Altered protein makes mice smarter

By tweaking a single gene, scientists have turned average mice into supersmart daredevils. The findings are preliminary but hint at therapies that may one day ease the symptoms of such disorders as Alzheimer’s disease and schizophrenia, scientists report August 14 in Neuropsychopharmacology.

The altered gene provides instructions for a protein called phosphodiesterase-4B, or PDE4B, which has been implicated in schizophrenia. It’s too early to say whether PDE4B will turn out to be a useful target for drugs that treat these disorders, cautions pharmacologist Ernesto Fedele of the University of Genoa in Italy. Nonetheless, the protein certainly deserves further investigation, he says.

The genetic change interfered with PDE4B’s ability to do its job breaking down a molecular messenger called cAMP. Mice designed to have this disabled form of PDE4B showed a suite of curious behaviors, including signs of smarts, says study coauthor Alexander McGirr of the University of British Columbia. Compared with normal mice, these mice more quickly learned which objects in a cage had been moved to a new location, for instance, and could better recognize a familiar mouse after 24 hours. “The system is primed and ready to learn, and it doesn’t require the same kind of input as a normal mouse,” McGirr says.

These mice also spent more time than usual exploring brightly lit spaces, spots that normal mice avoid. But this devil-may-care attitude sometimes made the “smart” mice blind to risky situations. The mice were happy to spend time poking around an area that had been sprinkled with bobcat urine. “Not being afraid of cat urine is not a good thing for a mouse,” McGirr says.

PDE4B may play other roles in the brain, McGirr says. And because the protein has jobs in the heart, lungs and immune system as well, it might be difficult to find drugs that have the desired effect on PDE4B in the brain but few side effects elsewhere. “It’s a very reasonable target but we are quite a ways from having good medicines,” McGirr says.