Changes in alternative brain-derived neurotrophic factor transcript expression in the developing human prefrontal cortex

Authors

  • Jenny Wong,

    1. Schizophrenia Research Institute, Sydney, Australia
    2. Schizophrenia Research Laboratory, Prince of Wales Medical Research Institute, University of New South Wales, Sydney, Australia
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  • Maree J. Webster,

    1. Stanley Medical Research Institute, Rockville, MD, USA
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  • Hope Cassano,

    1. MiNDS Unit, Clinical Brain Disorders Branch, IRP, NIMH, NIH, Bethesda, MD, USA
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  • Cynthia S. Weickert

    1. Schizophrenia Research Institute, Sydney, Australia
    2. Schizophrenia Research Laboratory, Prince of Wales Medical Research Institute, University of New South Wales, Sydney, Australia
    3. MiNDS Unit, Clinical Brain Disorders Branch, IRP, NIMH, NIH, Bethesda, MD, USA
    4. Department of Psychiatry, Prince of Wales Medical Research Institute, University of New South Wales, Corner of Barker and Easy Street, Randwick, Sydney, New South Wales 2031, Australia
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Dr C. S. Weickert, 5Department of Psychiatry, as above.
E-mail: c.weickert@powmri.edu.au

Abstract

In this study, we determined when and through which promoter brain-derived neurotrophic factor (BDNF) transcription is regulated during the protracted period of human frontal cortex development. Using quantitative real-time polymerase chain reaction, we examined the expression of the four most abundant alternative 5′ exons of the BDNF gene (exons I, II, IV, and VI) in RNA extracted from the prefrontal cortex. We found that expression of transcripts I–IX and VI–IX was highest during infancy, whereas that of transcript II–IX was lowest just after birth, slowly increasing to reach a peak in toddlers. Transcript IV–IX was significantly upregulated within the first year of life, and was maintained at this level until school age. Quantification of BDNF protein revealed that levels followed a similar developmental pattern as transcript IV–IX. In situ hybridization of mRNA in cortical sections showed the highest expression in layers V and VI for all four BDNF transcripts, whereas moderate expression was observed in layers II and III. Interestingly, although low expression of BDNF was observed in cortical layer IV, this BDNF mRNA low-zone decreased in prominence with age and showed an increase in neuronal mRNA localization. In summary, our findings show that dynamic regulation of BDNF expression occurs through differential use of alternative promoters during the development of the human prefrontal cortex, particularly in the younger age groups, when the prefrontal cortex is more plastic.

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