PCB 95 promotes dendritic growth in primary rat hippocampal neurons via mTOR-dependent mechanisms

Kimberly P. Keil, Galen W. Miller, Hao Chen, Sunjay Sethi, Martin R. Schmuck, Kiran Dhakal, Ji Won Kim, Pamela J Lein

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Polychlorinated biphenyls (PCBs), and in particular non-dioxin-like (NDL) congeners, continue to pose a significant risk to the developing nervous system. PCB 95, a prevalent NDL congener in the human chemosphere, promotes dendritic growth in rodent primary neurons by activating calcium-dependent transcriptional mechanisms that normally function to link activity to dendritic growth. Activity-dependent dendritic growth is also mediated by calcium-dependent translational mechanisms involving mechanistic target of rapamycin (mTOR), suggesting that the dendrite-promoting activity of PCB 95 may also involve mTOR signaling. Here, we test this hypothesis using primary neuron-glia co-cultures derived from the hippocampi of postnatal day 0 Sprague Dawley rats. PCB 95 (1 nM) activated mTOR in hippocampal cultures as evidenced by increased phosphorylation of mTOR at ser2448. Pharmacologic inhibition of mTOR signaling using rapamycin (20 nM), FK506 (5 nM), or 4EGI-1 (1 µM), and siRNA knockdown of mTOR, or the mTOR complex binding proteins, raptor or rictor, blocked PCB 95-induced dendritic growth. These data identify mTOR activation as a novel molecular mechanism contributing to the effects of PCB 95 on dendritic arborization. In light of clinical data linking gain-of-function mutations in mTOR signaling to neurodevelopmental disorders, our findings suggest that mTOR signaling may represent a convergence point for gene by environment interactions that confer risk for adverse neurodevelopmental outcomes.

Original languageEnglish (US)
Pages (from-to)3163-3173
Number of pages11
JournalArchives of Toxicology
Volume92
Issue number10
DOIs
StatePublished - Oct 1 2018

Keywords

  • Developmental neurotoxicity
  • Neurodevelopmental disorders
  • Persistent organic pollutants
  • Sholl analysis

ASJC Scopus subject areas

  • Toxicology
  • Health, Toxicology and Mutagenesis

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    Keil, K. P., Miller, G. W., Chen, H., Sethi, S., Schmuck, M. R., Dhakal, K., Kim, J. W., & Lein, P. J. (2018). PCB 95 promotes dendritic growth in primary rat hippocampal neurons via mTOR-dependent mechanisms. Archives of Toxicology, 92(10), 3163-3173. https://doi.org/10.1007/s00204-018-2285-x