform better in tasks such as learning to avoid mild electric shocks (New Scientist, 4 Sep 99, p 15).

But Min Zhuo and his colleagues from the Washington University School of Medicine now report the mice are overly sensitive to prolonged pain. The researchers injected formalin into animals' paws and watched how often they licked the wound.

After the first hour, the smart mice did so more often. The smart mice also had more active forebrains following the injection. "We believe that these areas of the brain are coding the unpleasantness of pain," says Zhuo.

Pain reliever

When the mice were tested for their sensitivity to acute pain, both groups of animals reacted the same. Zhuo thinks that this could make NMDA a potential target for pain relieving drugs. "We want to get rid of chronic pain, but not to affect acute pain," he says.

But Tsien doesn't agree with Zhuo's explanation of the results. He says the smart mice lick their paws more often long after the injury because of their better memories. "It is just that they haven't forgotten the injury," he says.

The increased brain activity could also be related to the injury, not the pain. "We know that the hippocampus is crucial for the formation of memory of places and events," Tsien explains.

He believes that drugs targeting NMDA could be developed to enhance memory in people whose ability to remember is deteriorating with age: "We would be restoring juvenile brain features."

Source: Nature Neuroscience (vol 4, p 164)

Joanna Marchant

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