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 (Ca2++)-dependent activation of Ca2++/calmodulin kinase-I (CaMKI), which triggers cAMP response element binding protein (CREB)-dependent Wnt2 transcription. RyRs regulate the spatiotemporal dynamics of intracellular Ca2++ 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. Methods and Results: Ca2++ 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 Ca2++ 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.
Original language | English (US) |
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Pages (from-to) | 1003-1009 |
Number of pages | 7 |
Journal | Environmental health perspectives |
Volume | 120 |
Issue number | 7 |
DOIs | |
State | Published - Jun 2012 |
Keywords
- CREB
- Ca
- CaMKI
- Dendrites
- Developmental neurotoxicity
- Hippocampal MEK
- Neuronal connectivity
- Neurons
- Non-dioxin-like PCBs
- Ryanodine receptor
- Utism
- Wnt2
ASJC Scopus subject areas
- Public Health, Environmental and Occupational Health
- Health, Toxicology and Mutagenesis