title: Increases in two truncated TrkB isoforms in the prefrontal cortex of people with schizophrenia.
abstract: The truncated brain-derived neurotrophic factor (BDNF) receptors (truncated TrkB [TrkB-TK-] and sarc homology containing TrkB [TrkB-Shc]) are alternative transcripts of the full-length TrkB receptor (TrkB-TK+) that produce isoforms capable of binding to BDNF but not being able to mediate the classic neurotrophic response via tyrosine kinase signaling. We hypothesized that in the dorsolateral prefrontal cortex (DLPFC) of people with schizophrenia, truncated TrkB receptors (TK- and Shc) would be altered and may contribute to deficits in BDNF function. Using a large cohort of controls and schizophrenics (n = 72/72), we measured mRNA expression of the full-length TrkB receptor, TrkB-TK+ and the truncated TrkB receptors, TrkB-TK- and TrkB-Shc, by quantitative real-time polymerase chain reaction and protein expression by western blotting. We found highly significant increases in mRNA expression of both truncated TrkB receptor isoforms in people with schizophrenia. When we examined the full-length TrkB-TK+:truncated TrkB ratios, we observed significant decreases in schizophrenia both on the mRNA and protein level. We found a slight reduction in TrkB-TK+ mRNA and a significant reduction in TrkB-TK+ protein expression in schizophrenia, which was evident in females. No gender-specific changes were found for the truncated TrkB receptors. Diagnostic changes in TrkB-TK+ mRNA and protein may be subtle and/or gender-specific, whereas changes in TrkB-TK- and TrkB-Shc expression are robust and may generalize to both males and females with schizophrenia. Increased truncated TrkB receptors may contribute to reduced overall BDNF/tyrosine receptor kinase B (TrkB) signaling and lead to reduced neuronal plasticity in the DLPFC in schizophrenia suggesting that therapies aimed at ameliorating neurotrophin deficits may need to consider blocking excessive truncated TrkB function.
authors.affiliation: Schizophrenia Research Institute, Sydney, Australia.
authors.forename: Jenny
authors.initials: J
authors.lastname: Wong
authors.forename: Debora A
authors.initials: DA
authors.lastname: Rothmond
authors.forename: Maree J
authors.initials: MJ
authors.lastname: Webster
authors.forename: Cynthia Shannon
authors.initials: CS
authors.lastname: Weickert
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D019208:Brain-Derived Neurotrophic Factor / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism; D015331:Cohort Studies; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009473:Neuronal Plasticity; D017397:Prefrontal Cortex / Q000378:metabolism* / Q000473:pathology; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020813:Receptor, trkB / Q000096:biosynthesis* / Q000235:genetics; D012559:Schizophrenia / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D020033:Protein Isoforms; D012333:RNA, Messenger; D020813:Receptor, trkB