“Brainy” mice raise hope of better treatments for cognitive disorders
Researchers have created unusually intelligent mice by altering a single gene and as a result 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, is published today 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”.
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.
Dr Alexander McGirr, a psychiatrist in training at the University of British Columbia, who co-led the study, said: “”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.”
Dr Laura Phipps of Alzheimer’s Research UK, who were not involved in the study, 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.”
The study involved researchers from Leeds, Mount Sinai Hospital, University of BritishColumbia, 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.
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Further Readings of Interest
Expression of phosphodiesterase 4 is altered in the brains of subjects with autism
http://www.ncbi.nlm.nih.gov/pubmed/18090323
The cyclic adenosine monophosphate-specific phosphodiesterase-4 (PDE4) gene family is the target of several potential therapeutic inhibitors and the PDE4B gene has been associated with schizophrenia and depression. Little, however, is known of any connection between this gene family and autism, with limited effective treatment being available for autism. We measured the expression of PDE4A and PDE4B by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western blotting in Brodmann’s area 40 (BA40, parietal cortex), BA9 (superior frontal cortex), and cerebellum from subjects with autism and matched controls. We observed a lower expression of PDE4A5, PDE4B1, PDE4B3, PDE4B4, and PDE4B2 in the cerebella of subjects with autism when compared with matched controls. In BA9, we observed the opposite: a higher expression of PDE4AX, PDE4A1, and PDE4B2 in subjects with autism. No changes were observed in BA40. Our results demonstrate altered expressions of the PDE4A and PDE4B proteins in the brains of subjects with autism and might provide new therapeutic avenues for the treatment of this debilitating disorder.
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