title: Histamine up-regulates fibroblast growth factor receptor 1 and increases FOXP2 neurons in cultured neural precursors by histamine type 1 receptor activation: conceivable role of histamine in neurogenesis during cortical development in vivo.
abstract: BACKGROUND
  During rat development, histamine (HA) is one of the first neuroactive molecules to appear in the brain, reaching its maximal value at embryonic day 14, a period when neurogenesis of deep layers is occurring in the cerebral cortex, suggesting a role of this amine in neuronal specification. We previously reported, using high-density cerebrocortical neural precursor cultures, that micromolar HA enhanced the effect of fibroblast growth factor (FGF)-2 on proliferation, and that HA increased neuronal differentiation, due to HA type 1 receptor (H(1)R) activation.
  
  
  RESULTS
  Clonal experiments performed here showed that HA decreased colony size and caused a significant increase in the percentage of clones containing mature neurons through H(1)R stimulation. In proliferating precursors, we studied whether HA activates G protein-coupled receptors linked to intracellular calcium increases. Neural cells presented an increase in cytoplasmic calcium even in the absence of extracellular calcium, a response mediated by H(1)R. Since FGF receptors (FGFRs) are known to be key players in cell proliferation and differentiation, we determined whether HA modifies the expression of FGFRs1-4 by using RT-PCR. An important transcriptional increase in FGFR1 was elicited after H(1)R activation. We also tested whether HA promotes differentiation specifically to neurons with molecular markers of different cortical layers by immunocytochemistry. HA caused significant increases in cells expressing the deep layer neuronal marker FOXP2; this induction of FOXP2-positive neurons elicited by HA was blocked by the H(1)R antagonist chlorpheniramine in vitro. Finally, we found a notable decrease in FOXP2+ cortical neurons in vivo, when chlorpheniramine was infused in the cerebral ventricles through intrauterine injection.
  
  
  CONCLUSIONS
  These results show that HA, by activating H(1)R, has a neurogenic effect in clonal conditions and suggest that intracellular calcium elevation and transcriptional up-regulation of FGFR1 participate in HA-induced neuronal differentiation to FOXP2 cells in vitro; furthermore, H(1)R blockade in vivo resulted in decreased cortical FOXP2+ neurons.
authors.affiliation: Instituto de Fisiología Celular - Neurociencias, Universidad Nacional Autónoma de México, México, D.F. 04510, México.
authors.forename: Anayansi
authors.initials: A
authors.lastname: Molina-Hernández
authors.forename: Griselda
authors.initials: G
authors.lastname: Rodríguez-Martínez
authors.forename: Itzel
authors.initials: I
authors.lastname: Escobedo-Ávila
authors.forename: Iván
authors.initials: I
authors.lastname: Velasco
mesh_terms: D000818:Animals; D002452:Cell Count; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000196:embryology*; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006632:Histamine / Q000378:metabolism*; D007150:Immunohistochemistry; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism; D055495:Neurogenesis / Q000502:physiology*; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000378:metabolism*; D011968:Receptors, Histamine / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D015854:Up-Regulation
chemical_list: D051858:Forkhead Transcription Factors; C558285:Foxp2 protein, rat; D011968:Receptors, Histamine; D006632:Histamine; C496350:Fgfr1 protein, rat; D051496:Receptor, Fibroblast Growth Factor, Type 1