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Published on: September 15, 2014
Promoter specific alterations of brain-derived neurotrophic factor mRNA in schizophrenia
J Wong1, T M Hyde, H L Cassano
1Schizophrenia Research Institute, Sydney, Australia.
Abstract:
The brain-derived neurotrophic factor (BDNF) gene contains multiple 5' promoters which generate alternate transcripts. Previously, we found that pan-BDNF mRNA and protein are reduced in the dorsolateral prefrontal cortex (DLPFC) from patients with schizophrenia. In this study, we determined which of the four most abundant and best characterized 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 BDNF protein expression [including prepro ( approximately 32 kDa), pro ( approximately 28 kDa) and mature ( approximately 14 kDa) BDNF] is reduced in the DLPFC of patients with schizophrenia. We next determined the regional specificity of the BDNF mRNA reduction by measuring BDNF transcripts in the parietal cortex and hippocampus and found no significant changes. The effect of antipsychotics on BDNF alternate transcript expression was also examined and we found no relationship between BDNF mRNA expression and antipsychotic use. As schizophrenic patients 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 schizophrenic patients treated with antidepressants. Moreover, we found significant reductions in BDNF transcripts II-IX and IV-IX in the parietal cortex and VI-IX in the hippocampus of patients with schizophrenia who did not have a history of treatment with antidepressants. This suggests that down-regulation of at least one out of four 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.
Insights
Brain-derived neurotrophic factor (BDNF) gene transcripts are reduced in schizophrenia patients, particularly in the dorsolateral prefrontal cortex. Antidepressant treatment, however, up-regulates BDNF expression in these patients.
Area of Science:
- Neuroscience
- Genetics
- Psychiatry
Background:
- Brain-derived neurotrophic factor (BDNF) plays a crucial role in neuronal survival, growth, and plasticity.
- Previous research indicated reduced pan-BDNF mRNA and protein in the dorsolateral prefrontal cortex (DLPFC) of schizophrenia patients.
- The specific BDNF alternate transcripts affected in schizophrenia remain largely uncharacterized.
Purpose of the Study:
- To investigate the expression levels of four major BDNF alternate transcripts (I-IX, II-IX, IV-IX, and VI-IX) in the DLPFC of schizophrenia patients.
- To determine the regional specificity of BDNF transcript alterations in schizophrenia.
- To examine the influence of antipsychotic and antidepressant medications on BDNF transcript expression.
Main Methods:
- Quantitative analysis of BDNF mRNA transcripts (II-IX, IV-IX, VI-IX) using two independent patient cohorts (NIMH, USA and Sydney, Australia).
- Measurement of BDNF protein levels (prepro-, pro-, and mature BDNF) in the DLPFC.
- Assessment of BDNF transcript expression in the parietal cortex and hippocampus to determine regional specificity.
- Correlation analysis between BDNF transcript levels and medication history (antipsychotics, antidepressants).
Main Results:
- BDNF II-IX mRNA was significantly reduced in the DLPFC of schizophrenia patients across both cohorts.
- BDNF protein expression (prepro-, pro-, and mature forms) was also reduced in the DLPFC.
- No significant changes in BDNF transcripts were observed in the parietal cortex or hippocampus in the absence of antidepressant treatment.
- Antidepressant treatment significantly up-regulated all four examined BDNF transcripts in schizophrenia patients.
- Significant reductions in BDNF II-IX, IV-IX (parietal cortex), and VI-IX (hippocampus) were found in patients not treated with antidepressants, suggesting regional deficits.
Conclusions:
- Specific BDNF alternate transcripts, notably BDNF II-IX, are down-regulated in the DLPFC of schizophrenia patients.
- The DLPFC exhibits the most pronounced BDNF deficit in schizophrenia.
- Antidepressant use can mask or reverse BDNF down-regulation, highlighting the importance of considering medication history in research.
- BDNF down-regulation occurs in multiple brain regions in schizophrenia, particularly in the absence of antidepressant treatment.
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