Expression and Dendritic Trafficking of BDNF-6 Splice Variant are Impaired in Knock-In Mice Carrying Human BDNF Val66Met Polymorphism

Abstract

Background:The human Val66Met polymorphism in brain-derived neurotrophic factor (BDNF), a key factor in neuroplasticity, synaptic function, and cognition, has been implicated in the pathophysiology of neuropsychiatric and neurodegenerative disorders. BDNF is encoded by multiple transcripts with distinct regulation and localization, but the impact of the Val66Met polymorphism on BDNF regulation remains unclear.Methods:In BDNF Val66Met knock-in mice, which recapitulate the phenotypic hallmarks of individuals carrying the BDNFMet allele, we measured expression levels, epigenetic changes at promoters, and dendritic trafficking of distinct BDNF transcripts using quantitative PCR, chromatin immunoprecipitation (ChIP), and in situ hybridization.Results:BDNF-4 and BDNF-6 transcripts were reduced in BDNFMet/Met mice, compared with BDNFVal/Val mice. ChIP for acetyl-histone H3, a marker of active gene transcription, and trimethyl-histone-H3-Lys27 (H3K27me3), a marker of gene repression, showed higher H3K27me3 binding to exon 5, 6, and 8 promoters in BDNFMet/Met. The H3K27 methyltransferase enhancer of zeste homolog 2 (EZH2) is involved in epigenetic regulation of BDNF expression, because in neuroblastoma cells BDNF expression was increased both by short interference RNA for EZH2 and incubation with 3-deazaneplanocin A, an inhibitor of EZH2. In situ hybridization for BDNF-2, BDNF-4, and BDNF-6 after pilocarpine treatment showed that BDNF-6 transcript was virtually absent from distal dendrites of the CA1 and CA3 regions in BDNFMet/Met mice, while no changes were found for BDNF-2 and BDNF-4.Conclusions:Impaired BDNF expression and dendritic targeting in BDNFMet/Met mice may contribute to reduced regulated secretion of BDNF at synapses, and may be a specific correlate of pathology in individuals carrying the Met allele.

Distinct effects on the dendritic arbor occur by microbead versus bath administration of brain-derived neurotrophic factor

“…The different 5′ UTRs selectively alter outgrowth of proximal or distal dendrites, depending on where BDNF mRNA is localized by the 5′ UTRs, and these changes in dendritic arborization may be related to selective activation of TrkB in these dendritic regions [48]. Additionally, trafficking of the BDNF 5′ UTR splice variant resulting from exon 6 is impaired in mice expressing the BDNF human variant Val66Met [81], having implications for BDNF action on the dendritic arbor. Finally, as the Val66Met mutation results in decreased transport of BDNF mRNA in the dendrites (as reviewed in [82]), and thus a disruption of the BDNF mRNA spatial code [83], it is possible that local stimulation of the dendritic arbor by BDNF-coated beads may alleviate some of the issues caused by this dysregulation in BDNF mRNA transport.…”

The roles of RNA processing in translating genotype to phenotype

“…This G–A substitution decreases trafficking of BDNF transcripts to the distal dendrites of neurons by disrupting the interaction between BDNF mRNA and the mRNA trafficking protein translin. In combination with altered protein function due to the Val66Met amino acid change, this SNV-induced loss of BDNF mRNA at the dendrites is thought to contribute to allele-specific defects in activity-dependent secretion of BDNF protein at dendrites 105,108,111 .…”

Brain-Derived Neurotrophic Factor Val66Met Human Polymorphism Impairs the Beneficial Exercise-Induced Neurobiological Changes in Mice

“…(Aid et al, 2007;Lyons and West, 2011). In particular, it has been demonstrated that BDNF transcripts are specifically segregated within the soma (BDNFs 1 and 4) or the dendrites (BDNFs 2 and 6), therefore working as a spatial code (Baj et al, 2012(Baj et al, , 2013Mallei et al, 2015).…”