Compartmentalized PDE4A5 signaling impairs hippocampal synaptic plasticity and long-term memory

Havekes, R. et al. (2016) Compartmentalized PDE4A5 signaling impairs hippocampal synaptic plasticity and long-term memory. Journal of Neuroscience, 36(34), pp. 8936-8946. (doi: 10.1523/JNEUROSCI.0248-16.2016) (PMID:27559174) (PMCID:PMC4995304)

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Alterations in cAMP signaling are thought to contribute to neurocognitive and neuropsychiatric disorders. Members of the cAMP-specific phosphodiesterase 4 (PDE4) family, which contains >25 different isoforms, play a key role in determining spatial cAMP degradation so as to orchestrate compartmentalized cAMP signaling in cells. Each isoform binds to a different set of protein complexes through its unique N-terminal domain, thereby leading to targeted degradation of cAMP in specific intracellular compartments. However, the functional role of specific compartmentalized PDE4 isoforms has not been examined in vivo. Here, we show that increasing protein levels of the PDE4A5 isoform in mouse hippocampal excitatory neurons impairs a long-lasting form of hippocampal synaptic plasticity and attenuates hippocampus-dependent long-term memories without affecting anxiety. In contrast, viral expression of a truncated version of PDE4A5, which lacks the unique N-terminal targeting domain, does not affect long-term memory. Further, overexpression of the PDE4A1 isoform, which targets a different subset of signalosomes, leaves memory undisturbed. Fluorescence resonance energy transfer sensor-based cAMP measurements reveal that the full-length PDE4A5, in contrast to the truncated form, hampers forskolin-mediated increases in neuronal cAMP levels. Our study indicates that the unique N-terminal localization domain of PDE4A5 is essential for the targeting of specific cAMP-dependent signaling underlying synaptic plasticity and memory. The development of compounds to disrupt the compartmentalization of individual PDE4 isoforms by targeting their unique N-terminal domains may provide a fruitful approach to prevent cognitive deficits in neuropsychiatric and neurocognitive disorders that are associated with alterations in cAMP signaling.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Houslay, Professor Miles and Baillie, Professor George
Authors: Havekes, R., Park, A. J., Tolentino, R. E., Bruinenberg, V. M., Tudor, J. C., Lee, Y., Hansen, R. T., Guercio, L. A., Linton, E., Neves, S. R., Meerlo, P., Baillie, G. W., Houslay, M. D., and Abel, T.
College/School:College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
College of Medical Veterinary and Life Sciences > School of Psychology & Neuroscience
Journal Name:Journal of Neuroscience
Publisher:The Society for Neuroscience
ISSN (Online):1529-2401
Copyright Holders:Copyright © 2016 The Authors
First Published:First published in Journal of Neuroscience 36(34):8936-8946
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
588611cAMP phosphodiesterase-4: signalling complexes, regulation and potential therapeutic targets.George BaillieMedical Research Council (MRC)MR/J007412/1RI CARDIOVASCULAR & MEDICAL SCIENCES