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.
abstract: 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 18weeks 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.
authors.affiliation: Departament 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. Electronic address: marta.anglada@dzne.de.
authors.forename: Marta
authors.initials: M
authors.lastname: Anglada-Huguet
authors.affiliation: Departament 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, Spain. Electronic address: lauravidalsancho@gmail.com.
authors.forename: Laura
authors.initials: L
authors.lastname: Vidal-Sancho
authors.affiliation: Departament 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. Electronic address: albert.giralt@inserm.fr.
authors.forename: Albert
authors.initials: A
authors.lastname: Giralt
authors.affiliation: Departament 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. Electronic address: gerardogarcia@ub.edu.
authors.forename: Gerardo
authors.initials: G
authors.lastname: García-Díaz Barriga
authors.affiliation: Departament 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, Spain. Electronic address: Xavier.xifro@ub.edu.
authors.forename: Xavier
authors.initials: X
authors.lastname: Xifró
authors.affiliation: Departament 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. Electronic address: alberch@ub.edu.
authors.forename: Jordi
authors.initials: J
authors.lastname: Alberch
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D003072:Cognition Disorders / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D004195:Disease Models, Animal; D006624:Hippocampus / Q000378:metabolism; D006816:Huntington Disease / Q000378:metabolism / Q000503:physiopathology*; D008568:Memory / Q000502:physiology*; D008569:Memory Disorders / Q000188:drug therapy / Q000503:physiopathology*; D008822:Mice, Transgenic; D009473:Neuronal Plasticity / Q000502:physiology*; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000378:metabolism*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D058307:Receptors, Prostaglandin E, EP2 Subtype; D015232:Dinoprostone
keywords: Hippocampus,; Huntingtin,; Misoprostol,; PSD-95