Mutation to single gene makes mice brainy

Vancouver, BC – Scientists at the University of British Columbia (UBC) have created unusually intelligent mice by causing a mutation to a single gene. While the research is a long way from reaching human trials, it helps researchers identify a target for improving memory and cognitive function in people with dementia.

The study, led by Dr. Alexander McGirr, a medical resident in the Department of Psychiatry at UBC, along with colleagues at the University of Toronto, University of Leeds and MRC Harwell, an organization that studies the links between genetics and disease, was published today in the journal Neuropsychopharmacology. In this Q&A, McGirr talks about his results.

How did you create intelligent mice?

We identified a mutation in the gene that codes for an important protein in the brain, Phosphodiesterase-4B (PDE4B). Though our study is in mice, this protein is very important in the human brain as well.

Mice with the mutation performed remarkably well on many memory and problem-solving tasks. For instance, they were able to remember where they had already been in a maze, find a platform hidden under water, and they had better social memory, meaning they remembered meeting other mice. What was really interesting is that even when we made some tasks that are impossible for normal mice, the ‘brainy mice’ continued to perform well.

What can intelligent mice teach us about dementia?

Understanding the function of PDE4B teaches us about how the brain encodes experience into memory. Cognitive impairment is a major clinical challenge and our work suggests a new target for medicines that may eventually help patients and their families.

‘Brainy mice’ learned better and their brains changed in ways that are relevant to treating dementia. We found that these mice had more new neurons being born, and that neurons in memory centres made more connections with other neurons, suggesting that the network was more interconnected and perhaps more robust. Though a long way from being directly relevant to human dementia, this is a promising new target for developing medicines to help cognitive impairment.

What surprises did you come across?

Our PDE4B mice showed many signs of being better learners than normal mice, but when we tested them for fear memory after 24 hours, as is typical, they performed no better than normal mice. Yet, despite this intact ability to learn fearful associations, something peculiar happened when we tested them after a week: they didn’t seem to remember the fearful event. We did a number of different tests and ultimately found that the brainy mice were also less anxious.

Our research suggests that medicines affecting PDE4B might be useful after traumatic events. In humans, traumatic events can result in Post-Traumatic Stress Disorder (PTSD) and result in severe impairment. Our findings point to a potentially novel way of thinking about preventing the development of PTSD.

It is worth noting another surprising finding, however. Our PDE4B mice didn’t seem to be afraid of cat urine, which normal mice are understandably avoidant of. It suggests that caution is needed in developing medicines to target PDE4B for humans.