Effects of neurotoxicants on synaptic transmission: lessons learned from electrophysiological studies

A number of environmentally-important neurotoxicants affect chemical synaptic transmission in the peripheral and central nervous system. These include heavy metals such as lead, mercury, cadmium and tin; organophosphates; pyrethroid insecticides, and 2,5-hexanedione. Electrophysiological techniques including intracellular microelectrode recording of nerve-evoked and spontaneously occurring synaptic potentials, iontophoresis of neurotransmitter, and voltage clamp of presynaptic and postsynaptic membrane ionic current have proven to be especially useful in analyzing the cellular mechanisms by which these toxicants affect neurotransmission. The process of synaptic transmission can be broadly subdivided into those processes associated with transmitter synthesis, storage and release and sometimes termination of transmitter action (presynaptic processes), and those processes associated with binding of transmitter to its receptors on the receiving cell, activation of the receptor-associated ionic channel and degradation of chemical transmitter (postsynaptic processes). The processes associated with release of neurotransmitter are the target of a number of naturally-occurring toxins and environmentally important toxicants. General mechanisms by which these agents disrupt presynaptic processes associated with transmission include: prevention or disruption of axonal excitability (pyrethroid insecticides); disruption of calcium-dependent neurotransmitter release (heavy metals, antibiotics, certain snake and spider venom toxins, botulinum toxin); and disruption of intracellular buffering of calcium (heavy metals), Mechanisms by which these agents may disrupt postsynaptic processes include effects on transmitter degradation (organophosphates) or effects on the postsynaptic membrane receptors or associated ionic channels (organophosphates, antibiotics, and perhaps pyrethroids). Microelectrode studies have shown that cadmium, lead and mercury (organic and inorganic forms) suppress release of neurotransmitter by presynaptic mechanisms and increase spontaneous discharge of transmitter quanta from the presynaptic nerve terminal. This has led to the suggestion that a component of synaptic toxicity of these agents entails block of Ca entry into and buffering by the presynaptic nerve terminals. Conventional and patch voltage clamp studies have been used to measure effects of neurotoxicants on ionic currents carried through voltage-sensitive and receptor-operated ionic channels.(ABSTRACT TRUNCATED AT 400 WORDS)