Super-clever mice increase hopes for treatment of cognitive disorders

A team of researchers created a group of unusually clever mice by altering a single gene, resulting in mice being less likely to behave anxiously or experience fear.

The study, published in the journal of Neuropsychopharmacology, was carried out by a team at the University of Leeds and Mount Sinai Hospital in Toronto, Canada.

Researchers altered a gene in mice to prevent the activity of enzyme, phosphodiesterase 4B (PDE4B), which is found in many organs, including the brain.

Dr Steve Clapcote, lecturer in Pharmacology in the School of Biomedical Sciences and the University of Leeds’ led the study. He said: “Cognitive impairments are currently poorly treated, so I’m excited that our work using mice has identified phosphodiesterase-4B as a promising target for potential new treatments."

The study was funded by the UK Medical Research Council and involved researches from the University of Leeds, Mount Sinai Hospital, University of British Columbia, the University of Toronto, the National Genetic Centre in Oman, the Centre for Addiction and Mental Health in Toronto, the University of Glasgow and Swansea University.

This particular study could form the basis of research into age-relative cognitive decline, such as Alzheimer’s disease, schizophrenia and other conditions, by shedding lighting on molecular underpinnings associated with learning and memory.

Mice were the subject of various behavioural tests, while mice with inhibited PDE4B shower improved cognitive ability than those without, learning faster, remembering events longer and being able to solve complex exercises faster and better than ordinary mice.

The ‘brainy mice’ showed an improved ability to recognise another mouse, that had been recently introduced just the day before and were quicker at learning the location of a hidden escape platform in a test called the ‘Morris water maze’.

Mice with PDE4B-inhibited showed a reduced ability to recall fearful events after several days than ordinary mice.

Psychiatrist in training at the University of British Columbia, Dr Alexander McGirr, co-led the study. He added: "In the future, medicines targeting PDE4B may potentially improve the lives of individuals with neurocognitive disorders and life-impairing anxiety, and they may have a time-limited role after traumatic events.”

While the results of the study are limited only to mice and have not been tested in humans, PDE4B is also present in humans. The reduction in fear, experienced by mice with PDE4B inhibited could be beneficial to researchers looking into the treatment of pathological fear – found in people experiencing Post-Traumatic Stress Disorder (PTSD).

The PDE4B-inhibited mice showed less anxiety, spent more time in open, well lit spaces than ordinary mice who preferred small, dark enclosed areas.

The study further examined the link between mice being naturally afraid of cats, mice with inhibited PDE4B demonstrated reduced fear in response to cat urine, suggesting that inhibiting the enzyme could increase risk-taking behaviour.

While mouse with PDE4B inhibited excelled when completing complex exercise, low levels of anxiety could be counterproductive if applied to wild mice.

Commenting on the findings of the study, Dr Laura Phipps of Alzheimer’s Research UK, said: “This study highlights a potentially important role for the PDE4B gene in learning and memory in mice, but further studies will be needed to know whether the findings could have implications for Alzheimer’s disease or other dementias. We’d need to see how this gene could influence memory and thinking in people to get a better idea of whether it could hold potential as a target to treat Alzheimer’s.

“There is currently a lack of effective treatments for dementia and understanding the effect of genes can be a key early step on the road to developing new drugs. With so many people affected by dementia, it is important that there is research into a wide array of treatment approaches to have the best chance of helping people sooner.”

Researchers are now working on developing drugs that can inhibit PDE4B which will then be tested on animals to see if it will be suitable for clinical trials in humans.