Prostaglandin E2 EP2 activation reduces memory decline in R6/1 mouse model of Huntington's disease by the induction of BDNF-dependent synaptic plasticity
Huntington's disease (HD) patients and mouse models show learning and memory impairment even before the onset of motor symptoms. Deficits in hippocampal synaptic plasticity have been involved in the HD memory impairment. Several studies show that prostaglandin E2 (PGE2) EP2 receptor stimulates...
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Elsevier
2016-11-01
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Series: | Neurobiology of Disease |
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Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996115300474 |
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doaj-cb2389e17973429a90512f8b43474e9a |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Marta Anglada-Huguet Laura Vidal-Sancho Albert Giralt Gerardo García-Díaz Barriga Xavier Xifró Jordi Alberch |
spellingShingle |
Marta Anglada-Huguet Laura Vidal-Sancho Albert Giralt Gerardo García-Díaz Barriga Xavier Xifró Jordi Alberch Prostaglandin E2 EP2 activation reduces memory decline in R6/1 mouse model of Huntington's disease by the induction of BDNF-dependent synaptic plasticity Neurobiology of Disease Hippocampus, Huntingtin, Misoprostol, PSD-95 |
author_facet |
Marta Anglada-Huguet Laura Vidal-Sancho Albert Giralt Gerardo García-Díaz Barriga Xavier Xifró Jordi Alberch |
author_sort |
Marta Anglada-Huguet |
title |
Prostaglandin E2 EP2 activation reduces memory decline in R6/1 mouse model of Huntington's disease by the induction of BDNF-dependent synaptic plasticity |
title_short |
Prostaglandin E2 EP2 activation reduces memory decline in R6/1 mouse model of Huntington's disease by the induction of BDNF-dependent synaptic plasticity |
title_full |
Prostaglandin E2 EP2 activation reduces memory decline in R6/1 mouse model of Huntington's disease by the induction of BDNF-dependent synaptic plasticity |
title_fullStr |
Prostaglandin E2 EP2 activation reduces memory decline in R6/1 mouse model of Huntington's disease by the induction of BDNF-dependent synaptic plasticity |
title_full_unstemmed |
Prostaglandin E2 EP2 activation reduces memory decline in R6/1 mouse model of Huntington's disease by the induction of BDNF-dependent synaptic plasticity |
title_sort |
prostaglandin e2 ep2 activation reduces memory decline in r6/1 mouse model of huntington's disease by the induction of bdnf-dependent synaptic plasticity |
publisher |
Elsevier |
series |
Neurobiology of Disease |
issn |
1095-953X |
publishDate |
2016-11-01 |
description |
Huntington's disease (HD) patients and mouse models show learning and memory impairment even before the onset of motor symptoms. Deficits in hippocampal synaptic plasticity have been involved in the HD memory impairment. Several studies show that prostaglandin E2 (PGE2) EP2 receptor stimulates synaptic plasticity and memory formation. However, this role was not explored in neurodegenerative diseases. Here, we investigated the capacity of PGE2 EP2 receptor to promote synaptic plasticity and memory improvements in a model of HD, the R6/1 mice, by administration of the agonist misoprostol. We found that misoprostol increases dendritic branching in cultured hippocampal neurons in a brain-derived neurotrophic factor (BDNF)-dependent manner. Then, we implanted an osmotic mini-pump system to chronically administrate misoprostol to R6/1 mice from 14 to 18 weeks of age. We observed that misoprostol treatment ameliorates the R6/1 long-term memory deficits as analyzed by the T-maze spontaneous alternation task and the novel object recognition test. Importantly, administration of misoprostol promoted the expression of hippocampal BDNF. Moreover, the treatment with misoprostol in R6/1 mice blocked the reduction in the number of PSD-95 and VGluT-1 positive particles observed in hippocampus of vehicle-R6/1 mice. In addition, we observed an increase of cAMP levels in the dentate ` of WT and R6/1 mice treated with misoprostol. Accordingly, we showed a reduction in the number of mutant huntingtin nuclear inclusions in the dentate gyrus of R6/1 mice. Altogether, these results suggest a putative therapeutic effect of PGE2 EP2 receptor in reducing cognitive deficits in HD. |
topic |
Hippocampus, Huntingtin, Misoprostol, PSD-95 |
url |
http://www.sciencedirect.com/science/article/pii/S0969996115300474 |
work_keys_str_mv |
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doaj-cb2389e17973429a90512f8b43474e9a2021-03-22T12:43:30ZengElsevierNeurobiology of Disease1095-953X2016-11-01952234Prostaglandin E2 EP2 activation reduces memory decline in R6/1 mouse model of Huntington's disease by the induction of BDNF-dependent synaptic plasticityMarta Anglada-Huguet0Laura Vidal-Sancho1Albert Giralt2Gerardo García-Díaz Barriga3Xavier Xifró4Jordi Alberch5Departament de Biologia Cel·lular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, Casanova, 143, 08036 Barcelona, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Casanova, 143, 08036 Barcelona, SpainDepartament de Biologia Cel·lular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, Casanova, 143, 08036 Barcelona, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Casanova, 143, 08036 Barcelona, Spain; New Therapeutic Targets Group (TargetsLab), Departament de Ciències Mèdiques, Facultat de Medicina, Universitat de Girona, c/ Emili Grahit, 77, 17071 Girona, SpainDepartament de Biologia Cel·lular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, Casanova, 143, 08036 Barcelona, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Casanova, 143, 08036 Barcelona, SpainDepartament de Biologia Cel·lular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, Casanova, 143, 08036 Barcelona, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Casanova, 143, 08036 Barcelona, SpainDepartament de Biologia Cel·lular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, Casanova, 143, 08036 Barcelona, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Casanova, 143, 08036 Barcelona, Spain; New Therapeutic Targets Group (TargetsLab), Departament de Ciències Mèdiques, Facultat de Medicina, Universitat de Girona, c/ Emili Grahit, 77, 17071 Girona, SpainDepartament de Biologia Cel·lular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, Casanova, 143, 08036 Barcelona, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Casanova, 143, 08036 Barcelona, Spain; Corresponding author at: Departament de Biologia Cellular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, C/ Casanova, 143, 08036 Barcelona, Spain.Huntington's disease (HD) patients and mouse models show learning and memory impairment even before the onset of motor symptoms. Deficits in hippocampal synaptic plasticity have been involved in the HD memory impairment. Several studies show that prostaglandin E2 (PGE2) EP2 receptor stimulates synaptic plasticity and memory formation. However, this role was not explored in neurodegenerative diseases. Here, we investigated the capacity of PGE2 EP2 receptor to promote synaptic plasticity and memory improvements in a model of HD, the R6/1 mice, by administration of the agonist misoprostol. We found that misoprostol increases dendritic branching in cultured hippocampal neurons in a brain-derived neurotrophic factor (BDNF)-dependent manner. Then, we implanted an osmotic mini-pump system to chronically administrate misoprostol to R6/1 mice from 14 to 18 weeks of age. We observed that misoprostol treatment ameliorates the R6/1 long-term memory deficits as analyzed by the T-maze spontaneous alternation task and the novel object recognition test. Importantly, administration of misoprostol promoted the expression of hippocampal BDNF. Moreover, the treatment with misoprostol in R6/1 mice blocked the reduction in the number of PSD-95 and VGluT-1 positive particles observed in hippocampus of vehicle-R6/1 mice. In addition, we observed an increase of cAMP levels in the dentate ` of WT and R6/1 mice treated with misoprostol. Accordingly, we showed a reduction in the number of mutant huntingtin nuclear inclusions in the dentate gyrus of R6/1 mice. Altogether, these results suggest a putative therapeutic effect of PGE2 EP2 receptor in reducing cognitive deficits in HD.http://www.sciencedirect.com/science/article/pii/S0969996115300474Hippocampus,Huntingtin,Misoprostol,PSD-95 |