The team of researchers, from UT Southwestern Medical Center, have conditionally knocked out a specific gene to prevent an enzyme called cyclin-dependent kinase 5 (Cdk5) from being produced, but only in the brain.
This led to the mice becoming more adept at learning and also able to more quickly decipher environmental changes.
This enzyme has been implicated in the progression of Alzheimer's disease and drug addiction and understanding how it affects the brain and behaviour might help new treatments be developed, according to lead scientist Dr James Bibb, assistant professor of psychiatry.
"It's pretty rare that you make mice 'smarter,' so there are a lot of cognitive implications," said Dr Bibb.
"Everything is more meaningful to these mice," he said.
"The increase in sensitivity to their surroundings seems to have made them smarter."
The mice were better at learning to navigate a water maze and remembering that being in a certain box involves a mild shock.
Also, when a situation changed, such as a water maze being rearranged, the engineered mice were much faster at working out that things had changed and calculating a new route.
Conditional gene knockout is a relatively new technique and allows much more sophisticated experiments than traditional knockout, which eliminates the gene throughout the body.
"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."
Cdk5 works with another a protease called calpain, to break up NMDA receptor 2B (NR2B), which is found in nerve-cell membranes and stimulates the cell to fire when a neurotransmitter binds to it.
The researchers discovered that Cdk5 mediates the destruction of NR2B by directly interacting with both targets.
NR2B has previously been implicated in the early stages of learning and by removing Cdk5 from the brain, levels of NR2B are significantly increased.
In Alzheimer's, Cdk5 facilitates the progress of the disease by adding phosphate groups to the Tau protein, which is a key perpetrator in the disease.
As phosphate is added to it, Tau is modified and becomes dysfunctional - getting tangled in the brain's of Alzheimer's patients.
The results results were published in the 27 May online edition of Nature Neuroscience.
However, Dr Bibb acknowledged that the long-term effects of deleting Cdk5 were still yet to be fully understood.
The group are already looking into this and are also searching for drugs that could create the same effects without genetic modification.
One of the other areas the research could make an impact, is treating post-traumatic stress disorder, where getting a patient to learn that a once-threatening situation no longer poses a danger is a major goal.
"We made the animals 'smarter,' but in doing so and applying this technology, we also found biochemical targets that hold promise for future treatments of a variety of cognitive disorders," said Dr Bibb.
The scientists found that in slices of the hippocampus area of the mice' brains responded much more strongly to electrical stimulation, which indicates the engineered mice were more prepared to learn.
Whether or not the same effect could be reproduced with a drug in humans is unknown.
However, any drug that could theoretically make humans more adept at learning could have pharmaceutical companies tripping over themselves for the rights to market it.