RGD Reference Report - Compartmentalized PDE4A5 Signaling Impairs Hippocampal Synaptic Plasticity and Long-Term Memory. - Rat Genome Database

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Compartmentalized PDE4A5 Signaling Impairs Hippocampal Synaptic Plasticity and Long-Term Memory.

Authors: Havekes, Robbert  Park, Alan J  Tolentino, Rosa E  Bruinenberg, Vibeke M  Tudor, Jennifer C  Lee, Yool  Hansen, Rolf T  Guercio, Leonardo A  Linton, Edward  Neves-Zaph, Susana R  Meerlo, Peter  Baillie, George S  Houslay, Miles D  Abel, Ted 
Citation: Havekes R, etal., J Neurosci. 2016 Aug 24;36(34):8936-46. doi: 10.1523/JNEUROSCI.0248-16.2016.
RGD ID: 13702343
Pubmed: PMID:27559174   (View Abstract at PubMed)
PMCID: PMC4995304   (View Article at PubMed Central)
DOI: DOI:10.1523/JNEUROSCI.0248-16.2016   (Journal Full-text)


UNLABELLED: 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.
SIGNIFICANCE STATEMENT: 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.



Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Pde4aRatmodulation of chemical synaptic transmission involved_inIDA PMID:27559174SynGO 
Pde4aRatmodulation of chemical synaptic transmission involved_inIMP PMID:27559174SynGO 

Cellular Component

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Pde4aRatSchaffer collateral - CA1 synapse is_active_inIDA PMID:27559174SynGO 
Pde4aRatSchaffer collateral - CA1 synapse is_active_inIMP PMID:27559174SynGO 

Objects Annotated

Genes (Rattus norvegicus)
Pde4a  (phosphodiesterase 4A)


Additional Information