title: A polymorphism associated with depressive disorders differentially regulates brain derived neurotrophic factor promoter IV activity.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: School of Medical Sciences, Institute of Medical Sciences, Foresterhill, University of Aberdeen, Scotland, United Kingdom.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Hing
authors.forename: Scott
authors.initials: S
authors.lastname: Davidson
authors.forename: Marrisa
authors.initials: M
authors.lastname: Lear
authors.forename: Gerome
authors.initials: G
authors.lastname: Breen
authors.forename: John
authors.initials: J
authors.lastname: Quinn
authors.forename: Peter
authors.initials: P
authors.lastname: McGuffin
authors.forename: Alasdair
authors.initials: A
authors.lastname: MacKenzie
mesh_terms: D000483:Alleles; D000679:Amygdala / Q000378:metabolism; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D002540:Cerebral Cortex / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D003866:Depressive Disorder / Q000235:genetics*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D023281:Genomics / Q000379:methods; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D018021:Lithium Chloride / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D010703:Phorbol Esters / Q000494:pharmacology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics / Q000502:physiology*; D011189:Potassium Chloride / Q000494:pharmacology; D061251:Primary Cell Culture; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D011493:Protein Kinase C / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D010703:Phorbol Esters; D005576:Colforsin; C119222:phorbol-12-myristate; D011189:Potassium Chloride; D011493:Protein Kinase C; D018021:Lithium Chloride