Prostaglandin E2 EP2 activation reduces memory decline in R6/1 mouse model of Huntington's disease by the induction of BDNF-dependent synaptic plasticity

• Published in: Neurobiology of disease Vol. 95; pp. 22 - 34
• Main Authors: Anglada-Huguet, Marta, Vidal, Laura, Giralt, Albert, García-Díaz Barriga, Gerardo, Xifró, Xavier, Alberch, Jordi
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2016; Elsevier
• Subjects: Animals; Brain-Derived Neurotrophic Factor - metabolism; Cognition Disorders - metabolism; Dinoprostone - metabolism; Disease Models, Animal; Hippocampus; Hippocampus - metabolism; Huntingtin; Huntington Disease - metabolism; Huntington Disease - physiopathology; Memory - physiology; Memory Disorders - drug therapy; Memory Disorders - physiopathology; Mice, Transgenic; Misoprostol; Neurology; Neuronal Plasticity - physiology; PSD-95; Receptors, Prostaglandin E, EP2 Subtype - metabolism; TNFα; LTM; neuronal intra-nuclear inclusions; PGE 2; IBA1; VGluT1; long-term memory; Misoprostol; CBP; T-spontaneous alternation task; interleukin 6; CREB-binding protein; ionized calcium-binding adapter molecule 1; CREB; tumor necrosis factor alpha; prostaglandin E2; huntingtin; post-synaptic protein 95; brain-derived neurotrophic factor; mutant huntingtin; CA; cAMP-response element binding protein; novel object recognition test; NIIs; BDNF; NORT; mhtt; htt; Huntington's disease; IL-6; GFAP; DIV; T-SAT; Cornu Ammonis; vesicular glutamate transporter 1; days in vitro; HD; PSD-95; glial fibrillary acidic protein; Hippocampus; PGE2; Huntingtin
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2015.09.001

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 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.