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Specific Inhibition of Phosphodiesterase-4B Results in Anxiolysis and Facilitates Memory Acquisition

Cognitive dysfunction is a core feature of dementia and a prominent feature in psychiatric disease. As non-redundant regulators of intracellular cAMP gradients, phosphodiesterases (PDE) mediate fundamental aspects of brain function relevant to learning, memory, and higher cognitive functions. Phosph...

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Autores principales: McGirr, Alexander, Lipina, Tatiana V, Mun, Ho-Suk, Georgiou, John, Al-Amri, Ahmed H, Ng, Enoch, Zhai, Dongxu, Elliott, Christina, Cameron, Ryan T, Mullins, Jonathan GL, Liu, Fang, Baillie, George S, Clapcote, Steven J, Roder, John C
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4748432/
https://www.ncbi.nlm.nih.gov/pubmed/26272049
http://dx.doi.org/10.1038/npp.2015.240
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author McGirr, Alexander
Lipina, Tatiana V
Mun, Ho-Suk
Georgiou, John
Al-Amri, Ahmed H
Ng, Enoch
Zhai, Dongxu
Elliott, Christina
Cameron, Ryan T
Mullins, Jonathan GL
Liu, Fang
Baillie, George S
Clapcote, Steven J
Roder, John C
author_facet McGirr, Alexander
Lipina, Tatiana V
Mun, Ho-Suk
Georgiou, John
Al-Amri, Ahmed H
Ng, Enoch
Zhai, Dongxu
Elliott, Christina
Cameron, Ryan T
Mullins, Jonathan GL
Liu, Fang
Baillie, George S
Clapcote, Steven J
Roder, John C
author_sort McGirr, Alexander
collection PubMed
description Cognitive dysfunction is a core feature of dementia and a prominent feature in psychiatric disease. As non-redundant regulators of intracellular cAMP gradients, phosphodiesterases (PDE) mediate fundamental aspects of brain function relevant to learning, memory, and higher cognitive functions. Phosphodiesterase-4B (PDE4B) is an important phosphodiesterase in the hippocampal formation, is a major Disrupted in Schizophrenia 1 (DISC1) binding partner and is itself a risk gene for psychiatric illness. To define the effects of specific inhibition of the PDE4B subtype, we generated mice with a catalytic domain mutant form of PDE4B (Y358C) that has decreased ability to hydrolyze cAMP. Structural modeling predictions of decreased function and impaired binding with DISC1 were confirmed in cell assays. Phenotypic characterization of the PDE4B(Y358C) mice revealed facilitated phosphorylation of CREB, decreased binding to DISC1, and upregulation of DISC1 and β-Arrestin in hippocampus and amygdala. In behavioral assays, PDE4B(Y358C) mice displayed decreased anxiety and increased exploration, as well as cognitive enhancement across several tests of learning and memory, consistent with synaptic changes including enhanced long-term potentiation and impaired depotentiation ex vivo. PDE4B(Y358C) mice also demonstrated enhanced neurogenesis. Contextual fear memory, though intact at 24 h, was decreased at 7 days in PDE4B(Y358C) mice, an effect replicated pharmacologically with a non-selective PDE4 inhibitor, implicating cAMP signaling by PDE4B in a very late phase of consolidation. No effect of the PDE4B(Y358C) mutation was observed in the prepulse inhibition and forced swim tests. Our data establish specific inhibition of PDE4B as a promising therapeutic approach for disorders of cognition and anxiety, and a putative target for pathological fear memory.
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spelling pubmed-47484322017-03-01 Specific Inhibition of Phosphodiesterase-4B Results in Anxiolysis and Facilitates Memory Acquisition McGirr, Alexander Lipina, Tatiana V Mun, Ho-Suk Georgiou, John Al-Amri, Ahmed H Ng, Enoch Zhai, Dongxu Elliott, Christina Cameron, Ryan T Mullins, Jonathan GL Liu, Fang Baillie, George S Clapcote, Steven J Roder, John C Neuropsychopharmacology Original Article Cognitive dysfunction is a core feature of dementia and a prominent feature in psychiatric disease. As non-redundant regulators of intracellular cAMP gradients, phosphodiesterases (PDE) mediate fundamental aspects of brain function relevant to learning, memory, and higher cognitive functions. Phosphodiesterase-4B (PDE4B) is an important phosphodiesterase in the hippocampal formation, is a major Disrupted in Schizophrenia 1 (DISC1) binding partner and is itself a risk gene for psychiatric illness. To define the effects of specific inhibition of the PDE4B subtype, we generated mice with a catalytic domain mutant form of PDE4B (Y358C) that has decreased ability to hydrolyze cAMP. Structural modeling predictions of decreased function and impaired binding with DISC1 were confirmed in cell assays. Phenotypic characterization of the PDE4B(Y358C) mice revealed facilitated phosphorylation of CREB, decreased binding to DISC1, and upregulation of DISC1 and β-Arrestin in hippocampus and amygdala. In behavioral assays, PDE4B(Y358C) mice displayed decreased anxiety and increased exploration, as well as cognitive enhancement across several tests of learning and memory, consistent with synaptic changes including enhanced long-term potentiation and impaired depotentiation ex vivo. PDE4B(Y358C) mice also demonstrated enhanced neurogenesis. Contextual fear memory, though intact at 24 h, was decreased at 7 days in PDE4B(Y358C) mice, an effect replicated pharmacologically with a non-selective PDE4 inhibitor, implicating cAMP signaling by PDE4B in a very late phase of consolidation. No effect of the PDE4B(Y358C) mutation was observed in the prepulse inhibition and forced swim tests. Our data establish specific inhibition of PDE4B as a promising therapeutic approach for disorders of cognition and anxiety, and a putative target for pathological fear memory. Nature Publishing Group 2016-03 2015-09-02 /pmc/articles/PMC4748432/ /pubmed/26272049 http://dx.doi.org/10.1038/npp.2015.240 Text en Copyright © 2016 American College of Neuropsychopharmacology http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Original Article
McGirr, Alexander
Lipina, Tatiana V
Mun, Ho-Suk
Georgiou, John
Al-Amri, Ahmed H
Ng, Enoch
Zhai, Dongxu
Elliott, Christina
Cameron, Ryan T
Mullins, Jonathan GL
Liu, Fang
Baillie, George S
Clapcote, Steven J
Roder, John C
Specific Inhibition of Phosphodiesterase-4B Results in Anxiolysis and Facilitates Memory Acquisition
title Specific Inhibition of Phosphodiesterase-4B Results in Anxiolysis and Facilitates Memory Acquisition
title_full Specific Inhibition of Phosphodiesterase-4B Results in Anxiolysis and Facilitates Memory Acquisition
title_fullStr Specific Inhibition of Phosphodiesterase-4B Results in Anxiolysis and Facilitates Memory Acquisition
title_full_unstemmed Specific Inhibition of Phosphodiesterase-4B Results in Anxiolysis and Facilitates Memory Acquisition
title_short Specific Inhibition of Phosphodiesterase-4B Results in Anxiolysis and Facilitates Memory Acquisition
title_sort specific inhibition of phosphodiesterase-4b results in anxiolysis and facilitates memory acquisition
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4748432/
https://www.ncbi.nlm.nih.gov/pubmed/26272049
http://dx.doi.org/10.1038/npp.2015.240
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