RGD Reference Report - Targeted silencing of TrkA expression in rat forebrain neurons via the p75 receptor. - Rat Genome Database

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Targeted silencing of TrkA expression in rat forebrain neurons via the p75 receptor.

Authors: Berhanu, DA  Rush, RA 
Citation: Berhanu DA and Rush RA, Neuroscience. 2008 Jun 2;153(4):1115-25. Epub 2008 Mar 22.
RGD ID: 5684387
Pubmed: PMID:18440710   (View Abstract at PubMed)
DOI: DOI:10.1016/j.neuroscience.2008.03.025   (Journal Full-text)

Basal forebrain neurons express the neurotrophin receptors, p75NTR and tyrosine kinase receptor A (TrkA). We tested the hypothesis that impairment of memory in rats could be achieved by RNA interference (RNAi) -induced silencing of TrkA specifically within these neurons. A novel fusogenic, karyophilic immunoporter (fkAb(p75)-ipr) was constructed from the antibody, MC192 (monoclonal antibody to the rat neurotrophin receptor p75NTR, Ab(p75)), poly-l-lysine together with the hemagglutinin 2 and VP1 nuclear localization peptides of influenza and SV40 virus, respectively. Plasmid DNA constructs containing short hairpin sequences inhibitory to tyrosine kinase receptor A expression (TrkAi) and the gene encoding cGFP (green fluorescent protein from coral fish) was produced. These TrkAi plasmids were mixed with the immunoporter, forming the immunogene, TrkAi-fkAb(p75). A control TrkAsc complexed with fkAb(p75) (TrkAsc-fkAb(p75)) immunogene was constructed from a scrambled sequence (TrkAsc) and fkAb(p75)-ipr. Rats were infused using an osmotic mini-pump into the third ventricle with either TrkAi-fkAb(p75) or TrkAsc-fkAb(p75). Naive rats were also included as additional controls. After 7 days, examination of gene expression on forebrain sections of some rats revealed cGFP expression in TrkA neurons. Fifteen to 19 days after infusion, rats were tested in a Morris water maze apparatus. Animals that received TrkAi-fkAb(p75) showed significantly impaired spatial memory learning ability compared with naive or TrkAsc-fkAb(p75)-treated rats. Western blot and immunofluorescence analysis showed that TrkA protein levels and numbers of TrkA positive neurons were reduced by 60% and 55% respectively in TrkAi-fkAb(p75)-infused rats compared with infused controls or naive animals. We conclude that p75-receptor-mediated RNAi-induced silencing of genes offers a novel and powerful way to study the function of specific endogenous genes within distinct neuronal subpopulations of the brain.



Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Ntrk1Ratlearning or memory  IMP  RGD 

Objects Annotated

Genes (Rattus norvegicus)
Ntrk1  (neurotrophic receptor tyrosine kinase 1)


Additional Information