The brain-derived neurotrophic factor (BDNF) gene contains 4 major 5′ promoters which generate alternate transcripts. Previously, we found that pan-BDNF mRNA and protein is reduced in the dorsolateral prefrontal cortex (DLPFC) from patients with schizophrenia. In this study, we determined which of the 4 most abundant BDNF alternate transcripts (I–IX, II–IX, IV–IX and VI–IX) are altered in schizophrenia. Using a cohort from the NIMH, USA, we found that BDNF II–IX mRNA was significantly reduced in the DLPFC of patients with schizophrenia, and we replicated this finding using a second cohort from Sydney, Australia. Moreover, we show that the mature BDNF protein is reduced in the DLPFC of patients with schizophrenia, confirming and replicating our previous findings. We next determined the regional specificity of these findings by measuring BDNF transcripts in the parietal cortex and hippocampus and found no significant changes in these two brain regions. Since patients with schizophrenia are often prescribed antidepressants which can up-regulate expression of BDNF, we investigated the relationship between antidepressant treatment and BDNF transcript expression. All four BDNF transcripts were significantly up-regulated in schizophrenics patients treated with antidepressants. When we removed cases with recorded use of antidepressants, this revealed significant reductions in BDNF II–IX and IV–IX in the parietal cortex and VI–IX in the hippocampus of patients with schizophrenia. This suggests that down-regulation of at least 1/4 major BDNF transcripts occurs in various brain regions of patients with schizophrenia, particularly in the DLPFC which appears to have the most robust BDNF deficit in schizophrenia.

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.

Previous studies have shown that inherited taste blindness to bitter compounds like 6-n-propylthiouracil (PROP) may be a risk factor for obesity, but this literature has been highly controversial. The objectives of this study were (i) to confirm findings that show an interaction between PROP status and sex on BMI z-score, and (ii) to determine if sex also interacts with variations in TAS2R38 (phenylthiocarbamide (PTC) genotype) to influence weight status in 4-6 year olds. Also, we tested whether nontaster children consumed more fat and total energy at laboratory-based meals. Seventy-two ethnically diverse children who ranged in weight status were classified as tasters (N = 52) or nontasters (N = 20) using a standard PROP screening solution. Anthropometric measures were taken, and at the end of each visit, children ate ad libitum from test meals intended for exploratory purposes. Genomic DNA was extracted from saliva and alleles at TAS2R38 were genotyped for A49P polymorphisms. In 75.8% of children, PTC genotype predicted PROP phenotype, whereas in 24.4%, genotype did not predict phenotype. PROP nontaster males had higher BMI z-scores than taster-males and females in both groups (P < 0.05), but due to a three-way interaction between PROP phenotype, TAS2R38 genotype, and sex, this relationship was only true for children who were homozygous for the bitter-insensitive allele (P < 0.0005). There were no differences in test-meal intake as a function of PROP phenotype or TAS2R38 genotype. These results suggest that the TAS2R38 variation, PROP phenotype, and sex interact to impact obesity risk in children. Future studies should be done to determine how this trait influences energy balance.