Metal Toxicity at the Synapse: Presynaptic, Postsynaptic, and Long-Term Effects

Abstract

Metal neurotoxicity is a global health concern. This paper summarizes the evidence for metal interactions with synaptic transmission and synaptic plasticity. Presynaptically metal ions modulate neurotransmitter release through their interaction with synaptic vesicles, ion channels, and the metabolism of neurotransmitters (NT). Many metals (e.g., 𝑃𝑏2+, 𝐶𝑑2+, and 𝐻𝑔+) also interact with intracellular signaling pathways. Postsynaptically, processes associated with the binding of NT to their receptors, activation of channels, and degradation of NT are altered by metals. 𝑍𝑛2+, 𝑃𝑏2+, 𝐶𝑢2+, 𝐶𝑑2+, 𝑁𝑖2+, 𝐶𝑜2+, 𝐿𝑖3+, 𝐻𝑔+, and methylmercury modulate NMDA, AMPA/kainate, and/or GABA receptors activity. 𝐴𝑙3+, 𝑃𝑏2+, 𝐶𝑑2+, and 𝐴𝑠2𝑂3 also impair synaptic plasticity by targeting molecules such as CaM, PKC, and NOS as well as the transcription machinery involved in the maintenance of synaptic plasticity. The multiple effects of metals might occur simultaneously and are based on the specific metal species, metal concentrations, and the types of neurons involved.