Abstract
Bath application of methylmercury (MeHg) causes an early stimulation before block of synaptic transmission in the CA1 region of hippocampal slices. Effects of MeHg and Hg++ on inhibitory postsynaptic potentials (IPSPs) or currents (IPSCs) and excitatory postsynaptic potentials (EPSPs) or currents (EPSCs) were compared to test whether or not early block by MeHg of GABAA-mediated inhibitory synaptic transmission and MeHg-induced alterations of the resting membrane potentials of CA1 neurons contribute to this initial enhancement of excitability. MeHg affected IPSPs and IPSCs similarly, and more rapidly than EPSPs and EPSCs. In contrast, although Hg++ blocked IPSPs more rapidly than EPSPs, times to block of IPSCs and EPSCs by Hg++ were virtually identical when CA1 neurons were voltage-clamped at their resting membrane potential levels. MeHg increased EPSC amplitudes before their subsequent decrease even when CA1 neuronal membranes were voltage-clamped at their resting potentials. This suggests that effects of MeHg on CA1 cell membrane potentials are not a major factor for MeHg-induced early stimulation of hippocampal synaptic transmission. Effects of MeHg and Hg++on the reversal potentials for IPSCs also differed. Both metals blocked all outward and inward currents generated at different holding potentials. However, MeHg shifted the current-voltage (I/V) relationship to more positive potentials, although Hg++shifted the I/V curve to more negative potentials. Hg++ was a less potent blocker of on IPSCs and EPSPs or EPSCs than was MeHg. To determine if the early increase in amplitude of population spikes or EPSPs is due to an action of MeHg at GABAA receptors, extracellular recordings of population spikes and intracellular recordings of EPSPs were compared with or without pretreatment of hippocampal slices with bicuculline. After preincubation of slices with 10 μM bicuculline for 30 to 60 min, MeHg only decreased the amplitudes of population spikes and EPSPs to block; no early increase of synaptic transmission occurred. Pretreatment of slices with strychnine, did not prevent MeHg-induced early increase in population spikes. MeHg also blocked responses evoked by bath application of muscimol, a GABAA agonist. Thus, block by MeHg of GABAA receptor-mediated inhibitory synaptic transmission may result in disinhibition of excitatory hippocampal synaptic transmission, and appears to be primarily responsible for the initial excitatory effect of MeHg on hippocampal synaptic transmission.
Footnotes
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Send reprint requests to: Dr. William D. Atchison, Department of Pharmacology and Toxicology, B-331 Life Sciences Building, Michigan State University, East Lansing, MI 48824-1317. email: atchisol{at}pilot.msu.edu
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↵1 This work was supported by National Institutes of Health Grant ES03299. Preliminary results of parts of these studies were presented at the 25th Annual Meeting of the Society for Neuroscience, November 11–16, 1995, San Diego, CA and the 35th Annual Meeting of the Society of Toxicology, March 10–14, 1996, Anaheim, CA and published in abstract form in Society for Neuroscience Abstracts 21:1985, 1995 and Fundamental and Applied Toxicology (Suppl.)30: 24, 1996, respectively. This work was submitted by Y.Y. in partial completion of the requirements of the Ph.D. degree in Pharmacology and Toxicology at Michigan State University.
- Abbreviations:
- MeHg
- methylmercury
- GABA
- γ-aminobutyric acid
- EPSPs
- excitatory postsynaptic potentials
- EPSCs
- excitatory postsynaptic currents
- IPSPs
- inhibitory postsynaptic potentials
- IPSCs
- inhibitory postsynaptic currents
- ACSF
- artificial cerebrospinal fluid
- DNQX
- 6,7-dinitroquinoxaline-2,3-dione
- AP-5
- amino-5-phosphonopentanoic acid
- I/V curve
- voltage-current relationship
- DMSO
- dimethyl sulfoxide
- Received August 5, 1996.
- Accepted March 7, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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