By disrupting a single gene, scientists have created mice that excel at tasks involving memory and problem solving and exhibit less anxiety than normal mice. The research suggests that drugs targeting the protein encoded by the gene called phosphodiesterase-4B (PDE4B), might be useful in treating anxiety disorders or improving cognition (thinking) in people with dementia.

Steven J. Clapcote, Ph.D., a 2007 NARSAD Young Investigator, was the senior scientist on the international team, which included 2006 Distinguished Investigator John C. Roder, Ph.D.; 2007 Young Investigator John Georgiou, Ph.D.; and 2003 Young Investigator and 2006 Independent Investigator Fang Liu, M.D., Ph.D. Their study appeared August 14th in the journal Neuropsychopharmacology.

PDE4B belongs to a family of proteins called PDE4s that are active in different parts of the brain. These proteins are involved in processes that affect learning, memory, and higher cognitive functions. Blocking these proteins as a group has been found to improve several aspects of memory and cognition in laboratory animals, but drugs that broadly target PDE4 proteins cause nausea and vomiting, making them unsuitable for patients.

Dr. Clapcote and his colleagues set out to determine whether they could boost cognitive functions in mice by interfering with just one of the PDE4 proteins, PDE4B. They disrupted the PDE4B gene and studied the animals’ behavior in a variety of tests.

Mice with the PDE4B mutation performed better than normal mice on several tests of learning and memory, such as navigating a maze, finding a hidden underwater platform, and recognizing other mice.

The mice also displayed less anxiety than normal mice, spending more time exploring new places, even in exposed environments––that is, areas in which they can be plainly seen by others. Normally in such circumstances, mice behave tentatively.

The scientists also examined the brains of the mice, focusing on regions involved in forming and storing memories. In mice with the PDE4B mutations, these regions formed more connections with one another than in normal mice. Growth of new neurons was also enhanced in the mice with PDE4B mutations.

The scientists noted evidence suggesting that blocking PDE4B with pharmaceuticals is likely to cause fewer side effects in people than general inhibition of the entire PDE4 family of proteins. Thus, developing ways to interfere with the protein could lead to new treatments that benefit people with anxiety disorders or impaired cognition.