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Wheel running and environmental enrichment differentially modify exon-specific BDNF expression in the hippocampus of wild-type and pre-motor symptomatic male and female Huntington's disease mice
journal contribution
posted on 2010-05-01, 00:00 authored by M S Zajac, T Y C Pang, N Wong, B Weinrich, L S K Leang, Jeffrey CraigJeffrey Craig, R Saffery, A J HannanBrain-derived neurotrophic factor (BDNF) is an essential neurotrophin and regulation of its expression is complex due to multiple 5' untranslated exons which are separately spliced to a common coding exon to form unique mRNA transcripts. Disruption of BDNF gene expression is a key to the development of symptoms in Huntington's disease (HD), a fatal neurodegenerative condition. Abnormal epigenetic modifications are associated with reduced gene expression in late-stage HD but such regulation of BDNF gene expression has yet to be investigated. We hypothesized that BDNF gene expression is altered in the HD hippocampus of pre-motor symptomatic R6/1 transgenic HD mice, correlating with a change in the DNA methylation profile. The effects of wheel-running and environmental enrichment on wild-type mice, in association with a proposed environment-mediated correction of BDNF gene expression deficits in HD mice, were also investigated. Using real-time PCR, levels of total BDNF mRNA were found to be reduced in the hippocampus of both male and female HD mice. Wheel-running significantly increased total BDNF gene expression in all groups of mice except male HD mice. In contrast, environmental enrichment significantly increased expression only in male wild-type animals. Further quantification of BDNF exon-specific transcripts revealed sex-specific changes in relation to the effect of the HD mutation and differential effects on gene expression by wheel-running and environmental enrichment. The HD-associated reduction of BDNF gene expression was not due to increased methylation of the gene sequence. Furthermore, environment-induced changes in BDNF gene expression in the wild-type hippocampus were independent of the extent of DNA methylation. Overall, the results of this study provide new insight into the role of BDNF in HD pathogenesis in addition to the mechanisms regulating normal BDNF gene expression.
History
Journal
HippocampusVolume
20Issue
5Pagination
621 - 636Publisher
John Wiley & SonsLocation
Chichester, Eng.Publisher DOI
eISSN
1098-1063Language
engPublication classification
C1.1 Refereed article in a scholarly journalCopyright notice
2009, Wiley‐Liss, Inc.Usage metrics
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Analysis of VarianceAnimalsBrain-Derived Neurotrophic FactorChromatin ImmunoprecipitationDisease Models, AnimalEnvironmentExonsFemaleGene Expression RegulationHippocampusHuntingtin ProteinHuntington DiseaseMaleMiceMice, TransgenicMutationNerve Tissue ProteinsNuclear ProteinsPhysical ExertionRNA, MessengerSex Characteristicsexerciseneurodegenerationsex differencespolyglutamine diseaseScience & TechnologyLife Sciences & BiomedicineNeurosciencesNeurosciences & NeurologyACTIVITY-DEPENDENT EXPRESSIONNERVE GROWTH-FACTORNEUROTROPHIC FACTORTRANSCRIPTION FACTORSYNAPTIC PLASTICITYMOUSE MODELIN-VIVOGENE-TRANSCRIPTIONGLUCOCORTICOID-RECEPTOREPIGENETIC REGULATION
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