Disruption by Methylmercury of Membrane Excitability and Synaptic Transmission of CA1 Neurons in Hippocampal Slices of the Rat

Abstract

In order to examine the effects of methylmercury (MeHg) on central synaptic transmission, field potentials were recorded in the CA1 neurons of hippocampal slices by using extracellular microelectrode recording techniques. After stimulation of Schaffer collaterals at low frequency (0.25 Hz), population spikes and excitatory postsynaptic potentials (EPSPs) were recorded at the cell bodies and apical dendrites of CA1 pyramidal cells, respectively. Antidromically activated population spikes were also recorded at the cell bodies of CA1 pyramidal cells by stimulating the alveus. Long-term potentiation (LTP) was induced by application of brief high-frequency stimulation (15 trains of four stimuli per train at 100 Hz) after 25 min of population spike baseline recordings. MeHg was applied to slices acutely by bath perfusion with artificial cerebrospinal fluid (ACSF). At 20-500 μM, MeHg significantly increased and then decreased the amplitudes of, or blocked, the population spikes, EPSPs, and antidromically activated population spikes. Time to increase and time to block of these field potentials were concentration-dependent. Exposure of slices to 4 μM MeHg for 180 min increased but did not reduce the amplitudes of population spikes, EPSPs, or antidromically activated population spikes. The effects of MeHg on population spikes induced by either orthodromic or antidromic stimulation were similar. In the absence of MeHg, application of high-frequency stimulation increased population spike amplitudes by 60-100%. This effect (LTP) could be sustained for more than 2 hr in the absence of MeHg. When 100 μM MeHg was applied concomitantly with high-frequency stimulation, the population spike amplitudes were increased by an additional 20-50% based on the already elevated population spike amplitude by high-frequency stimulation. Subsequently, population spike amplitudes were reduced and finally blocked in a manner similar to the effect of MeHg on population spikes recorded without high-frequency stimulation. Application of MeHg (100 μM) for 20 min prior to high-frequency stimulation did not prevent induction of LTP even though the population spike amplitudes had been decreased by more than 10% of the control level, suggesting that MeHg may not alter induction of LTP. Reversibility of the effects of MeHg was examined by washing slices with MeHg-free ACSF or 1 mM D-penicillamine for 60-120 min after MeHg treatment. Washing slices with MeHg-free ACSF caused at best partial reversal of effects of MeHg. D-Penicillamine, a chelator of MeHg, completely reversed the effects of MeHg on EPSPs but only partially reversed the effects of MeHg on population spikes, antidromically activated population spikes, and LTP. This suggested that effects of MeHg on EPSPs differ somewhat from those on orthodromically and antidromically activated population spikes and LTP. In those slices refractory to reversal by washing with MeHg-free ACSF or D-penicillamine, increasing the stimulus intensity induced recovery of the population spikes, suggesting that neuronal membrane excitability was decreased by MeHg. Thus, acute bath application of MeHg causes biphasic and partially reversible effects on central neuronal membrane excitability and synaptic transmission in the CA1 region of hippocampal slices. The time course, concentration-dependence, and general pattern of these effects are all similar to those observed in peripheral motor nerve synapses and suggest that acutely MeHg affects both peripheral and central synaptic transmission in a similar manner.