Miniature endplate potentials as a tool in neurotoxicology

The toxic effect of thallium added to the bath solution was studied with intra- and extracellular recordings from mammalian nerve-muscle preparations. To elucidate the target region, 3 different functional parameters were studied: (1) Post-synaptic endplate potentials (EPPs) resulting from evoked transmitter release; (2) Post-synaptic miniature endplate potentials (MEPPSs) resulting from spontaneous transmitter release; and (3) Presynaptic ion currents at the nerve terminal. At a concentration of 0.5 mM/l thallium acetate, EPP amplitudes were irreversibly decreased while MEPP amplitudes remained unaffected. MEPP frequencies were reversibly increased, indicating a presynaptic rather than a post-synaptic target site of thallium toxicity. The subpopulation of small MEPPs (sub-MEPPs) behaved like the MEPP population, except that upon addition of 4-AP, the sub-MEPP population was augmented at the cost of the MEPP population. In view of the slow time course of the toxic effects (30 min for a 10-fold increase of MEPP frequency, 100-180 min for a 50% reduction of EPP amplitudes), it is concluded that thallium needs to be transported across the cell membrane before it finally interferes with release mechanisms. It is hypothesised that thallium reduces the number of active sites recruited by one action potential (reduced EPP amplitude), while at the same time the probability of transmitter liberation is enhanced (increased MEPP frequency). The rather indirect mode of action of thallium was also found when presynaptic ion currents were recorded using extracellular electrodes. In proportion to the decrease of the EPP amplitudes, a reduction of all inward and outward currents was observed. This effect was also irreversible. It is concluded that in spite of some similarities, thallium behaves quite differently from bivalent heavy metals like cobalt and cadmium, which act as competitive calcium antagonists at the presynaptic nerve terminal. In these toxic substances, the time course of intoxication is much faster, the required concentration is much lower, and the inhibition of the slow calcium current is reversible.