title: Compartmentalized PDE4A5 Signaling Impairs Hippocampal Synaptic Plasticity and Long-Term Memory.
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.
authors: Groningen Institute for Evolutionary Life Sciences, University of Groningen, 9700 AB, Groningen, The Netherlands, Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, r.havekes@rug.nl abele@sas.upenn.edu.
authors: Robbert
authors: 0000-0003-0757-4739
authors: R
authors: Havekes
authors: Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors: Alan J
authors: 0000-0002-7644-8886
authors: AJ
authors: Park
authors: Department of Systems Pharmacology and Translational Therapeutics, Institute for Translational Medicine and Therapeutics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors: Rosa E
authors: 0000-0002-4261-3230
authors: RE
authors: Tolentino
authors: Groningen Institute for Evolutionary Life Sciences, University of Groningen, 9700 AB, Groningen, The Netherlands.
authors: Vibeke M
authors: VM
authors: Bruinenberg
authors: Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors: Jennifer C
authors: 0000-0002-3826-3012
authors: JC
authors: Tudor
authors: Department of Systems Pharmacology and Translational Therapeutics, Institute for Translational Medicine and Therapeutics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors: Yool
authors: 0000-0003-0498-3342
authors: Y
authors: Lee
authors: Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors: Rolf T
authors: 0000-0002-1343-3556
authors: RT
authors: Hansen
authors: Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors: Leonardo A
authors: LA
authors: Guercio
authors: Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors: Edward
authors: 0000-0001-7058-9576
authors: E
authors: Linton
authors: Departments of Pharmacology and Systems Therapeutics, Friedman Brain Institute, and System Biology Center New York, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
authors: Susana R
authors: SR
authors: Neves-Zaph
authors: Groningen Institute for Evolutionary Life Sciences, University of Groningen, 9700 AB, Groningen, The Netherlands.
authors: Peter
authors: P
authors: Meerlo
authors: Institute of Cardiovascular and Medical Science, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, United Kingdom, and.
authors: George S
authors: 0000-0003-2469-6316
authors: GS
authors: Baillie
authors: Institute of Pharmaceutical Science, King's College London, London SE1 9NH, United Kingdom.
authors: Miles D
authors: 0000-0002-3826-8091
authors: MD
authors: Houslay
authors: Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, r.havekes@rug.nl abele@sas.upenn.edu.
authors: Ted
authors: 0000-0003-2423-4592
authors: T
authors: Abel
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D003214:Conditioning, Classical / Q000502:physiology; D000242:Cyclic AMP / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000235:genetics / Q000378:metabolism*; D004558:Electric Stimulation; D004797:Enzyme-Linked Immunosorbent Assay; D005239:Fear; D031541:Fluorescence Resonance Energy Transfer; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology* / Q000502:physiology*; D008297:Male; D057567:Memory, Long-Term / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009473:Neuronal Plasticity / Q000235:genetics / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D051381:Rats; D021641:Recognition, Psychology / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics; D014161:Transduction, Genetic; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D005904:Glial Fibrillary Acidic Protein; D020033:Protein Isoforms; D014665:Vasodilator Agents; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D005576:Colforsin; D000242:Cyclic AMP; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C095813:Pde4a protein, mouse
keywords: LTP; PDE; cAMP; hippocampus; memory; phosphodiesterase