Compartmentalized PDE4A5 signaling impairs hippocampal synaptic plasticity and long-term memory
| العنوان: | Compartmentalized PDE4A5 signaling impairs hippocampal synaptic plasticity and long-term memory |
|---|---|
| المؤلفون: | Vibeke M. Bruinenberg, Edward F Linton, Yool Lee, George S. Baillie, Leonardo A. Guercio, Jennifer C. Tudor, Susana R. Neves-Zaph, Alan J. Park, Peter Meerlo, Robbert Havekes, Rosa E. Tolentino, Rolf T. Hansen, Ted Abel, Miles D. Houslay |
| المساهمون: | Havekes lab, Van der Zee lab, Meerlo lab |
| المصدر: | The Journal of Neuroscience, 36(34), 8936-8946. Oxford University Press 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-zaph, S R, Meerlo, P, Baillie, G S, Houslay, M D & Abel, T 2016, ' Compartmentalized PDE4A5 Signaling Impairs Hippocampal Synaptic Plasticity and Long-Term Memory ', Journal of Neuroscience, vol. 36, no. 34, pp. 8936-8946 . https://doi.org/10.1523/JNEUROSCI.0248-16.2016Test |
| سنة النشر: | 2016 |
| مصطلحات موضوعية: | 0301 basic medicine, Male, hippocampus, Vasodilator Agents, Conditioning, Classical, CYCLIC-AMP, Hippocampus, Hippocampal formation, memory, Mice, 0302 clinical medicine, COGNITION ENHANCEMENT, Transduction, Genetic, Cyclic AMP, Fluorescence Resonance Energy Transfer, Protein Isoforms, Cells, Cultured, IN-VIVO, Neurons, Neuronal Plasticity, Long-term memory, MICE DEFICIENT, General Neuroscience, Long-term potentiation, Articles, Fear, MOUSE MODEL, Compartmentalization (psychology), OBJECT RECOGNITION MEMORY, Signal transduction, LTP, phosphodiesterase, Signal Transduction, Gene isoform, Memory, Long-Term, Green Fluorescent Proteins, TRAUMATIC BRAIN-INJURY, Enzyme-Linked Immunosorbent Assay, Biology, PDE, DIFFERENTIAL EXPRESSION, 03 medical and health sciences, cAMP, Glial Fibrillary Acidic Protein, Animals, CAMP-SPECIFIC PHOSPHODIESTERASE, Analysis of Variance, Colforsin, Recognition, Psychology, Electric Stimulation, Cyclic Nucleotide Phosphodiesterases, Type 4, Rats, Mice, Inbred C57BL, 030104 developmental biology, Synaptic plasticity, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Neuroscience, 030217 neurology & neurosurgery, SLEEP-DEPRIVATION |
| الوصف: | 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. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 0270-6474 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f066094eb6b375ccc87e6f63868de2c7Test https://research.rug.nl/en/publications/d36184e1-ab2b-4089-95ef-547641b3cc75Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....f066094eb6b375ccc87e6f63868de2c7 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 02706474 |
|---|