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PDE4 inhibition enhances hippocampal synaptic plasticity in vivo and rescues MK801-induced impairment of long-term potentiation and object recognition memory in an animal model of psychosis

Inhibition of phosphodiesterase type 4 (PDE4) by rolipram (4-(3-(cyclopentyloxy)-4-methoxyphenyl)-pyrrolidin-2-one) has been the focus of many behavioral and molecular studies in the recent years. Rolipram exhibits memory-enhancing effects in rodents. In vitro studies have shown that long-term poten...

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Autores principales: Wiescholleck, V, Manahan-Vaughan, D
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3309535/
https://www.ncbi.nlm.nih.gov/pubmed/22832854
http://dx.doi.org/10.1038/tp.2012.17
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author Wiescholleck, V
Manahan-Vaughan, D
author_facet Wiescholleck, V
Manahan-Vaughan, D
author_sort Wiescholleck, V
collection PubMed
description Inhibition of phosphodiesterase type 4 (PDE4) by rolipram (4-(3-(cyclopentyloxy)-4-methoxyphenyl)-pyrrolidin-2-one) has been the focus of many behavioral and molecular studies in the recent years. Rolipram exhibits memory-enhancing effects in rodents. In vitro studies have shown that long-term potentiation (LTP), which may comprise a cellular substrate for learning, is also enhanced by rolipram. However, effects have not been assessed in vivo. Rolipram has antipsychotic properties. Psychosis affects cognition and in animal models of psychosis LTP is impaired. In this study, we investigated if PDE4 inhibition improves LTP in healthy animals in vivo and if PDE4 inhibition rescues impaired LTP and prevents object recognition memory deficits in an animal model of psychosis. Recordings were made from the hippocampus of adult, freely behaving Wistar rats. Thirty minutes after treatment with rolipram or vehicle, a tetanus was applied to the medial perforant path to elicit short-term potentiation (STP) in the dentate gyrus. At this time-point, radioimmunoassay revealed that rolipram significantly elevated cyclic adenosine monophosphate levels in the dorsal hippocampus, in line with reports by others that rolipram mediates decreased PDE4 activity. In healthy animals, both intracerebroventricular and subcutaneous treatment with rolipram facilitated STP into LTP, suggesting that PDE4 inhibition may have a permissive role in plasticity mechanisms that are relevant for learning and memory. One week after a single systemic treatment with the irreversible N-methyl--aspartate antagonist, MK801, LTP and object recognition memory were significantly impaired, but could be rescued by PDE4 inhibition. These data suggest that the relief of cognitive disturbances in psychosis models by rolipram may be mediated in part by a rescue of hippocampal LTP.
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spelling pubmed-33095352012-04-03 PDE4 inhibition enhances hippocampal synaptic plasticity in vivo and rescues MK801-induced impairment of long-term potentiation and object recognition memory in an animal model of psychosis Wiescholleck, V Manahan-Vaughan, D Transl Psychiatry Original Article Inhibition of phosphodiesterase type 4 (PDE4) by rolipram (4-(3-(cyclopentyloxy)-4-methoxyphenyl)-pyrrolidin-2-one) has been the focus of many behavioral and molecular studies in the recent years. Rolipram exhibits memory-enhancing effects in rodents. In vitro studies have shown that long-term potentiation (LTP), which may comprise a cellular substrate for learning, is also enhanced by rolipram. However, effects have not been assessed in vivo. Rolipram has antipsychotic properties. Psychosis affects cognition and in animal models of psychosis LTP is impaired. In this study, we investigated if PDE4 inhibition improves LTP in healthy animals in vivo and if PDE4 inhibition rescues impaired LTP and prevents object recognition memory deficits in an animal model of psychosis. Recordings were made from the hippocampus of adult, freely behaving Wistar rats. Thirty minutes after treatment with rolipram or vehicle, a tetanus was applied to the medial perforant path to elicit short-term potentiation (STP) in the dentate gyrus. At this time-point, radioimmunoassay revealed that rolipram significantly elevated cyclic adenosine monophosphate levels in the dorsal hippocampus, in line with reports by others that rolipram mediates decreased PDE4 activity. In healthy animals, both intracerebroventricular and subcutaneous treatment with rolipram facilitated STP into LTP, suggesting that PDE4 inhibition may have a permissive role in plasticity mechanisms that are relevant for learning and memory. One week after a single systemic treatment with the irreversible N-methyl--aspartate antagonist, MK801, LTP and object recognition memory were significantly impaired, but could be rescued by PDE4 inhibition. These data suggest that the relief of cognitive disturbances in psychosis models by rolipram may be mediated in part by a rescue of hippocampal LTP. Nature Publishing Group 2012-03 2012-03-13 /pmc/articles/PMC3309535/ /pubmed/22832854 http://dx.doi.org/10.1038/tp.2012.17 Text en Copyright © 2012 Macmillan Publishers Limited http://creativecommons.org/licenses/by-nc-nd/3.0/ This work is licensed under the Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/
spellingShingle Original Article
Wiescholleck, V
Manahan-Vaughan, D
PDE4 inhibition enhances hippocampal synaptic plasticity in vivo and rescues MK801-induced impairment of long-term potentiation and object recognition memory in an animal model of psychosis
title PDE4 inhibition enhances hippocampal synaptic plasticity in vivo and rescues MK801-induced impairment of long-term potentiation and object recognition memory in an animal model of psychosis
title_full PDE4 inhibition enhances hippocampal synaptic plasticity in vivo and rescues MK801-induced impairment of long-term potentiation and object recognition memory in an animal model of psychosis
title_fullStr PDE4 inhibition enhances hippocampal synaptic plasticity in vivo and rescues MK801-induced impairment of long-term potentiation and object recognition memory in an animal model of psychosis
title_full_unstemmed PDE4 inhibition enhances hippocampal synaptic plasticity in vivo and rescues MK801-induced impairment of long-term potentiation and object recognition memory in an animal model of psychosis
title_short PDE4 inhibition enhances hippocampal synaptic plasticity in vivo and rescues MK801-induced impairment of long-term potentiation and object recognition memory in an animal model of psychosis
title_sort pde4 inhibition enhances hippocampal synaptic plasticity in vivo and rescues mk801-induced impairment of long-term potentiation and object recognition memory in an animal model of psychosis
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3309535/
https://www.ncbi.nlm.nih.gov/pubmed/22832854
http://dx.doi.org/10.1038/tp.2012.17
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