title: The responsiveness of TrkB to BDNF and antidepressant drugs is differentially regulated during mouse development.
abstract: BACKGROUND
  Previous studies suggest that the responsiveness of TrkB receptor to BDNF is developmentally regulated in rats. Antidepressant drugs (AD) have been shown to increase TrkB signalling in the adult rodent brain, and recent findings implicate a BDNF-independent mechanism behind this phenomenon. When administered during early postnatal life, ADs produce long-lasting biochemical and behavioural alterations that are observed in adult animals.
  
  
  METHODS
  We have here examined the responsiveness of brain TrkB receptors to BDNF and ADs during early postnatal life of mouse, measured as autophosphorylation of TrkB (pTrkB).
  
  
  RESULTS
  We found that ADs fail to induce TrkB signalling before postnatal day 12 (P12) after which an adult response of TrkB to ADs was observed. Interestingly, there was a temporally inverse correlation between the appearance of the responsiveness of TrkB to systemic ADs and the marked developmental reduction of BDNF-induced TrkB in brain microslices ex vivo. Basal p-TrkB status in the brain of BDNF deficient mice was significantly reduced only during early postnatal period. Enhancing cAMP (cyclic adenosine monophosphate) signalling failed to facilitate TrkB responsiveness to BDNF. Reduced responsiveness of TrkB to BDNF was not produced by the developmental increase in the expression of dominant-negative truncated TrkB.T1 because this reduction was similarly observed in the brain microslices of trkB.T1(-/-) mice. Moreover, postnatal AD administration produced long-lasting behavioural alterations observable in adult mice, but the responses were different when mice were treated during the time when ADs did not (P4-9) or did (P16-21) activate TrkB.
  
  
  CONCLUSIONS
  We have found that ADs induce the activation of TrkB only in mice older than 2 weeks and that responsiveness of brain microslices to BDNF is reduced during the same time period. Exposure to ADs before and after the age when ADs activate TrkB produces differential long-term behavioural responses in adult mice.
authors.affiliation: Sigrid Jusélius Laboratory, Neuroscience Center, University of Helsinki, Helsinki, Finland.
authors.forename: Antonio
authors.initials: A
authors.lastname: Di Lieto
authors.forename: Tomi
authors.initials: T
authors.lastname: Rantamäki
authors.forename: Liisa
authors.initials: L
authors.lastname: Vesa
authors.forename: Sudhirkumar
authors.initials: S
authors.lastname: Yanpallewar
authors.forename: Hanna
authors.initials: H
authors.lastname: Antila
authors.forename: Jesse
authors.initials: J
authors.lastname: Lindholm
authors.forename: Maribel
authors.initials: M
authors.lastname: Rios
authors.forename: Lino
authors.initials: L
authors.lastname: Tessarollo
authors.forename: Eero
authors.initials: E
authors.lastname: Castrén
mesh_terms: D000367:Age Factors; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001522:Behavior, Animal; D001921:Brain / Q000196:embryology*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D002474:Cell-Free System; D002997:Clomipramine / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental; D007099:Imipramine / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D010766:Phosphorylation; D020813:Receptor, trkB / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors
chemical_list: D000928:Antidepressive Agents; D019208:Brain-Derived Neurotrophic Factor; D000242:Cyclic AMP; D020813:Receptor, trkB; D002997:Clomipramine; D007099:Imipramine