The environmental neurotoxicant PCB 95 promotes synaptogenesis via ryanodine receptor-dependent miR132 upregulation

Adam Lesiak, Mingyan Zhu, Hao Chen, Suzanne M. Appleyard, Soren Impey, Pamela J Lein, Gary A. Wayman

Research output: Contribution to journalArticle

47 Scopus citations

Abstract

Non-dioxin-like (NDL) polychlorinated biphenyls (PCBs) are widespread environmental contaminants linked to neuropsychological dysfunction in children. NDL PCBs increase spontaneous Ca2+ oscillations in neurons by stabilizing ryanodine receptor (RyR) calcium release channels in the open configuration, which results in CREB-dependent dendritic outgrowth. In this study, we address the question of whether activation of CREB by NDL PCBs also triggers dendritic spine formation. Nanomolar concentrations of PCB 95, a NDL congener with potent RyR activity, significantly increased spine density and the frequency of miniature EPSCs in primary dissociated rat hippocampal cultures coincident with upregulation of miR132. Inhibition of RyR, CREB, or miR132 as well as expression of a mutant p250GAP cDNA construct that is not suppressed by miR132 blocked PCB 95 effects on spines and miniature EPSCs. PCB 95 also induced spine formation via RyR- and miR132-dependent mechanisms in hippocampal slice cultures. These data demonstrate a novel mechanism of PCB developmental neurotoxicity whereby RyR sensitization modulates spine formation and synaptogenesis via CREB-mediated miR132 upregulation, which in turn suppresses the translation of p250GAP, a negative regulator of synaptogenesis. In light of recent evidence implicating miR132 dysregulation in Rett syndrome and schizophrenia, these findings identify NDL PCBs as potential environmental risk factors for neurodevelopmental disorders.

Original languageEnglish (US)
Pages (from-to)717-725
Number of pages9
JournalJournal of Neuroscience
Volume34
Issue number3
DOIs
StatePublished - 2014

Keywords

  • CREB
  • Dendritic spines
  • Developmental neurotoxicity
  • MicroRNA
  • Polychlorinated biphenyls
  • Synaptogenesis

ASJC Scopus subject areas

  • Neuroscience(all)

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