Pb2+ via protein kinase C inhibits nicotinic cholinergic modulation of synaptic transmission in the hippocampus

Maria F.M. Braga, Edna F.R. Pereira, Arpad Mike, Edson X. Albuquerque

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Abstract

The present study was designed to investigate the effects of Pb 2+ on modulation of synaptic transmission by nicotinic receptors (nAChRs) in the rat hippocampus. To this end, inhibitory and excitatory postsynaptic currents (IPSCs and EPSCs, respectively) were recorded by means of the whole-cell mode of the patch-clamp technique from rat hippocampal neurons in culture. Acetylcholine (ACh, 1 mM; 1-s pulses) triggered GABA release via activation of α4β2* and α7* nAChRs. It also triggered glutamate release via activation of α7* nAChRs. Pb 2+ (0.1 and 1 μM) blocked ACh-triggered transmitter release. Blockade by Pb2+ of ACh-triggered IPSCs was partially reversible upon washing of the neurons. In contrast, even after 30- to 60-min washing, there was no reversibility of Pb2+-induced blockade of ACh-triggered EPSCs. The effects of Pb2+ on GABA release triggered by activation of α7* and α4β2* nACRs were mimicked by the protein kinase C (PKC) activator phorbol-12-myristate-13-acetate (1 μM) and blocked by the indolocarbazole Gö 7874 (50 nM) and the bisindolylmaleimide Ro-31-8425 (150 nM), which are selective PKC inhibitors. After washing of fully functional neuronal networks that had been exposed for 5 min to Pb2+, the irreversible inhibition by Pb2+ of ACh-triggered glutamate release was partially overridden by a disinhibitory mechanism that is likely to involve α4β2* nAChR activation in interneurons that synapse onto other interneurons synapsing onto pyramidal neurons. Long-lasting inhibition of α7* nAChR modulation of synaptic transmission may contribute to the persistent cognitive impairment that results from childhood Pb2+ intoxication.

Original languageEnglish
Pages (from-to)700-710
Number of pages11
JournalJournal of Pharmacology and Experimental Therapeutics
Volume311
Issue number2
DOIs
Publication statusPublished - Nov 1 2004

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ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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