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Journal article
Compartmentalized PDE4A5 Signaling Impairs Hippocampal Synaptic Plasticity and Long-Term Memory
The Journal of neuroscience, Vol.36(34), pp.8936-8946
08/24/2016
PMID: 27559174
Abstract
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.
Neurons exhibit localized signaling processes that enable biochemical cascades to be activated selectively in specific subcellular compartments. The phosphodiesterase 4 (PDE4) family coordinates the degradation of cAMP, leading to the local attenuation of cAMP-dependent signaling pathways. Sleep deprivation leads to increased hippocampal expression of the PDE4A5 isoform. Here, we explored whether PDE4A5 overexpression mimics behavioral and synaptic plasticity phenotypes associated with sleep deprivation. Viral expression of PDE4A5 in hippocampal neurons impairs long-term potentiation and attenuates the formation of hippocampus-dependent long-term memories. Our findings suggest that PDE4A5 is a molecular constraint on cognitive processes and may contribute to the development of novel therapeutic approaches to prevent cognitive deficits in neuropsychiatric and neurocognitive disorders that are associated with alterations in cAMP signaling.
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Details
- Title
- Compartmentalized PDE4A5 Signaling Impairs Hippocampal Synaptic Plasticity and Long-Term Memory
- Creators
- Robbert Havekes - University of PennsylvaniaAlan J Park - Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104Rosa E Tolentino - Translational TherapeuticsVibeke M Bruinenberg - University of GroningenJennifer C Tudor - University of PennsylvaniaYool Lee - Washington State University, Biomedical Sciences, Department ofRolf T Hansen - University of PennsylvaniaLeonardo A Guercio - University of PennsylvaniaEdward Linton - University of PennsylvaniaSusana R Neves-Zaph - Icahn School of Medicine at Mount SinaiPeter Meerlo - University of GroningenGeorge S Baillie - University of GlasgowMiles D Houslay - King's College LondonTed Abel - Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, r.havekes@rug.nl abele@sas.upenn.edu
- Publication Details
- The Journal of neuroscience, Vol.36(34), pp.8936-8946
- Academic Unit
- Elson S. Floyd College of Medicine
- Grant note
- P01 AG017628 / NIA NIH HHS MR/J007412/1 / Medical Research Council R01 DK087650 / NIDDK NIH HHS R01 MH086415 / NIMH NIH HHS K12 GM081259 / NIGMS NIH HHS
- Identifiers
- 99901132535501842
- Language
- English
- Resource Type
- Journal article