Research collaborative team between Canadian and British scientists. 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 experiments, the PDE4B-inhibited mice showed enhanced cognitive abilities and excelled at solving complex exercises better than ordinary mice. This research identified phosphodiesterase-4B as a promising target for potential new treatments. Drugs targeting Phosphodiesterase PDE4B may potentially improve the lives of individuals with cognitive disorders and life-impairing anxiety, and they may have a time-limited role after traumatic events.
Alexander McGirr1,2, Tatiana V Lipina2, Ho-Suk Mun2,3, John Georgiou2, Ahmed H Al-Amri4,5, Enoch Ng2,6, Dongxu Zhai7, Christina Elliott8, Ryan T Cameron8, Jonathan GL Mullins9, Fang Liu7, George S Baillie8, Steven J Clapcote4 and John C Roder2,10
Neuropsychopharmacology, Online August 2015.[expand title=”Show Affiliations”]
1Department of Psychiatry, University of British Columbia, Vancouver, British Columbia, Canada
2Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
3Department of Medical Genetics, University of Toronto, Toronto, Ontario, Canada
4School of Biomedical Sciences, University of Leeds, Leeds LS2 9JT, UK
5National Genetic Centre, Royal Hospital, Muscat, Oman
6Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
7Department of Neuroscience, Centre for Addiction and Mental Health, Toronto, Ontario, Canada
8Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
9Institute of Life Science, College of Medicine, Swansea University, Swansea, UK
10Department of Physiology, University of Toronto, Toronto, Ontario, Canada[/expand]
Cognitive dysfunction is a core feature of dementia and a prominent feature in psychiatric disease. As non-redundant regulators of intracellular cAMP gradients, phosphodiesterases (PDE) mediate fundamental aspects of brain function relevant to learning, memory, and higher cognitive functions. Phosphodiesterase-4B (PDE4B) is an important phosphodiesterase in the hippocampal formation, is a major Disrupted in Schizophrenia 1 (DISC1) binding partner and is itself a risk gene for psychiatric illness. To define the effects of specific inhibition of the PDE4B subtype, we generated mice with a catalytic domain mutant form of PDE4B (Y358C) that has decreased ability to hydrolyze cAMP. Structural modelling predictions of decreased function and impaired binding with DISC1 were confirmed in cell assays. Phenotypic characterization of the PDE4BY358C mice revealed facilitated phosphorylation of CREB, decreased binding to DISC1, and upregulation of DISC1 and β-Arrestin in hippocampus and amygdala. In behavioural assays, PDE4BY358C mice displayed decreased anxiety and increased exploration, as well as cognitive enhancement across several tests of learning and memory, consistent with synaptic changes including enhanced long-term potentiation and impaired depotentiation ex vivo. PDE4BY358C mice also demonstrated enhanced neurogenesis. Contextual fear memory, though intact at 24 h, was decreased at 7 days in PDE4BY358C mice, an effect replicated pharmacologically with a non-selective Phosphodiesterase-4B inhibitor, implicating cAMP signalling by Phosphodiesterase-4B in a very late phase of consolidation. No effect of the PDE4BY358C mutation was observed in the pre-pulse inhibition and forced swim tests. Our data establish specific inhibition of PDE4B as a promising therapeutic approach for disorders of cognition and anxiety, and a putative target for pathological fear memory.