Specific inhibition of phosphodiesterase-4B results in anxiolysis and facilitates memory acquisition

McGirr, A. et al. (2015) Specific inhibition of phosphodiesterase-4B results in anxiolysis and facilitates memory acquisition. Neuropsychopharmacology, 41(4), pp. 1080-1092. (doi:10.1038/npp.2015.240)

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Abstract

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 PDE4 inhibitor, implicating cAMP signalling by PDE4B 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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Baillie, Professor George and Elliott, Dr Christina and Cameron, Mr Ryan
Authors: McGirr, A., Lipina, T. V., Mun, H.-S., Georgiou, J., Al-Amri, A. H., Ng, E., Zhai, D., Elliott, C., Cameron, R. T., Mullins, J. G., Liu, F., Baillie, G. S., Clapcote, S. J., and Roder, J. C.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Neuropsychopharmacology
Publisher:Nature Publishing Group
ISSN:0893-133X
ISSN (Online):1740-634X

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