Abstract
The present study was designed to investigate the effects of Pb2+ 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. Pb2+ (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.
Footnotes
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↵1 Current address: Department of Psychiatry, F. Edward Herbert School of Medicine, Uniformed Services University of Health Sciences, Rockville, MD 20842.
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↵2 Current address: Department of Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary.
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This work was supported by U.S. Public Health Service Grants ES05730 and NS41671 (for E.X.A.). Part of this work was presented as an abstract at the 1999 Meeting of the Society for Neurosciences.
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According to the current status of the nomenclature for nicotinic receptors (nAChRs) and their subunits (Lukas et al., 1999), the asterisk next to nAChR subunits throughout the text is meant to indicate that the exact receptor subunit composition is not known.
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doi:10.1124/jpet.104.070466.
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ABBREVIATIONS: VGCC, voltage-gated Ca2+ channels; NMDA, N-methyl-d-aspartate; nAChR, nicotinic acetylcholine receptor; PKC, protein kinase C; IPSC, inhibitory postsynaptic current; EPSC, excitatory postsynaptic current; ACh, acetylcholine; PMA, phorbol 12-myristate 13-acetate; CNQX, 6-cyano-7-nitroquinoxaline-2,3-dione; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; MLA, methyllycaconitine; DHβE, dihydro-β-erythroidine.
- Received April 30, 2004.
- Accepted June 28, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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Pb2+ via Protein Kinase C Inhibits Nicotinic Cholinergic Modulation of Synaptic Transmission in the Hippocampus
