title: PCB-95 modulates the calcium-dependent signaling pathway responsible for activity-dependent dendritic growth.
abstract: BACKGROUND
  Non-dioxin-like (NDL) polychlorinated biphenyls (PCBs) promote dendritic growth in hippocampal neurons via ryanodine receptor (RyR)-dependent mechanisms; however, downstream signaling events that link enhanced RyR activity to dendritic growth are unknown. Activity-dependent dendritic growth, which is a critical determinant of neuronal connectivity in the developing brain, is mediated by calcium ion (Ca(2+))-dependent activation of Ca(2+)/calmodulin kinase-I (CaMKI), which triggers cAMP response element binding protein (CREB)-dependent Wnt2 transcription. RyRs regulate the spatiotemporal dynamics of intracellular Ca(2+) signals, but whether RyRs promote dendritic growth via modulation of this signaling pathway is not known.
  
  
  OBJECTIVE
  We tested the hypothesis that the CaMKI-CREB-Wnt2 signaling pathway couples NDL PCB-enhanced RyR activity to dendritic arborization.
  
  
  RESULTS
  Ca(2+) imaging of dissociated cultures of primary rat hippocampal neurons indicated that PCB-95 (2,2',3,5'6-pentachlorobiphenyl; a potent RyR potentiator), enhanced synchronized Ca(2+) oscillations in somata and dendrites that were blocked by ryanodine. As determined by Western blotting and quantitative polymerase chain reaction, PCB-95 also activated CREB and up-regulated Wnt2. Blocking CaMKK, CaMKIα/γ, MEK/ERK, CREB, or Wnt2 prevented PCB-95-induced dendritic growth. Antagonism of γ-aminobutyric acid (GABA) receptors with bicuculline (BIC) phenocopied the dendrite-promoting effects of PCB-95, and pharmacological antagonism or siRNA knockdown of RyR blocked BIC-induced dendritic growth in dissociated and slice cultures of hippocampal neurons.
  
  
  CONCLUSIONS
  RyR activity contributes to dynamic remodeling of dendritic architecture in response to NDL PCBs via CaMKI-CREB-Wnt2 signaling in rats. Our findings identify PCBs as candidate environmental risk factors for neurodevelopmental disorders, especially in children with heritable deficits in calcium signaling associated with autism.
authors.affiliation: Program in Neuroscience, Department of Veterinary and Comparative Anatomy, Pharmacology and Physiology, Washington State University, Pullman, Washington, USA.
authors.forename: Gary A
authors.initials: GA
authors.lastname: Wayman
authors.forename: Diptiman D
authors.initials: DD
authors.lastname: Bose
authors.forename: Dongren
authors.initials: D
authors.lastname: Yang
authors.forename: Adam
authors.initials: A
authors.lastname: Lesiak
authors.forename: Donald
authors.initials: D
authors.lastname: Bruun
authors.forename: Soren
authors.initials: S
authors.lastname: Impey
authors.forename: Veronica
authors.initials: V
authors.lastname: Ledoux
authors.forename: Isaac N
authors.initials: IN
authors.lastname: Pessah
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Lein
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D003712:Dendrites / Q000187:drug effects*; D006624:Hippocampus / Q000166:cytology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D011078:Polychlorinated Biphenyls / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: C032904:2,2',3,5',6-pentachlorobiphenyl; D011078:Polychlorinated Biphenyls; D002118:Calcium