Mice With Single Neuronal Gene Turned Off Are Smarter

DALLAS, May 30 -- Mice missing a single key gene in their brain tissue are smarter than the average mouse, researchers here have found.

The discovery, made using a technique for turning off a gene in adult mice, may have implications for understanding -- and possibly treating -- a range of human cognitive disorders, according to James Bibb, Ph.D., of the University of Texas Southwestern Medical Center.

"It's pretty rare that you make mice 'smarter,' so there are a lot of cognitive implications," Dr. Bibb said.

The key player in the experiments is a neuronal protein called cyclin-dependent kinase 5 (or Cdk5), which has been implicated in many human cognitive disorders, Dr. Bibb and colleagues reported online in Nature Neuroscience.

But the function of the protein has been difficult to tease out, because mice born without the gene that codes for it have congenital abnormalities and perinatal lethality, the researchers said.

To get around that, they used a genetic engineering technique called conditional knockout, in which the gene for Cdk5 was linked to a gene that turned it off when the mice were given the estrogen receptor antagonist hydroxytamoxifen.

The transgenic mice developed normally, but when they were given the drug levels of Cdk5 in their brains dropped between 45.7% and 73.8% depending on which tissues were sampled.

"Being able to turn a gene off throughout a brain is a really advanced thing to do," Dr. Bibb said. "It's been shown that it can be done, but we put the system together and actually applied it."

But the big finding was that the knockout mice learned more quickly than their wild-type cousins in a range of standard cognitive tests, he said.

For instance, they were put in a cage that gave them shocks through their feet. When they were put back in the cage later, the knockout mice were significantly more likely to freeze in anticipation (P<0.001) than were control mice.

In another experiment, the mice were trained to find their way through a water maze to a submerged platform, using distant visual cues. Once they learned where it was, the researchers moved the platform and retrained the mice to find it.

The knockout mice were significantly faster (P<0.05) at finding the new location, Dr. Bibb and colleagues found.

The researchers said the enhanced learning ability appears to be linked to reduced degradation of NMDA receptors in the brain -- a process in which Cdk5 plays a role.

The NMDA receptors, which involve glutamate, and thought to play a role in synaptic plasticity, which is a cellular mechanism for learning and memory.

Indeed, the researchers said, the increased learning and memory abilities of the knockout mice were reversed when they were treated with NMDA receptor antagonists -- mimicking the normal role of Cdk5.

Dr. Bibb and colleagues cautioned that the long-term effects of removing the protein from brain tissue are still being studied. But Dr. Bibb said the finding suggests possible "biochemical targets that hold promise for future treatments of a variety of cognitive disorders."