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

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.

Decreased BDNF and TrkB mRNA expression in multiple cortical areas of patients with schizophrenia and mood disorders

“…10,14,20,59 Likewise, it may be that the blood levels of BDNF in the periphery reflect the brain levels as has been shown in the development and aging of the rat. 60 Thus, measuring peripheral BDNF levels may provide a biomarker for disease state or provide a marker for treatment response.…”

BDNF promoter I methylation correlates between post-mortem human peripheral and brain tissues

“…Indeed, a recent study suggests that a single CpG site could be a good proxy for the whole CpG Island to which the site belongs to in terms of methylation (Barrera and Peinado, 2012). The different promoters located at the 5 side of the BDNF gene combined with different splice sites and the presence of an antisense regulatory mechanism are thought to be responsible for the production of different transcript isoforms of BDNF that are differentially expressed among tissues and at various development periods (Wong et al, 2009). Previous work performed in mice showed that promoter IV was active in nonneural tissues (lung, heart, and muscle), whereas promoters I, II, and III were predominantly used in the brain (Timmusk et al, 1993(Timmusk et al, , 1999.…”

Dynamic molecular and anatomical changes in the glucocorticoid receptor in human cortical development

“…Four 'housekeeper' genes that did not change expression with development were chosen: hydroxymethylbilane synthase (Hs00609297_m1), glucuronidase-b (Hs99999908_m1), ubiquitin C (Hs00824723_m1) and cyclophilin A (Hs99999904_m1). 63 Serial dilutions of pooled cDNA (from seven samples, one from each developmental time point) were included on every qPCR plate for quantification of sample expression by the relative standard curve method. Efficiencies of the qPCR reactions ranged from 77-100%, with R 2 values ranging between 0.95 and 1.00.…”