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  • Title: Pb2+ via protein kinase C inhibits nicotinic cholinergic modulation of synaptic transmission in the hippocampus.
    Author: Braga MF, Pereira EF, Mike A, Albuquerque EX.
    Journal: J Pharmacol Exp Ther; 2004 Nov; 311(2):700-10. PubMed ID: 15226386.
    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 alpha4beta2* and alpha7* nAChRs. It also triggered glutamate release via activation of alpha7* nAChRs. Pb(2+) (0.1 and 1 microM) blocked ACh-triggered transmitter release. Blockade by Pb(2+) 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 Pb(2+)-induced blockade of ACh-triggered EPSCs. The effects of Pb(2+) on GABA release triggered by activation of alpha7* and alpha4beta2* nACRs were mimicked by the protein kinase C (PKC) activator phorbol-12-myristate-13-acetate (1 microM) and blocked by the indolocarbazole Go 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 Pb(2+), the irreversible inhibition by Pb(2+) of ACh-triggered glutamate release was partially overridden by a disinhibitory mechanism that is likely to involve alpha4beta2* nAChR activation in interneurons that synapse onto other interneurons synapsing onto pyramidal neurons. Long-lasting inhibition of alpha7* nAChR modulation of synaptic transmission may contribute to the persistent cognitive impairment that results from childhood Pb(2+) intoxication.
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