'Brainy' mice raise hope of better treatments for cognitive disorders

Published: 14 August 2015

Researchers have created unusually intelligent mice by altering a single gene, but found the mice were also less likely to feel anxiety or recall fear.

Researchers have created unusually intelligent mice by altering a single gene, but found the mice were also less likely to feel anxiety or recall fear.

The study, led by the University of Leeds and Mount Sinai Hospital in Toronto, with input from the University of Glasgow, is published in the journal Neuropsychopharmacology.

It sheds light on the molecular underpinnings of learning and memory and could form the basis for research into new treatments for age-related cognitive decline, cognitive disorders such as Alzheimer’s disease and schizophrenia, and other conditions.

The researchers altered a gene in mice to inhibit the activity of an enzyme called phosphodiesterase-4B (PDE4B), which is present in many organs of the vertebrate body, including the brain.

In behavioural tests, the PDE4B-inhibited mice showed enhanced cognitive abilities.

They tended to learn faster, remember events longer and solve complex exercises better than ordinary mice.

For example, the “brainy mice” showed a better ability than ordinary mice to recognise another mouse that they had been introduced to the day before. They were also quicker at learning the location of a hidden escape platform in a test called the Morris water maze.

However, the PDE4B-inhibited mice also showed less recall of a fearful event after several days than ordinary mice.

The published findings are limited to mice and have not been tested in humans, but PDE4B is present in humans. The diminished memory of fear among mice with inhibited PDE4B could be of interest to researchers looking for treatments for pathological fear, typified by Post-Traumatic Stress Disorder (PTSD).

The PDE4B-inhibited mice also showed less anxiety. They spent more time in open, brightly-lit spaces than ordinary mice, which preferred dark, enclosed spaces.

Ordinary mice are naturally fearful of cats, but the PDE4B-inhibited mice showed a decreased fear response to cat urine, suggesting that one effect of inhibiting PDE4B could be an increase in risk-taking behaviour.

So, while the PDE4B-inhibited mice excelled at solving complex exercises, their low levels of anxiety could be counterproductive for a wild mouse.

Dr Steve Clapcote, Lecturer in Pharmacology in the University of Leeds’ School of Biomedical Sciences, 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”.

Professor George Baillie, of the Institute of Cardiovascular and Medical Sciences at the University of Glasgow, said: “The role of Phosphodiesterase enzymes in cognition has been known for some time, however the link between the PDE4B-sub family and harboured anxiety following a fearful event is new.

“The real worth of this research is the realisation that PDE4B specific inhibitors, once fully developed, may be used to treat conditions of pathological fear such as PTSD which are not well served by currently available pharmaceuticals.

“It should be pointed out, that active site directed inhibitors of PDE4B will be difficult to perfect as all of the PDE4 enzymes in humans (approximately 25, of which 5 are PDE4B types) have near identical catalytic sites.

“We at the University of Glasgow and others around the world are currently involved in the development of such compounds and hope in the future they can be used to  treat patients with fearful memories and retard cognitive decline in the elderly population."

The researchers are now working on developing drugs that will specifically inhibit PDE4B. These drugs will be tested in animals to see whether any would be suitable for clinical trials in humans.

The study involved researchers from 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. The study was funded by the UK Medical Research Council.

Media enquiries: stuart.forsyth@glasgow.ac.uk / 0141 330 4831 or c.jbunting@leeds.ac.uk / 0113 343 2049

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First published: 14 August 2015

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