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A polymorphism associated with depressive disorders differentially regulates brain derived neurotrophic factor promoter IV activity.

ABSTRACT: Changes in brain derived neurotrophic factor (BDNF) expression have been associated with mood disorders and cognitive dysfunction. Transgenic models that overexpress or underexpress BDNF demonstrate similar deficits in cognition and mood. We explored the hypothesis that BDNF expression is controlled by balancing the activity of BDNF promoter IV (BP4) with a negative regulatory region containing a polymorphism associated with cognitive dysfunction and mood disorders.We used comparative genomics, transgenic mouse production, and magnetofection of primary neurons with luciferase reporters and signal transduction agonist treatments to identify novel polymorphic cis-regulatory regions that control BP4 activity.We show that BP4 is active in the hippocampus, the cortex, and the amygdala and responds strongly to stimuli such as potassium chloride, lithium chloride, and protein kinase C agonists. We also identified a highly conserved sequence 21 kilobase 5' of BP4 that we called BE5.2, which contains rs12273363, a polymorphism associated with decreased BDNF expression, mood disorders, and cognitive decline. BE5.2 modulated the ability of BP4 to respond to different stimuli. Intriguingly, the rarer disease associated allele, BE5.2(C), acted as a significantly stronger repressor of BP4 activity than the more common BE5.2(T) allele.This study shows that the C allele of rs12273363, which is associated with mood disorder, modulates BP4 activity in an allele-specific manner following cell depolarization or the combined activity of protein kinase A and protein kinase C pathways. The relevance of these findings to the role of BDNF misexpression in mood disorders and cognitive decline is discussed.

SUBMITTER: Hing B

PROVIDER: S-EPMC3712170 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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A polymorphism associated with depressive disorders differentially regulates brain derived neurotrophic factor promoter IV activity.

Hing Benjamin B Davidson Scott S Lear Marrisa M Breen Gerome G Quinn John J McGuffin Peter P MacKenzie Alasdair A

Biological psychiatry 20120120 7

<h4>Background</h4>Changes in brain derived neurotrophic factor (BDNF) expression have been associated with mood disorders and cognitive dysfunction. Transgenic models that overexpress or underexpress BDNF demonstrate similar deficits in cognition and mood. We explored the hypothesis that BDNF expression is controlled by balancing the activity of BDNF promoter IV (BP4) with a negative regulatory region containing a polymorphism associated with cognitive dysfunction and mood disorders.<h4>Methods ...[more]

PMID: 22265241

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Project description: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.

Dataset Information

A polymorphism associated with depressive disorders differentially regulates brain derived neurotrophic factor promoter IV activity.

Publications

A polymorphism associated with depressive disorders differentially regulates brain derived neurotrophic factor promoter IV activity.

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