Lead exposure during synaptogenesis alters vesicular proteins and impairs vesicular release: Potential role of NMDA receptor-dependent BDNF signaling

April P. Neal, Kirstie H. Stansfield, Paul F. Worley, Richard E. Thompson, Tomás R. Guilarte

Research output: Contribution to journalArticlepeer-review

Abstract

Lead (Pb2+) exposure is known to affect presynaptic neurotransmitter release in both in vivo and cell culture models. However, the precise mechanism by which Pb2+ impairs neurotransmitter release remains unknown. In the current study, we show that Pb2+ exposure during synaptogenesis in cultured hippocampal neurons produces the loss of synaptophysin (Syn) and synaptobrevin (Syb), two proteins involved in vesicular release. Pb2+ exposure also increased the number of presynaptic contact sites. However, many of these putative presynaptic contact sites lack Soluble NSF attachment protein receptor complex proteins involved in vesicular exocytosis. Analysis of vesicular release using FM 1-43 dye confirmed that Pb2+ exposure impaired vesicular release and reduced the number of fast-releasing sites. Because Pb2+ is a potent N-methyl-D-aspartate receptor (NMDAR) antagonist, we tested the hypothesis that NMDAR inhibition may be producing the presynaptic effects. We show that NMDAR inhibition by aminophosphonovaleric acid mimics the presynaptic effects of Pb2+ exposure. NMDAR activity has been linked to the signaling of the transsynaptic neurotrophin brain-derived neurotrophic factor (BDNF), and we observed that both the cellular expression of proBDNF and release of BDNF were decreased during the same period of Pb2+ exposure. Furthermore, exogenous addition of BDNF rescued the presynaptic effects of Pb2+. We suggest that the presynaptic deficits resulting from Pb2+ exposure during synaptogenesis are mediated by disruption of NMDAR-dependent BDNF signaling.

Original languageEnglish (US)
Pages (from-to)249-263
Number of pages15
JournalToxicological Sciences
Volume116
Issue number1
DOIs
StatePublished - Apr 7 2010

Keywords

  • BDNF
  • FM 1-43
  • Lead
  • Synaptobrevin
  • Synaptophysin
  • Vesicular release

ASJC Scopus subject areas

  • Toxicology

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