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From left, Amanda Vanhoose, graduate student, Danny Winder, Ph.D., and Carl Weitlauf, graduate student, worked on the smart mouse research paper that was recently published in Cell. (photo by Dana Johnson)

'Smart mice' offer clues to memory studies

BY: LEIGH MACMILLAN

3/16/2001 - These are not your average mice. Introduce them to plastic figures of Big Bird and Ernie, and days later they remember - better than their garden-variety cousins - that they’ve met the colorful toys.

By studying these genetically modified 'smart mice,' a multi-university team of researchers has unraveled another thread in the tangled field of learning and memory. The findings, reported in the March 9 issue of Cell, point to a potential target for treating learning and memory disorders.

The current studies are the most recent step in a long series of investigations focused on understanding which proteins play key roles in regulating nerve cell "plasticity" - the Play-doh like capacity for change in connections between neurons - and how that relates to learning and memory.

The group of researchers had previously demonstrated that a signaling molecule called calcineurin was important to learning and memory. They showed this by generating a mouse strain that makes too much calcineurin in the hippocampus, a brain area involved in learning and memory. These mice had impaired neuronal communication and had poor learning and memory, said Danny G. Winder, Ph.D., assistant professor of Molecular Physiology & Biophysics.

Winder participated in the earlier studies with Dr. Isabelle Mansuy, now at the Swiss Federal Institute of Technology, while they were both postdoctoral fellows in the laboratory of Dr. Eric Kandel, Howard Hughes Medical Institute investigator at Columbia University and co-recipient of the 2000 Nobel prize in Physiology or Medicine.

In the current work, which began in Kandel's laboratory, the investigators took the opposite approach compared to their earlier studies, Winder said. Instead of engineering mice to make too much calcineurin, they made a genetic modification that blocks the activity of calcineurin. And they made the modification inducible - the inhibitor gene that blocks calcineurin is only 'turned on' when the mice eat a drug called doxycycline.

Mansuy generated the modified calcineurin mice, and multiple investigators participated in analyzing them.

Winder and Vanderbilt graduate students Amanda Vanhoose and Carl Weitlauf examined neuronal communication in the hippocampus. When the genetic inhibitor of calcineurin was "turned on," Winder said, they found enhanced long-term potentiation (LTP), a lasting change in neuronal communication thought to reflect the cellular changes that underlie learning and memory.

Mansuy’s group tested learning and memory using a number of behavioral tasks. One of these was the "Novel Object Recognition Task" - the task that introduces the mice to Big Bird and Ernie, then tests their memory for the characters. In the test, mice first explore a cage that contains Big Bird and Ernie. After a rest period away from the characters, they explore the same cage, but now Big Bird or Ernie has been replaced with a new character. Mice that remember the objects they’ve already met spend more time exploring the “novel object, whereas mice with poorer memories must re-introduce themselves to the object they should already know.

In both this test and a spatial navigation test for learning and memory, the mice expressing the calcineurin inhibitor performed better than average mice.

"These studies address the question of whether calcineurin normally suppresses mechanisms of learning and memory, and that appears to be the case," Winder said. "Blocking calcineurin’s activity enhances the ability of the mice to learn and remember."

If the investigators turn the inhibitor gene “off” (by not feeding the mice doxycycline), the modified mice are indistinguishable from non-modified mice, Winder said.

"This is the first time that enhancement of memory has been shown to be inducible and reversible," Winder said.

A different strain of previously reported 'smart mice' had a genetic modification that was active early on in development. Such a mutation, Winder said, could affect the development and wiring of the brain, and consequently affect learning and memory. Because the current studies use an inducible mutation, the investigators can leave the modified gene "off" until the mice are adults, thereby avoiding potential developmental changes, he said.

"Our studies show that you can genetically enhance learning and memory acutely, so it doesn't require prolonged interaction between genetics and the environment," Winder said. "Calcineurin now becomes a tractable pharmacological target for things like age-related memory loss. Calcineurin inhibitors might make good memory enhancing drugs."

Another advantage of the inducible genetic system, Winder added, is the ability to use it to tease apart learning from memory. For example, the calcineurin inhibitor gene could be left “off” while the mice learn a task and could then be “turned on” to see its effects on subsequent memory tests. Mansuy plans to pursue these kinds of studies.

The work was supported by the Swiss Federal Institute of Technology, the Howard Hughes Medical Institute, and the Whitehall Foundation.

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