PCB-95 promotes dendritic growth via ryanodine receptor-dependent mechanisms

Gary A. Wayman, Dongren Yang, Diptiman D. Bose, Adam Lesiak, Veronica Ledoux, Donald Bruun, Isaac N Pessah, Pamela J Lein

Research output: Contribution to journalArticlepeer-review

76 Scopus citations

Abstract

Background: Aroclor 1254 (A1254) interferes with normal dendritic growth and plasticity in the developing rodent brain, but the mechanism(s) mediating this effect have yet to be established. Non-dioxin-like (NDL) polychlorinated biphenyls (PCBs) enhance the activity of ryanodine receptor (RyR) calcium ion (Ca2++) channels, which play a central role in regulating the spatiotemporal dynamics of intracellular Ca2++ signaling. Ca2++ signaling is a predominant factor in shaping dendritic arbors, but whether PCB potentiation of RyR activity influences dendritic growth is not known. Objective: We determined whether RyR activity is required for PCB effects on dendritic growth. Methods and Results: Golgi analysis of hippocampi from weanling rats confirmed that developmental exposure via the maternal diet to NDL PCB-95 (2,2 ́,3,5 ́6-pentachlorobiphenyl), a potent RyR potentiator, phenocopies the dendrite-promoting effects of A1254. Dendritic growth in dissociated cultures of primary hippocampal neurons and in hippocampal slice cultures is similarly enhanced by PCB-95 but not by PCB-66 (2,3,4 ́,4-tetrachlorobiphenyl), a congener with negligible effects on RyR activity. The dendrite-promoting effects of PCB-95 are evident at concentrations as low as 2 pM and are inhibited by either pharmacologic blockade or siRNA knockdown of RyRs. Conclusions: Our findings demonstrate that environmentally relevant levels of NDL PCBs modulate neuronal connectivity via RyR-dependent effects on dendritic arborization. In addition, these findings identify RyR channel dysregulation as a novel mechanism contributing to dysmorphic dendritogenesis associated with heritable and environmentally triggered neurodevelopmental disorders.

Original languageEnglish (US)
Pages (from-to)997-1002
Number of pages6
JournalEnvironmental Health Perspectives
Volume120
Issue number7
DOIs
StatePublished - Jun 2012

Keywords

  • Dendrites
  • Developmental neurotoxicity
  • Hippocampal neurons
  • Neuronal connectivity
  • Non-dioxin-like PCBs
  • Ryanodine receptor

ASJC Scopus subject areas

  • Health, Toxicology and Mutagenesis
  • Public Health, Environmental and Occupational Health

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