Title

Increases in two truncated TrkB isoforms in the prefrontal cortex of people with schizophrenia

RIS ID

39150

Publication Details

Wong, J., Rothmond, D., Webster, M. & Shannon Weickert, C. (2013). Increases in two truncated TrkB isoforms in the prefrontal cortex of people with schizophrenia. Schizophrenia Bulletin, 39 (1), 130-140.

Abstract

The truncated brain-derived neurotrophic factor (BDNF) receptors (truncated TrkB [TrkB-TK2] and sarc homology containing TrkB [TrkB-Shc]) are alternative transcripts of the full-length TrkB receptor (TrkB-TK1) 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 (TK2 and Shc) would be altered and may contribute to deficits in BDNF function. Using a large cohort of controls and schizophrenics (n 5 72/72), we measured mRNA expression of the full-length TrkB receptor, TrkB-TK1 and the truncated TrkB receptors, TrkB-TK2and 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-TK1:truncated TrkB ratios, we observed significant decreases in schizophrenia both on the mRNA and protein level. We found a slight reduction in TrkB-TK1mRNAand a significant reduction in TrkB-TK1 protein expression in schizophrenia, which was evident in females. No gender-specific changes were found for the truncated TrkB receptors. Diagnostic changes in TrkB-TK1 mRNA and protein may be subtle and/or gender- specific, whereas changes in TrkB-TK2and 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.

Grant Number

NHMRC/568884

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