Neuronal death/apoptosis induced by intracellular zinc deficiency associated with changes in amino-acid neurotransmitters and glutamate receptor subtypes

Abstract

In the present study, a model of zinc deficiency was developed by exposing primary neurons to an N,N,N′,N′-Tetrakis (2-pyridylmethyl) ethylenediamine (TPEN)-containing medium. The cell survival rate, apoptosis rate, intracellular and extracellular concentrations of 4 amino acids, and the expression of 2 glutamate receptor subtypes α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptor (GluR2)and N-methyl-d-aspartate receptor subtype 2B (NR2B) were evaluated in zinc-deficient cells. The results revealed that zinc deficiency led to a decrease in cell viability and an increase in the apoptosis rate. Additionally, in cultured neurons, zinc deficiency led to an increase in the concentration of aspartic acid (Asp) and a decrease in the concentrations of glutamate (Glu), glycine (Gly), and gamma-aminobutyric acid (GABA). These changes were reversed by concurrent zinc supplementation. Furthermore, zinc deficiency led to an increase in the secreted amounts of Glu, Gly, and Asp but a decrease in secreted amounts of GABA, as measured using the concentrations of these amino acids in the cell-culture medium. These changes were partially reversed by zinc supplementation. Finally, zinc deficiency led to a significant decrease in GluR2 expression and an increase in NR2B expression in cultured neurons, whereas simultaneous treatment with zinc sulfate (ZnSO4) prevented these changes. These results suggest that zinc deficiency-induced neuronal death/apoptosis involves changes in the concentrations of 4 amino acid neurotransmitters and the expression of 2 glutamate receptor subtypes.